Transcript Common Office Medical Problems

Common Office Medical
Problems
Christian Wagner, MD
Clinical Assistant Professor
Department of Family Medicine
University of Illinois College of Medicine
at Urbana-Champaign
June 2010
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Hyperlipidemia
Hypertension
Diabetes
Congestive Heart Failure
Hyperlipidemia
• Types:
• heterozygous form - associated with total cholesterol level > 300
mg/dL (7.7 mmol/L), high risk of coronary artery disease by 30-40,
50% reduction in LDL receptor activity
• homozygous form - associated with total cholesterol of 600-1000
mg/dL (15.5-26 mmol/L), rare, myocardial infarction by age 10 and
death by age 20 is common, total deficiency of LDL receptor activity
• familial hypercholesterolemia
• Fredrickson Type IIa hyperlipoproteinemia
• hyperbetalipoproteinemia
• group A hyperlipidemia
• LDL hyperlipoproteinemia
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Incidence/Prevalence:
hypercholesterolemia is eleventh most common diagnosis made during
family physician visits; analysis of patient visits to family physicians in
United States 1995-1998 in National Ambulatory Medical Care Survey;
hypercholesterolemia diagnosis coded in 2.8% of visits (Ann Fam Med 2004
Sep-Oct;2(5):411 full-text)
estimated risk for developing dyslipidemia by age 50 years
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> 80% for "borderline-high" LDL cholesterol (≥ 130 mg/dL [3.4 mmol/L])
50% for "high" LDL cholesterol (≥ 160 mg/dL [4.1 mmol/L])
25% women and 65% men for "low" HDL cholesterol (< 40 mg/dL [1 mmol/L])
Reference - based on 4,701 Framingham Offspring study participants (Am J Med
2007 Jul;120(7):623)
prevalence of elevated cholesterol in children and adolescents
– based on cohort of 9,868 children aged 6-17 years from National Health and
Nutrition Examination Survey 1999-2006
– prevalence of elevated total cholesterol (cut point 200 mg/dL or 5.2 mmol/L)
10.7%
– mean total cholesterol 163 mg/dL (4.2 mmol/L)
– prevalence of elevated LDL cholesterol in 2,724 adolescents aged 12-17 years
(cut point 130 mg/dL or 3.4 mmol/L) 6.6%
– mean LDL cholesterol in adolescents 90.2 mg/dL (2.3 mmol/L)
– estimated only 0.8% of adolescents exceed LDL threshold for considering for
pharmacological treatment by current AAP guideline
– Reference - Circulation 2009 Mar 3;119(8):1108
• Causes:
• autosomal dominant LDL receptor defect (heterozygous), inherited
as autosomal codominant trait, else polygenic hyperlipidemia
• Likely risk factors:
• diet
• hypothyroidism
• nephrotic syndrome
• obstructive liver disease
• hepatoma
• Cushing's syndrome
• anorexia nervosa
• Werner's syndrome
• acute intermittent porphyria
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Complications:
very high risk of CAD, premature atherosclerosis
elevated cholesterol clearly shown to be a risk factor for cardiovascular
mortality in men 40-64
elevated cholesterol in younger men (35-39) shown to be associated with
increased long-term risk for cardiovascular and total mortality; study of
64,205 men 35-39 followed 16 years plus 2 other studies of 12,283 men 1839 followed 25-34 years; increasing total cholesterol level associated with
strong graded independent risk for total mortality and cardiovascular
disease; total cholesterol > 240 mg/dL (6.2 mmol/L) compared with
cholesterol < 200 mg/dL (5.2 mmol/L) associated with significantly
increased risk for total mortality, corresponding to reduce life expectancy of
3.8-8.7 years (JAMA 2000 Jul 19;284(3):311), editorial can be found in
JAMA 2000 Jul 19;284(3):365
Associated conditions:
association with subclinical hypothyroidism controversial
– hypercholesterolemia associated with subclinical hypothyroidism, based on study
of 1,191 patients 40-60, 10.3% prevalence of subclinical hypothyroidism among
patients with total cholesterol > 309 mg/dL (8 mmol/L) (Clin Endocrinol (Oxf)
1999 Feb;50(2):217 in QuickScan Reviews in Fam Pract 1999 Sep;24(6):21)
– subclinical hypothyroidism not associated with abnormal lipid levels after
adjusting for confounding factors in US population-based study of 8,218 adults >
40 years old (Ann Fam Med 2004 Jul-Aug;2(4):351 full-text)
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smoking associated with elevated LDL cholesterol in study of 492 persons
aged 26-66 with hypercholesterolemia (Clin Exp Med 2002 Jul;2(2):83)
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Diagnosis Rule out:
hypothyroidism
nephrotic syndrome
diabetes
obstructive liver disease
hypercholesterolemia secondary to diet
anorexia nervosa
Testing to consider:
TSH, blood glucose, creatinine
fasting lipid profile
– LDL = total cholesterol - HDL - TG/5
– not valid if TG > 400
• cardiovascular risk by lipid panel appears similar in patients fasting
and non-fasting
– based on data from 302,430 people without initial vascular disease
– Reference - JAMA 2009 Nov 11;302(18):1993
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chemistry - cholesterol/triglyceride > 1.5 (high TG if IIb)
high cholesterol - 300-600 mg/dL (800-1000 homozygous)
electrophoresis - increased beta (increased pre-beta if IIb)
ultracentrifugation - high LDL, normal TG (high VLDL if IIb)
apolipoprotein B may help guide statin therapy in subgroup analysis
of Collaborative Atorvastatin Diabetes Study (CARDS) (Clin Chem
2009 Mar;55(3):473), editorial can be found in Clin Chem 2009
Mar;55(3):391)
• Prognosis:
• homozygous - myocardial infarction in teens,
heterozygous - MI in 40's
• about 40% persons with familial
hypercholesterolemia have normal lifespan,
based on study of large family pedigree (BMJ
2001 Apr 28;322(7293):1019 full-text)
• Treatment overview:
• diet low in cholesterol and total fat, increased polyunsaturated-tosaturated fat ratio
• statins are drug of choice
• target LDL cholesterol levels
– "high risk" if coronary heart disease, diabetes, peripheral arterial
disease, stroke, or 10-year cardiovascular risk > 20%
• LDL goal < 100 mg/dL (2.6 mmol/L)
• optional goal < 70 mg/dL (1.8 mmol/L) encouraged if very high risk
– "moderately high risk" if 2 or more major risk factors
• LDL goal < 130 mg/dL (3.4 mmol/L)
• optional goal < 100 mg/dL (2.6 mmol/L) if 10-year risk of cardiovascular
disease 10-20%
– "lower risk" if 0 or 1 major risk factor
• LDL goal < 160 mg/dL (4.1 mmol/L)
– Reference - 2004 update to NCEP/ATP III guidelines (Circulation 2004
Jul 13;110(2):227 full-text)
– see Cholesterol screening and management for cardiovascular disease
prevention for details
• Diet:
• diet low in cholesterol and total fat, increased polyunsaturated-tosaturated fat ratio
• adherence to diet may result in 10-15% reduction in cholesterol level
• insufficient evidence to evaluate cholesterol-lowering diet or
other dietary interventions for familial hypercholesterolemia
– based on Cochrane review
– systematic review of 11 short-term randomized and quasi-randomized
trials evaluating cholesterol-lowering diet in 331 children and adults with
familial hypercholesterolemia
– all trials of short duration and no primary outcomes evaluated ischemic
heart disease, number of deaths and age at death)
– no significant differences in most secondary outcomes
– Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD001918
• Activity:
• moderate intensity walking may reduce total
cholesterol/HDL ratio in men with
hypercholesterolemia (level 3 [lacking direct]
evidence)
– based on randomized trial without clinical outcomes
– 67 men (mean age 55.1 years) with
hypercholesterolemia randomized to brisk walking
(burning ≥ 300 kcal/walk) vs. control for 12 weeks
– walking group had significant reduction in total
cholesterol/HDL and weight and borderline reduction
in triglycerides
– Reference - Prev Med 2008 Jun;46(6):545
• use of medications depend on patient's risk factors for
atherosclerotic disease
• secondary prevention (treatment for patients with atherosclerotic
disease) typically targeted at LDL cholesterol level < 100 mg/dL (2.6
mmol/L)
• for help in determining need for medications in primary prevention of
atherosclerotic disease, see Revised Sheffield table for determining
risk of coronary artery disease
• evidence-based assessment finds that lipid-lowering therapy
generally indicated for patients with diabetes or diagnosis of
coronary artery disease (JAMA 1999 Dec 1;282(21):2051), summary
can be found in Am Fam Physician 2000 May 15;61(10):3133
• statins would be agents of first choice
• bile acid sequestrants - cholestyramine
(Questran), colestipol (Colestid), colesevelam
(Cholestagel)
• decreases LDL (and cholesterol) up to 25%
• second line drugs, large doses three times daily,
start at low dose
• side effects - constipation, fullness, discomfort,
increases TGs if type IIb, interferes with drug
absorption
• nicotinic acid
• side effects often occur > 1 year after initiating drug
therapy; follow-up of 110 individuals taking nicotinic acid
(133 drug exposures), 63 took regular nicotinic acid
(target dose 3,000 mg/day), 65 took SR nicotinic acid
(1500 mg/day); 42-43% of each group discontinued the
drug due to side effects, most commonly abnormal liver
function tests (11 reg, 9 SR), flushing (7 reg, 5 SR),
abdominal pain (6 reg, 7 SR), nausea/emesis (6 reg, 4
SR), rash (4 reg, 4 SR), hyperuricemia (6 reg, 1 SR),
and hyperglycemia (4 reg, 2 SR); other side effects
included fatigue, ankle swelling, headache, itching, and
arrhythmias; patients took nicotinic acid an average of
16.7 (reg) and 14.9 (SR) months prior to developing the
symptoms resulting in drug cessation (Am J Med 1995
Oct;99(4):378 in QuickScan Reviews in Fam Pract 1996
Mar;14)
• in children
• review of dietary therapy in children can be found in Am Fam
Physician 2000 Feb 1;61(3):675, editorial can be found in Am Fam
Physician 2000 Feb 1;61(3):633
• if cholesterol remains < 300 mg/dL (7.8 mmol/L), bile acid-binding
resins (cholestyramine, colestipol) are safe and efficacious
• little experience with other lipid-lowering drugs in children
• homozygous form very resistant to treatment - consider repeated
exchange transfusion, portocaval shunting, liver transplantation
• cholesterol-lowering treatments not associated with increased risk
for non-illness mortality; no significant associations between
cholesterol-lowering treatments (diet, drugs, partial ileal bypass) and
non-illness mortality (suicide, accident, trauma) in meta-analysis of
19 randomized controlled trials lasting at least 1 year; non-significant
trend observed in trials of dietary interventions and non-statin drugs,
no increase with statins (BMJ 2001 Jan 6;322(7277):11 full-text)
• Screening:
• see updated NCEP guidelines
• cardiac risk factors - male > 45, female >
55, FH premature CHD, smoking,
hypertension, HDL < 35; negative risk
factor if HDL > 60
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United States Preventive Services Task Force (USPSTF) screening
recommendations
USPSTF guidelines for screening for lipid disorders in adults
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strongly recommend routine screening in men ≥ 35 years old and women ≥ 45 years old
(USPSTF Grade A recommendation)
recommend screening men aged 20-35 years and women aged 20-45 years if at increased
risk for coronary heart disease (USPSTF Grade B recommendation)
no recommendation for or against routine screening in men aged 20-35 or women ≥ 20 years
old who are not at increased risk for coronary heart disease (USPSTF Grade C
recommendation)
Reference - USPSTF 2008 Jun or at National Guideline Clearinghouse 2008 Jul 28:12634,
previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73
USPSTF concludes there is insufficient evidence to recommend for or against routine
screening for lipid disorders in children (USPSTF Grade I recommendation)
(Pediatrics 2007 Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct
15:10865), supporting systematic review can be found in Pediatrics 2007
Jul;120(1):e189
United States Preventive Services Task Force (USPSTF) grades of recommendation
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grade A - USPSTF recommends the service with high certainty of substantial net benefit
grade B - USPSTF recommends the service with high certainty of moderate net benefit or
moderate certainty of moderate to substantial net benefit
grade C - USPSTF recommends against routinely providing the service with at least
moderate certainty that net benefit is small, but in individual patients considerations may
support providing the service
grade D - USPSTF recommends against providing the service with moderate to high
certainty of no net benefit or harms outweighing benefits
grade I - insufficient evidence to assess balance of benefits and harms
see USPSTF Grade Definitions for more detail
• Reviews:
• review can be found in BMJ 2008 Aug 21;337:a993, commentary
can be found in BMJ 2008 Sep 3;337:a1493, BMJ 2008 Sep
16;337:a1681
• review of treatment of cholesterol abnormalities can be found in Am
Fam Physician 2005 Mar 15;71(6):1137, commentary can be found
in Am Fam Physician 2006 Mar 15;73(6):973
• Applied Evidence review of treatment of hyperlipidemia can be
found in J Fam Pract 2002 Apr;51(4):370
• review of dyslipidemia can be found in Am Fam Physician 1998 May
1;57(9):2192
• review of drug treatment of lipid disorders can be found in N Engl J
Med 1999 Aug 12;341(7):498 (author may have conflict of interest [N
Engl J Med 2000 Feb 24;342(8):586]), commentary can be found in
N Engl J Med 1999 Dec 23;341(26):2020
• review of lifestyle, diet, dietary supplements and botanicals in
management of hyperlipidemia can be found in Altern Ther Health
Med 2003 May-Jun;9(3):28
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Guidelines:
synthesis of 3 guidelines (UMHS 2009, USPSTF 2008, VA/DoD 2006) on screening for lipid
disorders in adults can be found at National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7
United States Preventive Services Task Force (USPSTF) guidelines for screening for lipid
disorders in adults can be found in USPSTF 2008 Jun or at National Guideline Clearinghouse
2008 Jul 28:12634, previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73
USPSTF guidelines for screening for lipid disorders in children can be found in Pediatrics 2007
Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct 15:10865, supporting systematic
review can be found in Pediatrics 2007 Jul;120(1):e189
American Academy of Pediatrics (AAP) clinical report on lipid screening and cardiovascular health
in childhood (grade C recommendation [lacking direct evidence])
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recommendations include
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limitations of recommendations
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increased physical activity and dietary changes for children at risk of overweight or obesity
screening between age 2-10 years in children with family history of dyslipidemia or premature cardiovascular disease or
dyslipidemia (or if unknown family history or those with other cardiovascular disease risk factors)
consider pharmacologic intervention in patients ≥ 8 years old with LDL level ≥ 190 mg/dL (4.9 mmol/L) (≥ 160 mg/dL [4.1
mmol/L] with family history of early heart disease or 2 other risk factors present or ≥ 130 mg/dL [3.4 mmol/L] if diabetes
mellitus)
no data to predict risk of cardiovascular disease as an adult based on cholesterol levels in children
insufficient data to support specific evidence-based recommendation for cholesterol screening in children
insufficient data to support specific evidence-based recommendation for specific age to implement pharmacologic treatment
Reference - Pediatrics 2008 Jul;122(1):198 or at National Guideline Clearinghouse 2009 May 18:13438,
commentary can be found in BMJ 2008 Jul 23;337:a886
previous American Academy of Pediatrics statement on cholesterol levels in children can be found in
Pediatrics 1998 Jan (Am Fam Physician 1998 May 1;57(9):2266 full-text)
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commentary stating that childhood cholesterol screening is not justified can be found in Pediatrics 2000 Mar;105(3):637 and
in Pediatrics 2001 May;107(5):1229
parent history screening criteria not much better than random population screening in cohort of 2,475 Quebec youths ages
9-16 years; parent history had 41% sensitivity, 75% specificity, 8% positive predictive value and 96% negative predictive
value for identifying high LDL cholesterol (Pediatrics 2004 Jun;113(6):1723), commentary can be found in Pediatrics 2005
Jan;115(1):195, summary can be found in Am Fam Physician 2005 Mar 15;71(6):1203
Hypertension
Hypertension
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stage 1 hypertension if SBP 140-159 mm Hg or DBP 90-99 mm Hg
stage 2 hypertension if SBP > 160 mm Hg or DBP > 100 mm Hg
stages of hypertension in children and adolescents
stage 1 hypertension if blood pressure 95th percentile to 99th
percentile plus 5 mm Hg, based on charts for gender, age and
height
• stage 2 hypertension if blood pressure > 99th percentile plus 5 mm
Hg, based on charts for gender, age and height
• Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555 fulltext, commentary can be found in Pediatrics 2005 Mar;115(3):826
Types of Hypertension
• types of hypertension based on renin-angiotensin system
• type 1 hypertension is vasoconstrictor, high renin
– renin secretion inappropriately high for blood pressure, exaggerated
renal elimination of sodium
– common in young white people
– responds better to ACE inhibitors, angiotensin receptor blockers and
beta blockers
• type 2 hypertensin is sodium dependent, low renin
– renin secretion suppressed by kidney's detection of excessive sodium
reabsorption
– common in young black people
– responds better to diuretics and calcium channel blockers
• Reference - BMJ 2006 Apr 8;332(7545):833, commentary can be
found in BMJ 2006 Apr 22;332(7547):974
Causes
• unknown
• 90%-95% hypertension is essential hypertension
Pathogenesis
• volume expansion, vasoconstriction - increased total peripheral
resistance
• resistant hypertension associated with elevated aldosterone
and natriuretic peptide levels
• based on case-control study
• 279 consecutive patients with resistant hypertension (nonresponsive
to 3 antihypertensive drugs) were compared to 53 controls with
normal pressure or controlled hypertension
• resistant hypertension associated with higher levels of aldosterone,
brain-type natriurietic peptide and atrial natriuretic peptide
• Reference - Arch Intern Med 2008 Jun 9;168(11):1159
• bosentan, endothelin receptor antagonist, shown to reduce blood
pressure in 4-week randomized trial with effect similar to enalapril;
adverse effects included headache, flushing, leg edema and
elevated transaminases (N Engl J Med 1998 Mar 19;338(12):784),
commentary can be found in N Engl J Med 1998 Jul 30;339(5):346
• review of pathogenesis of hypertension can be found in BMJ 2001
Apr 14;322(7291):912
• review of pathogenesis of hypertension can be found in Ann Intern
Med 2003 Nov 4;139(9):761
• review of role of aldosterone in pathogenesis of
metabolic syndrome and resistant hypertension can be
found in Ann Intern Med 2009 Jun 2;150(11):776
• review of role of endothelin in pathogenesis of
hypertension can be found in Mayo Clin Proc 2005
Jan;80(1):84
• review of sodium and potassium in pathogenesis of
hypertension can be found in N Engl J Med 2007 May
10;356(19):1966, commentary can be found in N Engl J
Med 2007 Aug 23;357(8):827
• patients with normal and high-normal blood
pressure at significant risk for developing
hypertension over 4 years
• based on 9,845 men and women with blood pressure <
140/90 mm Hg in Framingham Heart Study
• 4-year risk for hypertension in persons < 65 years old
– 5.3% for those with optimum blood pressure (< 120/80 mm Hg)
– 17.6% with normal blood pressure (120-129/80-84 mm Hg)
– 37.3% with high-normal blood pressure (130-139/85-89 mm Hg)
• 4-year risk for hypertension in persons > 65 years old
– 16% for those with optimum blood pressure
– 25.5% with normal blood pressure
– 49.5% with high-normal blood pressure
• Reference - Lancet 2001 Nov 17;358(9294):1682,
editorial can be found in Lancet 2001 Nov
17;358(9294):1659
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light-to-moderate alcohol use associated with increased risk of hypertension in
men but not women
based on 2 prospective cohort studies
28,848 women from Women's Health Study followed for 10.9 years and 13,455 from
Physicians' Health Study followed for 21.8 years
all were without hypertension at baseline
8,680 women and 6,012 men developed hypertension
adjusted relative risks for developing hypertension in women (compared to rare/never
drinkers)
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adjusted relative risks for developing hypertension in men (compared to rare/never
drinkers) (p < 0.0001)
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0.98 (95% CI 0.91-1.05) for 1-3 drinks monthly
0.96 (95% CI 0.87-1.06) for 1 drink daily
1.1 (95% CI 0.97-1.25) for 2-3 drinks daily
1.84 (95% CI 1.36-2.48) for ≥ 4 drinks daily
1.11 (95% CI 1-1.23) for 1-3 drinks monthly
1.26 (95% CI 1.15-1.37) for 1 drink daily
1.29 (95% CI 1.08-1.53) for ≥ 4 drinks daily
in women, relative risks similar with specific alcohol types compare to total alcohol
intake
relative risks remained similar after adjusting for baseline blood pressure in women
and men
Reference - Hypertension 2008 Apr;51(4):1080
alcohol intake > 2 drinks/day associated with increased blood pressure in men but not
women in cross-sectional study of 5,448 adults > 20 years old (J Hypertens 2007
May;25(5):965)
• dyslipidemia modestly associated with subsequent
hypertension in prospective study of 16,130 women > 45 years old
followed for 10.8 years (Arch Intern Med 2005 Nov 14;165(20):2420)
• time urgency/impatience and hostility significantly associated with
developing hypertension in 15-year prospective follow-up of 3,308
black and white United States adults aged 18-30 years at baseline;
no consistent associations with depression, anxiety, or achievement
striving/competitiveness (JAMA 2003 Oct 22-29;290(16):2138),
editorial can be found in JAMA 2003 Oct 22-29;290(16):2190,
commentary can be found in JAMA 2004 Feb 11;291(6):692
• smaller retinal arteriolar diameters associated with development of
hypertension
• in cohort of 2,451 normotensive persons aged 43-84 years followed
for 10 years (BMJ 2004 Jul 10;329(7457):79), correction can be
found in BMJ 2004 Aug 14;329(7462):384, commentary can be
found in BMJ 2004 Aug 28;329(7464):514 and reply
Factors increasing risk of
Hypertension
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higher salt intake may be associated with increased risk for
hypertension
urinary sodium levels strongly associated with systolic blood
pressure in 10,074 men and women ages 20-59 years in 32 countries (BMJ
1996 May 18;312(7041):1249 full-text), editorial can be found in BMJ 1996
May 18;312(7041):1241, commentary can be found in BMJ 1996 Jun
29;312(7047):1659 and BMJ 1997 Aug 23;315(7106):484
some evidence supports international consensus of lower risk of
hypertension when salt intake is lower; 24-hour urinary sodium excretion
associated with systolic blood pressure, diastolic blood pressure and
hypertension over range of sodium excretion rates from 70-400 mmol/day
(Arch Intern Med 1997 Jan 27;157(2):234)
• red meat intake may be associated with risk of
hypertension in women ≥ 45 years old
• based on prospective cohort study
• 28,766 women ≥ 45 years old followed for 10 years
• frequency of red meat intake assessed by food surveys
and diagnosis of hypertension identified in annual followup questionnaires
• incidence of hypertension in women who consumed (p =
0.008 for trend)
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no red meat 21.7%
< 0.5 servings daily 29.2% (relative risk [RR] 1.24)
0.5-1 servings daily 29.8% (RR 1.25)
1-1.5 servings daily 33.1% (RR 1.32)
≥ 1.5 servings daily 35.6% (RR 1.35)
• Reference - J Hypertens 2008 Feb;26(2):215
• association of caffeine intake with hypertension may
depend on beverage type
• coffee intake over years associated with small increase
in blood pressure
– 1,017 white male former medical students (mean age 26)
followed for median 33 years
– consumption of 1 cup of coffee a day raised adjusted systolic
blood pressure by 0.19 mm Hg (95% CI 0.02-0.35) and diastolic
pressure by 0.27 mm Hg (95% CI 0.15-0.39)
– coffee drinkers had increased risk for hypertension compared
with nondrinkers at baseline (28.3% vs. 18.8%, p = 0.03),
drinking 5 or more cups/day associated with 1.35-1.6x relative
risk for hypertension; none of these associations were
statistically significant after adjusting for other variables
– Reference - Arch Intern Med 2002 Mar 25;162(6):657,
commentary can be found in Arch Intern Med 2003 Feb
10;163(3):370
• oral contraceptives may increase risk of
hypertension
• based on prospective cohort study of 68,297 healthy
female nurses aged 25-42 years followed for 4 years
• 1,567 developed hypertension
• 1.5 times relative risk of hypertension with current use of
oral contraceptives, increased to 1.8 times when
adjusted for other factors
• no increased risk from past use of oral contraceptives
• absolute risk of hypertension due to oral contraceptives
was only 41.5 cases/10,000 person-years
• Reference - Circulation 1996 Aug 1;94(3):483
• some prospective cohorts find increased risk of
hypertension with frequent analgesic use
• higher daily doses of acetaminophen and NSAIDs
associated with hypertension in 2 prospective cohort
studies of women ages 51-77 years and women ages
34-53 years (Hypertension 2005 Sep;46(3):500)
• frequent analgesic use, based on Nurses Health Study
with 80,020 women ages 31-50 years followed for 2
years (Arch Intern Med 2002 Oct 28;162(19):2204),
commentary can be found in Arch Intern Med 2003 May
12;163(9):1113
• aspirin, acetaminophen and ibuprofen use each
associated with increased risk of incident hypertension in
Nurses' Health Study (Hypertension 2002 Nov;40(5):604
in CMAJ 2003 May 27;168(11):1445)
• Short sleep duration:
• sleep duration < 5 hours/night associated with 2.1 times risk of
hypertension in cohort of 4,810 United States persons aged 32-59
years followed for 8-10 years of whom 647 were diagnosed with
hypertension (Hypertension 2006 May;47(5):833)
• sleep duration ≤ 5 hours/night associated with about 2 times
risk of hypertension for women (but not in men) in crosssectional analysis of 5,766 British persons aged 35-55 years, but
results not statistically significant in longitudinal analysis (3,691
participants normotensive at baseline and followed mean 5 years)
after adjusting for cardiovascular risk factors and psychiatric
comorbidities (Hypertension 2007 Oct;50(4):693)
• shorter sleep duration associated with increasing risk of
hypertension
– based on prospective cohort of 535 participants aged 33-45 years who
had objective sleep duration and maintenance measurements and
followed for 5 years
– incident hypertension in 14% over 5-year follow-up
– 37% increase in odds of incident hypertension associated with each
hour of reduction in sleep duration
– Reference - Arch Intern Med 2009 Jun 8;169(11):1055
• elevated C-reactive protein levels associated with
increased risk of developing hypertension
• based on 2 cohort studies
• elevated C-reactive protein levels associated with
increased risk of developing hypertension in dosedependent fashion in prospective cohort study of 20,525
United States nurses > 45 years old followed median 7.8
years (JAMA 2003 Dec 10;290(22):2945), editorial can
be found in JAMA 2003 Dec 10;290(22):3000,
commentary can be found in Am Fam Physician 2004
Jun 15;69(12):2924
• elevated C-reactive protein levels associated with
incident hypertension in 7-year follow-up of 3,919 young
adults ages 25-37 years, but no significant association
after adjusting for body mass index (Arch Intern Med
2006 Feb 13;166(3):345), commentary can be found in
Arch Intern Med 2006 Jul 24;166(14):1526
• various single nucleotide polymorphisms in CYP19A1 gene
associated with essential hypertension
• based on case-control study with 218 patients with essential
hypertension and 225 matched controls
• Reference - Int J Med Sci 2008 Feb 7;5(1):29 full-text
• low ghrelin levels associated with type 2 diabetes and
hypertension
• based on case-control study with 1,045 subjects
• Reference - Diabetes 2003 Oct;52(10):2546
• high levels of trait anger associated with increased risk for
hypertension in men but not in women
• based on cohort of 2,334 men and women aged 45-64 years with
prehypertension but without heart disease or stroke at baseline and
followed for 4-8 years
• risk of progression to hypertension
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59.9% with low trait anger
55.6% with medium trait anger
66.7% with high trait anger
association significant in men but not in women
Factors not associated with
increased risk:
• modifiable low-risk factors associated with decreased risk in
healthy women
• based on prospective cohort study
• 83,882 women aged 27-44 years in second Nurses Health Study
without hypertension, cardiovascular disease, diabetes, or cancer,
and with normal reported blood pressure were followed for 14 years
• incident hypertension in 14.7%
• modifiable low-risk factors independently associated with risk of
hypertension
– body mass index (BMI) < 25 kg/m2
– daily vigorous exercise (mean 30 minutes)
– high score on Dietary Approaches to Stop Hypertension (DASH) diet
based on responses to food frequency questionnaire
– modest alcohol intake (≤ 10 g/day)
– use of nonnarcotic analgesics < 1/week
– intake of supplemental folic acid ≥ 400 mcg/day
• high job stress not associated with developing
hypertension in 5-year follow-up of 292 healthy adults
(mean age 38 years) (Hypertension 2003
Dec;42(6):1112)
• job strain associated with modest increases in systolic
blood pressure in prospective study of 8,395 white-collar
workers followed 7.5 years (Am J Public Health 2006
Aug;96(8):1436)
• vitamin D intake not associated with risk of hypertension
in 3 cohorts with 209,313 nurses and physicians followed
for at least 8 years (Hypertension 2005 Oct;46(4):676)
• high levels of anxiety and depression appear
associated with lower systolic blood pressure 11
years later
• based on cohort study in Norway
• 36,530 persons aged 20-78 years followed for 11 years
• Reference - Br J Psychiatry 2008 Aug;193(2):108
• birth weight does not appear to significantly affect
adult blood pressure
– systematic review found that birth weight has little effect on blood
pressure later in life
• 55 studies that reported regression coefficients found weaker
associations with larger studies
• studies with > 3,000 participants found inverse association of birth
weight and blood pressure of only 0.6 mm Hg/kg
• only 25 of 48 studies that did not report regression coefficients
found inverse association
• Reference - Lancet 2002 Aug 31;360(9334):659, commentary can
be found in Lancet 2002 Dec 21-28;360(9350):2072
– low birth weight has been suggested as risk factor for
hypertension, but likely a confounding factor as maternal
hypertension associated with low birth weight and parental
hypertension increases risk of hypertension (BMJ 1998 Mar
14;316(7134):834), commentary can be found in BMJ 1998 Sep
5;317(7159):680 and in BMJ 1999 Apr 3;318(7188):943
Complications of Hypertension
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Hypertension is a risk factor for:
Coronary artery disease (CAD)
Heart failure
Chronic kidney disease
Stroke
Intracerebral hemorrhage
Transient ischemic attack (TIA)
Peripheral arterial disease (PAD)
Aortic regurgitation
Atrial flutter
Mortality associated with
Hypertension
•
•
•
•
•
•
•
•
usual blood pressure directly related to vascular mortality at all
pressures above 115/75 mm Hg and at all ages above 40 years
based on meta-analysis of individual patient data from 1 million adults in 61
prospective studies
Reference - Lancet 2002 Dec 14;360(9349):1903, correction can be found
in Lancet 2003 Mar 22;361(9362), commentary can be found in Lancet
2003 Apr 19;361(9366):1389, Evidence-Based Medicine 2003 JulAug;8(4):122
increased blood pressure associated with increased all-cause and
cardiovascular mortality
based on prospective cohort study in China
169,871 Chinese adults ≥ 40 years old examined in 1991 and followed up
1999-2000
hypertension and prehypertension associated with increased all-cause and
cardiovascular mortality (p < 0.0001)
estimated deaths attributable to increased blood pressure in China in 2005
– 2.33 million cardiovascular deaths
– 1.27 million premature (< 72 years old in men and < 75 years in women)
cardiovascular deaths
– 1.86 million blood pressure-related deaths attributed to cerebrovascular diseases
•
Reference - Lancet 2009 Nov 21;374(9703):1765, editorial can be found in
Lancet 2009 Nov 21;374(9703):1728
• elevated blood pressure associated with increased long-term
mortality in young men
– study of 10,874 men aged 18-39 years followed for 25 years
– blood pressure above normal associated with increased long-term
mortality due to coronary heart disease, cerebrovascular disease, and
all causes
– Reference - Arch Intern Med 2001 Jun 25;161(12):1501, commentary
can be found in Arch Intern Med 2002 Mar 11;162(5):610
• systolic (but not diastolic) blood pressure is a strong, positive,
continuous and independent indicator of mortality risk in the
elderly; 10-year follow-up of 3,858 outpatients > 65, 74 patients
(1.9%) were lost to follow-up and 1,561 (41.3%) died, 709 (45.4% all
deaths) died from cardiovascular causes; positive continuous,
graded, strong and independent association observed with both total
(P < 0.001) and cardiovascular (P < 0.001) mortality for systolic
blood pressure (SBP) but not for diastolic blood pressure (DBP), no
J-shaped mortality curve in subjects with lowest SBP and DBP (Arch
Intern Med 1999 Jun 14;159(11):1205)
• Stroke:
Stroke
• hypertension and type 2 diabetes increase risk of stroke
independently based on 19-year prospective follow-up of 49,582
Finnish persons ages 25-74 years (Stroke 2005 Dec;36(12):2538)
• stroke risk correlates with diastolic blood pressure (Lancet 1995 Dec
23-30;346(8991-8992):1647 in J Watch 1996 Jan 15;16(2);14)
• midlife blood pressure associated with late-life stroke risk (Arch
Intern Med 2001 Oct 22;161(19):2343), summary can be found in
Am Fam Physician 2002 Mar 1;65(5):963
• blood pressure important determinant of stroke risk in eastern Asian
populations, whereas cholesterol concentration less important;
association between blood pressure and stroke seems stronger than
in western populations; population-wide reduction of 3 mm Hg in
diastolic blood pressure should eventually decrease number of
strokes by about 1/3 (Lancet 1998 Dec 5;352(9143):1801)
• Cognitive decline:
• midlife hypertension associated with late-life cognitive dysfunction
(JAMA 1995 Dec 20;274:1846 in J Watch 1996 Jan 15;16(2):14)
• hypertension associated with cognitive decline in 20-year follow-up
of 529 persons aged 18-83 years (Hypertension 2004 Nov;44(5):631
in BMJ 2004 Nov 20;329(7476):1246)
• End-stage regnal disease:
• elevated blood pressure is a strong risk factor for the development
of end-stage renal disease (N Engl J Med 1996 Jan 4;334(1):13 in
QuickScan Reviews in Fam Pract 1996 Aug;21(5):9, Arch Intern
Med 2005 Apr 25;165(8):923)
• Perinatal mortality:
• maternal chronic hypertension associated
with increased perinatal mortality in male
infants
– based on prospective cohort study of 866,188 women
with singleton pregnancies
– 4,749 (0.55%) were diagnosed with chronic
hypertension
– chronic hypertension in mothers associated with
•
•
•
•
intrauterine death odds ratio 3.07 for males
neonatal death odds ratio 2.99 for males
intrauterine death odds ratio 0.98 for females (not significant)
neonatal death odds ratio 1.88 for females (not significant)
– Reference - BJOG 2008 Oct;115(11):1436
•
•
Associated Conditions
obstructive sleep apnea
sleep disordered breathing and sleep apnea syndrome associated with hypertension
–
–
–
–
•
strong association between hypertension and obstructive sleep apnea
–
–
•
–
based on prospective study of 709 persons who had polysomnography and were followed 4 years
dose-response relationship found even after adjustment for known confounding factors
Reference - N Engl J Med 2000 May 11;342(19):1378, commentary can be found in N Engl J Med 2000 Sep
28;343(13):966
drug-resistant hypertension may be associated with high rate of sleep apnea
–
–
–
•
based on study of 1,741 persons ages 20-100 years selected as those with higher risk for sleep-disordered
breathing from interviews of 16,583 persons
Reference - Arch Intern Med 2000 Aug 14/28;160(15):2289, commentary can be found in Arch Intern Med
2001 Nov 26;161(21):2634
sleep-disordered breathing associated with increased risk for hypertension
–
–
–
•
based on cohort of 2,677 adults ages 20-85 years referred to sleep clinic for suspected sleep apnea
Reference - BMJ 2000 Feb 19;320(7233):479 full-text, commentary can be found in BMJ 2000 Jul
22;321(7255):237 full-text
sleep-disordered breathing associated with hypertension
–
•
based on cross-sectional study of 6,132 middle aged or older individuals
association weak after adjustment for obesity
Reference - JAMA 2000 Apr 12;283(14):1829, correction can be found in JAMA 2002 Oct
23/30;288(16):1985
editorial states that hypertension alone does not warrant testing for sleep apnea (JAMA 2000 Apr
12;283(14):1880
based on case series of 41 patients on 3 or more antihypertensive medications
83% found to have AHI > 10/hour on overnight polysomnography
Reference - J Hypertens 2001 Dec;19(12):2271
see Cardiovascular disease and obstructive sleep apnea for details
• higher blood pressure associated with higher rate of bone loss
in 3,676 elderly white women followed mean 3.5 years, even among
women not taking antihypertensive agents (Lancet 1999 Sep
18;354(9183):971)
• increased prevalence of panic attacks and panic disorder
among hypertensive patients; 351 hypertensive patients
compared with normotensive controls, 17-19% vs. 11% had panic
attacks within 6 months, 33-39% vs. 22% had history of panic
attacks, 13% vs. 8% had panic disorder (Am J Med 1999
Oct;107(4):310 in JAMA 2000 Jan 5;283(1):29)
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•
hypertension is a risk factor for type 2 diabetes
prospective study of 12,550 persons 45-64 in Atherosclerosis Risk in Communities
(ARIC) study who did not have diabetes at baseline and were evaluated at 3 years
and 6 years
diabetes defined at all time points as fasting glucose > 125 mg/dL (7 mmol/L),
nonfasting glucose > 200 mg/dL (11 mmol/L), use of insulin or oral hypoglycemic
agent, or physician's diagnosis of diabetes
overall incidence of diabetes was 16.6 cases per 1,000 person-years
hypertension increased risk by relative risk of 2.43 (95% CI 2.16-2.73)
–
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•
among 3,804 subjects with hypertension
–
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•
incidence of diabetes was 12 per 1,000 person-years in 8,746 subjects with normal blood
pressure
incidence of diabetes was 29.1 per 1,000 person-years in 3,804 subjects with hypertension
subgroup analysis performed to examine risk differences between different classes of
antihypertensives and no treatment
classification of use of medications based on asking patient whether the medication had
been prescribed to treat high blood pressure
thiazide diuretics, ACE inhibitors and calcium channel blockers were not shown to increase
risk of diabetes {significance of this finding is that "risk" of diabetes is not a valid reason to
withhold thiazide diuretics}
no significant differences upon comparing drug classes
beta blockers associated with statistically significant increased risk for diabetes compared to
no treatment for hypertension with relative risk of 1.28 (95% CI 1.04-1.57, number needed to
harm [NNH] with use of beta blockers if this association is true is 122 patients per year)
Reference - N Engl J Med 2000 Mar 30;342(13):905, editorial can be found in N Engl
J Med 2000 Mar 30;342(13):969,
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hypothyroidism; thyroid replacement in 30 patients with hypothyroidism
and hypertension led to reduction in aortic stenosis in all and normalization
of blood pressure in 15 (Am Heart J 2002 Apr;143(4):718 in Am Fam
Physician 2002 Sep 1;66(5):851)
heart failure found in 2-3% patients with hypertension; study of 388
patients with hypertension, 1.8% had left ventricular systolic ejection fraction
< 40%, 2.8% had heart failure defined as dyspnea plus objective evidence
of cardiac dysfunction (systolic dysfunction, atrial fibrillation or clinically
significant valve disease) (BMJ 2002 Nov 16;325(7373):1156full-text)
erectile dysfunction common in men with hypertension; questionnaires
sent to 467 men aged 18-75 years with hypertension, 104 (22%) returned
questionnaires (mean age 62); 85% were sexually active, of whom 68%
reported some degree of erectile dysfunction, 45% reported severe erectile
dysfunction (J Urol 2000 Oct;164(4):1188)
systemic hypertension more common in glaucoma patients (odds ratio
1.29) based on case-control study with 27,080 glaucoma patients (Br J
Ophthalmol 2005 Aug;89(8):960)
hypermetropia (farsightedness) associated with hypertension in study of
321 patients with essential hypertension and 188 matched controls (Am J
Ophthalmol 2005 Sep;140(3):446)
review of retinal vascular disease associated with hypertension can be
found in Postgrad Med 2005 Jun;117(6):33, commentary can be found in
Postgrad Med 2005 Sep;118(3):1
• Family History (FH):
• 75% FH hypertension and cardiovascular disease
• parental hypertension associated with blood pressure change
and hypertension
– based on cohort study
– 1,160 male persons followed for 54 years (29,867 blood pressure
measurements)
– 264 (23%) reported a parent with hypertension and 583 new cases of
parental hypertension occurred during follow-up
– mean systolic and diastolic blood pressure significantly higher at
baseline with parental hypertension
– rate of annual blood pressure increase slightly higher (0.03 mm Hg) with
parental hypertension for systolic blood pressure (p = 0.04), but not
diastolic blood pressure
– risk of hypertension development in men (after adjustment for body
mass index, alcohol consumption, coffee drinking, physical activity, and
cigarette smoking) compared to men with parents without hypertension
• hazard ratio 1.5 (95% CI 1.2-2) with maternal hypertension only
• hazard ratio 1.8 (95% CI 1.4-2.4) with paternal hypertension only
• hazard ratio 2.4 (95% CI 1.8-3.2) with hypertension in both parents
– early-onset hypertension (age 55 years) in both parents associated with
• 6.2-fold higher adjusted risk (95% CI 3.6-10.7) for hypertension at any point
in adult life
• 20-fold higher adjusted risk (95% CI 8.4-47.9) at age 35 years
– Reference - Johns Hopkins Precursors Study (Arch Intern Med 2008
Mar 24;168(6):643)
Physical Findings
• General Physical:
• see Blood pressure measurement
• check pulse - decreased if increased ICP, increased if
hyperthyroidism (also a fib)
• BP 2 times at visit, both arms, lying and standing (orthostatic
hypotension with diabetic autonomic neuropathy, pheo, drugs)
• suggestion to use standing BP for management decisions in elderly,
to avoid risk of orthostatic hypotension (letter in Am Fam Physician
1996 May 15;53(7):2282)
• If BP difference between arms, use arm with consistently higher BP
readings for monitoring (letter in JAMA 1995 Nov 1;274(17):1345)
• height and weight important for determining hypertension in children
• HEENT:
• retinopathy
– Stage I and II arterial narrowing, AV compression, silver/copper wiring
(dilated vein over narrowed artery)
– Stage III soft exudates (cotton-wool spots, micro-infarctions), flame
hemorrhage
– Stage IV papilledema
– picture of hypertensive retinopathy can be found in Lancet 2004 Feb
7;363(9407):456
– review of hypertensive retinopathy can be found in N Engl J Med 2004
Nov 25;351(22):2310
– review of hypertensive retinopathy can be found in Lancet 2007 Feb
3;369(9559):425, correction can be found in Lancet 2007 Jun
23;369(9579):2078
– routine funduscopy not supported by current evidence; systematic
review of studies assessing hypertensive retinopathy in adults; large
variation between observers in assessment of microvascular retinal
changes; hypertensive retinopathy did not predict hypertension well with
3% to 21% sensitivity, 88% to 98% specificity, positive predictive values
from 47% to 72% and negative predictive values from 32% to 67%;
inconsistent associations between retinal microvascular changes and
cardiovascular risk except for retinopathy and stroke (increased risk of
stroke also present in normotensive people with retinopathy) (BMJ 2005
Jul 9;331(7508):73 full-text)
• check visual fields (tumor)
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Neck:
JVD, carotid bruits
Cardiac:
PMI, S3 (from high LA pressure, suggests CHF, volume overload,
need for treatment), S4 (usually stiff ventricle, diastolic heart failure),
RV heave and murmur in back with coarctation of aorta, murmurs
(TR and MR from dilation, rub in hyperthyroidism, murmurs with
increased pulse and anemia)
Abdomen:
AAA (palpate), abdominal bruits (press until scope pulsates),
hepatomegaly (pulsatile if tricuspid regurgitation), renal mass, striae
Extremities:
edema, decreased extremity pulses, listen for femoral bruits
decreased, absent and/or delayed femoral pulses in coarctation of
the aorta
Neuro:
look neurologic deficit as sign of stroke
Diagnosis of Hypertension
• in pediatric patients
• hypertension defined as average systolic and/or diastolic blood
pressure ≥ 95th percentile for gender, age, and height on 3 or more
occasions
– see blood pressure charts for boys and girls
– Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555 full-text,
commentary can be found in Pediatrics 2005 Mar;115(3):826
• new normative BP data in children and adolescents can be found in
NHLBI Update on 1987 Task Force Report (Pediatrics 1996;98:649
in Am Fam Physician 1997 May 1;55(6):2340)
• study suggests that recommendations on BP cuff selection in
children need to be reviewed, further study may be necessary to
establish accuracy of published nomogram on normal BP in children
(Pediatrics 1999 Sep;104(3):e30 full-text)
• JNC 7 report recommends blood pressure cutoff when using
ambulatory monitoring should be 135/85 while awake and 120/75
while asleep
• until relationship between self-recorded pressure and incidence of
cardiovascular morbidity and mortality is further clarified by
prospective studies, mean self-recorded blood pressure > 135 mm
Hg systolic or 85 mm Hg diastolic may be considered hypertensive;
based on meta-analysis of summary data from 17 studies comparing
self-recorded and standard blood pressures, 9 of which only
included normotensive subjects (Arch Intern Med 1998 Mar
9;158(5):481), commentary can be found in Arch Intern Med 1999
May 10;159(9):1007 and in Arch Intern Med 1999 Oct
25;159(19):2365
• evidence-based review of diagnosis of essential and secondary
hypertension can be found in Applied Evidence in J Fam Pract 2001
Aug;50(8):707
• review of diagnosing secondary hypertension can be found in Am
Fam Physician 2003 Jan 1;67(1):67, commentary noting excess
licorice as possible cause can be found in Am Fam Physician 2003
Jul 1;68(1):42
Recommended Testing
• diagnostic workup of hypertension recommended by
JNC 7
• electrocardiogram (ECG)
• urinalysis
• blood glucose
• serum potassium, creatinine, and calcium
• hematocrit
• lipid profile - HDL cholesterol, LDL cholesterol,
triglycerides
• optional - urinary albumin/creatinine ratio or urinary
albumin excretion
• assess for other major cardiovascular disease risk
factors - obesity (BMI > 30 kg/m2), dyslipidemia,
diabetes mellitus, cigarette smoking, physical inactivity,
microalbuminuria (estimated glomerular filtration < 60
mL/minute), age (men > 55 years, women > 65 years),
family history of premature cardiovascular disease (men
< 55 years, women < 65 years)
• assess for identifiable causes - sleep apnea, drugs
(including steroids), chronic kidney disease, primary
aldosteronism, renovascular disease, Cushing's
syndrome, pheochromocytoma, coarctation of aorta,
thyroid disease, parathyroid disease
• recommendations from expert panels
• 4 expert panels summarized are Joint National
Committee (JNC 7), 2003 European Society of
Cardiology, 2004 Canadian Hypertension Education
Program and Institute for Clinical Systems Improvement
(ICSI)
• all 4 expert panels recommend
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–
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serum potassium and creatinine
fasting blood glucose
fasting lipid panel
hematocrit
urinalysis
ECG
• in children and adolescents (workup of juvenile
hypertension)
• testing recommended in all children with persistent blood
pressure 95th percentile or higher
–
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BUN, creatinine, electrolytes, urinalysis, urine culture
CBC
renal ultrasound
fasting lipid panel, fasting glucose
echocardiogram
retinal exam
• drug screen if history suggestive
• polysomnography if history of loud, frequent snoring
• ambulatory blood pressure monitoring if white-coat
hypertension suspected and when other information on
blood pressure pattern needed
• additional testing in young children with stage 1
hypertension and any child or adolescent with stage 2
hypertension
• plasma renin (also if positive family history of severe
hypertension)
• renovascular imaging
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–
–
–
–
isotopic scintigraphy (renal scan)
magnetic resonance angiography
duplex doppler flow studies
3-dimensional CT
arteriography (DSA or classic)
• plasma and urine steroid levels
• plasma and urine catecholamines
• Reference - Pediatrics 2004 Aug;114(2 Suppl 4th
Report):555 full-text, commentary can be found in
Pediatrics 2005 Mar;115(3):826
Blood Tests
• persistent hypokalemia and metabolic alkalosis in Conn's syndrome
• fasting glucose abnormalities in diabetes mellitus, Cushing's
syndrome or acromegaly
• microangiopathic hemolytic anemia
• renal damage if creatinine > 1.5
• no association between serum ionized calcium levels and blood
pressure in 3,834 patients 65-89 from NHANES III study (J Am
Geriatr Soc 1998 Sep;46(9):S87,P281)
• genetic testing may eventually guide selection of antihypertensives;
case-control study among HMO patients taking drugs for
hypertension with 206 patients with first myocardial infarction, 177
patients with first stroke and 715 controls; among 653 with wild-type
adducin genotype, use of diuretics (compared to other
antihypertensives) was not associated with increased risk for
myocardial infarction and stroke; among 385 carriers of variant
adducin allele, use of diuretics was associated with decreased risk
(about 50% relative risk) for myocardial infarction and stroke (JAMA
2002 Apr 3;287(13):1680)
Urine Tests
• microalbuminuria associated with increased risk for cardiovascular
events
• increasing urine albumin-creatinine ratio associated with increasing
cardiovascular risk in cohort of 8,206 patients without diabetes with
stage II-III hypertension and left ventricular hypertrophy, with
increased risk starting at urine albumin-creatinine ratio > 1.16
mg/mmol (Ann Intern Med 2003 Dec 2;139(11):901), commentary
can be found in Ann Intern Med 2004 Aug 3;141(3):244 PDF
• microalbuminuria common in hypertension and associated with
increased risk for cardiovascular events; in series of 319 patients
with newly diagnosed mild-to-moderate essential hypertension, 40%
had microalbuminuria (Am J Kidney Dis 1999 Dec;34(6):996);
follow-up of 54 patients with microalbuminuria and 87 patients with
normal urinary albumin excretion for 7 years found 12 (21%) vs. 2
(2%) with cardiovascular events (p < 0.0002) (Am J Kidney Dis 1999
Dec;34(6):973), editorial can be found in Am J Kidney Dis 1999
Dec;34(6);1139 (QuickScan Reviews in Fam Pract 2000
Jul;25(4);3); no evidence that microalbuminuria screening in
hypertension affects patient-oriented outcomes (DynaMed
commentary)
• no studies to evaluate benefit of screening for microalbuminuria in
patients already taking ACE inhibitors or angiotensin II receptor
blockers for other indications (J Fam Pract 2003 Mar;52(3):229)
Imaging
• CXR (cardiomegaly, rule out CHF)
• echocardiography for LVH
• ACC/AHA/ASE 2003 guideline for clinical application of
echocardiography can be found in J Am Coll Cardiol
2003 Sep 3;42(5):954, J Am Soc Echocardiogr 2003
Oct;16(10):1091, Circulation 2003 Sep 2;108(9):1146
• American College of Radiology (ACR) Appropriateness
Criteria for routine chest radiographs in uncomplicated
hypertension can be found in National Guideline
Clearinghouse 2006 Sep 11:9606
EKG
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•
•
•
not done if mild and uncomplicated
may show left ventricular hypertension (LVH) with strain, ST changes in
ischemia, LVH if 35 mm in V1S and V5/6R
ECG screening for detecting LVH should use Cornell voltage criteria rather
than Sokolow-Lyon voltage criteria
Cornell criteria not affected by obesity in study of 380 patients (Am J Cardiol
1996 Apr 1;77(9):739 in Am Fam Physician 1996 Sep 1;54(3);1091)
Cornell voltage-duration product criteria for ECG LVH may be more
accurate than Sokolow-Lyon voltage criteria in obese patients
– based on study of 8,417 patients including 2,519 overweight and 1,573 obese
patients
– Reference - Hypertension 2000 Jan;35(1 Pt 1):13 in JAMA 2000 Apr
12;283(14):1803
– DynaMed commentary -- suggestion seems reasonable but results not definitive
since no gold standard applied to determine diagnosis of LVH, that is, unable to
distinguish between underdiagnosis by Sokolow-Lyon criteria or overdiagnosis by
Cornell criteria
•
decrease in Cornell product electrocardiographic LVH associated with
decreased risk for new-onset heart failure in 8,479 hypertensive patients
followed for mean 4.7 years (Ann Intern Med 2007 Sep 4;147(5):311)
• ECG criteria not sufficiently sensitive to rule out LVH in
patients with hypertension
• based on systematic review of 21 studies comparing any of 6 ECG
criteria with echocardiography in 5,608 patients with hypertension
• ECG criteria evaluated were Sokolow-Lyon index, Cornell voltage
index, Cornell product index, Gubner index, Romhilt-Estes score ≥ 4
points and Romhilt-Estes score ≥ 5 points
• median prevalence of LVH was 33% in primary care settings in 10
studies and 65% in secondary care settings in 11 studies
• median negative likelihood ratio ranged from 0.85 to 0.91 across
ECG criteria
• negative predictive values (at median prevalence) would be 69% in
primary care settings and 37% in secondary care settings
• Reference - BMJ 2007 Oct 6;335(7622):711 full-text, editorial can be
found in BMJ 2007 Oct 6;335(7622):681, commentary can be found
in BMJ 2007 Oct 20;335(7624):787
•
•
•
•
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•
American Heart Association/American College of Cardiology
Foundation/Heart Rhythm Society (AHA/ACCF/HRS) recommendations
and scientific statements for standardization and interpretation of
electrocardiograms
review of ECG technology and improving accuracy and clinical utility in
practice can be found in J Am Coll Cardiol 2007 Mar 13;49(10):1109 or in
Heart Rhythm 2007 Mar;4(3):394 or in Circulation 2007 Mar
13;115(10):1306 full-text
statement on diagnostic terms for ECG interpretation can be found in J Am
Coll Cardiol 2007 Mar 13;49(10):1128 or in Heart Rhythm 2007
Mar;4(3):413 or in Circulation 2007 Mar 13;115(10):1325 full-text
statement on intraventricular conduction disturbances can be found in J Am
Coll Cardiol 2009 Mar 17;53(11):976 or in Circulation 2009 Mar
17;119(10):e235 full-text
statement on T segment, T and U waves, and QT interval can be found in J
Am Coll Cardiol 2009 Mar 17;53(11):982 or in Circulation 2009 Mar
17;119(10):e241 full-text
statement on electrocardiogram changes associated with cardiac chamber
hypertrophy can be found in J Am Coll Cardiol 2009 Mar 17;53(11):992 or in
Circulation 2009 Mar 17;119(10):e251 full-text
statement on acute ischemia/infarction can be found in J Am Coll Cardiol
2009 Mar 17;53(11):1003 or in Circulation 2009 Mar 17;119(10):e262 fulltext
• Pathology tests:
• renal biopsy may show
– hyaline arteriolosclerosis - major characteristic of benign
nephrosclerosis, homogeneous pink hyaline thickening, loss of
underlying structural detail, narrowing of lumen, leakage of
plasma components
– hyperplastic arteriolosclerosis - fibroelastic hyperplasia with
reduplication of elastic lamina, related to more acute or severe
blood pressure elevations, diastolic blood pressure usually > 110
mm Hg, onionskinning, necrotizing arteriolitis (fibrinoid),
malignant nephrosclerosis
– normal or small kidneys
– granular cortical surface
– decreased cortex
Prognosis of Hypertension
•
•
•
•
hypertension at age 50 years associated with about 5-year reduction in
life expectancy compared with normotension, based on 3,128 participants
in Framingham Heart Study (Hypertension 2005 Aug;46(2):280)
risk of stroke is much more responsive to treatment than risk of heart
disease
greater reductions in systolic blood pressure associated with lower
risk of stroke, independent of medications used to lower blood
pressure (level 1 [likely reliable] evidence); based on meta-analysis of
meta-analysis of > 40 randomized trials (Stroke 2004 Mar;35(3):776)
risk of stroke clearly related to quality of blood pressure control in casecontrol study in England, consistent maintenance of blood pressure <
140/90 mm Hg needed for optimal stroke prevention; record review of 267
cases (patients < 80 with first stroke) vs. 534 controls, 61% vs. 42% were
hypertensive (defined as BP > 160/95 mm Hg); compared with nonhypertensive subjects, risk of stroke in hypertensive patients receiving
treatment was 1.3 times if BP controlled to < 140 mm Hg, 1.6 times if SBP
140-149 mm Hg, 2.2 times with SBP 150-159 mm Hg, 3.2 times if SBP 160
or greater; similar results for diastolic pressure (BMJ 1997 Jan 25;314(7076
):272)
• systolic (but not diastolic) blood pressure is a strong, positive,
continuous and independent indicator of mortality risk in the
elderly; 10-year follow-up of 3,858 outpatients > 65 years old, 74
patients (1.9%) were lost to follow-up and 1,561 (41.3%) died, 709
(45.4% all deaths) died from cardiovascular causes; positive
continuous, graded, strong and independent association observed
with both total (P < 0.001) and cardiovascular (P < 0.001) mortality
for systolic blood pressure (SBP) but not for diastolic blood pressure
(DBP), no J-shaped mortality curve in subjects with lowest SBP and
DBP (Arch Intern Med 1999 Jun 14;159(11);1205)
• systolic blood pressure predicts cardiovascular events in the
elderly
• cohort of 4,008 persons > 64 years old followed for at least 5 years
(mean 11.1 years)
• elevated systolic blood pressure strongly associated with
cardiovascular events, optimal systolic blood pressure < 120 mm Hg
• diastolic blood pressure not associated with cardiovascular events in
subjects < 75 years old
• diastolic blood pressure 80-90 mm Hg associated with lowest risk for
cardiovascular events in subjects > 75 years old
• Reference - J Hum Hypertens 2006 Jun;20(6):392
• hypertension (and high normal blood pressure to a lesser
degree) associated with increased risk for cardiovascular
events in women
• based on prospective cohort study
• 39,322 women followed for median 10.2 years
• 982 (2.5%) had major cardiovascular event (myocardial infarction,
stroke, or death from cardiovascular causes)
• 8,686 (30.1%) without baseline hypertension developed
hypertension
• age-adjusted rate of major cardiovascular events
– 1.6 per 1,000 person-years in 11,326 women with normal blood
pressure (120-129/75-84 mm Hg)
– 2.9 per 1,000 person-years in 4,988 women with high normal blood
pressure (130-139/85-89 mm Hg)
– 4.3 per 1,000 person-years in 10,459 women with baseline hypertension
• Reference - BMJ 2007 Sep 1;335(7617):432 full-text, editorial can
be found in BMJ 2007 Sep 1;335(7617):408
• systolic blood pressure (SBP), and not diastolic blood pressure
(DBP), predicts outcomes in treated hypertensive men
• 4,714 hypertensive men treated by their physician were followed for
mean 14 years
• the 85% with uncontrolled hypertension (SBP > 140 mm Hg and/or
DBP > 90 mm Hg) had increased risk for cardiovascular disease
mortality (risk ratio [RR] 1.66, 95% CI 1.04-2.64) and for coronary
heart disease mortality (RR 2.35, 95% CI 1.03-5.35) compared with
the 15% with controlled hypertension
• after controlling for DBP and risk factors, SBP 140-160 mm Hg had
RR 1.81 (95% CI 1.04-3.13) and SBP > 160 mm Hg had RR 1.94
(95% CI 1.1-3.43) for cardiovascular disease mortality compared to
SBP < 140 mm Hg
• after controlling for SBP and risk factors, DBP 90-99 mm Hg and
DBP > 100 mm Hg did not have significantly increased risk for
cardiovascular disease mortality compared to DBP < 90 mm Hg
• similar results seen for coronary heart disease mortality
• Reference - Arch Intern Med 2002 Mar 11;162(5):577, editorial can
be found in Arch Intern Med 2002 Mar 11;162(5):506, commentary
can be found in Arch Intern Med 2003 Jan 13;163(1):121
• patients ≥ 80 years old with higher blood pressure (up to 139/89
mm Hg) less likely to die than patients with lower blood
pressure in retrospective cohort study of 4,071 ambulatory patients
≥ 80 years old with hypertension, follow-up 5 years (J Am Geriatr
Soc 2007 Mar;55(3):383), commentary can be found in Am Fam
Physician 2008 Jan 1;77(1):94, J Am Geriatr Soc 2007
Dec;55(12):2102
• central systolic blood pressure may predict
cardiovascular mortality in patients ≥ 65 years (level
2 [mid-level] evidence)
• based on prospective cohort study
• 398 adults ≥ 65 years old with normal blood pressure or
untreated hypertension had central blood pressure and
brachial blood pressure measurements
• central carotid blood pressure measured by applanation
tonometry
• cardiovascular mortality associated with
– elevated carotid SBP (p = 0.029)
– history of coronary artery disease (p < 0.001)
– male gender (p < 0.001)
• Reference - J Am Coll Cardiol 2008 Jun 24;51(25):2432,
editorial can be found in J Am Coll Cardiol 2008 Jun
24;51(25):2440
• pulse pressure may be most important contributor to
cardiovascular risk in elderly; pooled results from 3 trials
with 7,929 patients > 60 with systolic blood pressure
160-239 mm Hg, increase in pulse pressure associated
with increased risk for cardiovascular events (Arch Intern
Med 2000 Apr 24;160(8):1085); DynaMed commentary -results may not be generalizable to younger patients,
patients with systolic blood pressure < 160 mm Hg or
patients with elevated diastolic blood pressure
• all-cause mortality and cardiovascular mortality is lower
in both men and women who are treated for
hypertension (Circulation 1996;93:697)
• home blood pressure but not office blood pressure predicted
cardiovascular mortality in 4,939 treated hypertensive elderly
(mean age 70 years) (level 1 [likely reliable] evidence) (JAMA
2004 Mar 17;291(11):1342), commentary can be found in J Fam
Pract 2004 Oct;53(10):832, commentary can be found in Am Fam
Physician 2004 Oct 15;70(8):1558
• self-measured home blood pressure better than clinic blood
pressure for predicting stroke or TIA in cohort of 1,702 Japanese
patients > 40 years old followed for mean 10.6 years (Stroke 2004
Oct;35(10):2356 in Evidence-Based Medicine 2005 MayJun;10(3):92)
Treatment
• JNC 7 treatment overview
• treat to BP < 140/90 mm Hg or < 130/80 mm Hg in patients with
diabetes or chronic kidney disease
• most patients will require 2 medications to reach goal
• lifestyle modifications
– weight reduction can reduce BP by 5-20 mm Hg per 10 kg lost (see also
Obesity in adults)
– DASH diet (fruits, vegetables, low-fat dairy, reduced fat) can reduce BP
by 8-14 mm Hg
– dietary sodium restriction can reduce BP by 2-8 mm Hg
– aerobic physical activity 30 minute/day can reduce BP by 4-9 mm Hg
– moderate alcohol consumption (1-2 drinks/day) can reduce BP by 2-4
mm Hg
– behavioral counseling for comprehensive lifestyle modification can lower
blood pressure
• initial drug choices
• if no compelling indications
– stage 1 hypertension (140-159/90-99 mm Hg) - thiazide-type
diuretics; may consider ACEI, ARB, BB, CCB or combination
– stage 2 hypertension (160/100 mm Hg or higher) - 2-drug
combination using thiazide-type diuretic plus ACEI, ARB, BB or
CCB
• compelling indications
– heart failure - thiazide diuretic, BB, ACEI, ARB, aldosterone
antagonist
– post-myocardial infarction - BB, ACEI, aldosterone antagonist
– high cardiovascular disease risk - thiazide diuretic, BB, ACEI,
CCB
– diabetes - thiazide diuretic, BB, ACEI, ARB, CCB
– chronic kidney disease - ACEI, ARB
– recurrent stroke prevention - thiazide diuretic, ACEI
• smoking cessation
• First-line therapy for hypertension
• Hypertension treatment in elderly patients
• Hypertension treatment considerations for race and
ethnicity
• Hypertension treatment in patients with diabetes
• Hypertension treatment in patients with chronic kidney
disease
• Antihypertensive medications overview
• Diuretics
• Beta blockers (BB)
• Angiotensin-Converting Enzyme (ACE) inhibitors (ACEI)
• Angiotensin II Receptor Blockers (ARBs)
• Calcium Channel Blockers (CCBs)
• Alpha-adrenergic antagonists (and centrally acting
alpha-2 agonists)
• Peripheral adrenergic neuron antagonists
• Combination antihypertensives
• evidence-based review of cardiovascular risk factors (with focus on
decision on treating hypertension) can be found in BMJ 2001 Apr
21;322(7292):967
• review of using cardiovascular risk profiles to individualize
hypertensive treatment can be found in BMJ 2001 May
12;322(7295):1164, correction can be found in BMJ 2001 Oct
27;323(7319):993
• guidelines, experts and standards of care may be overtreating
hypertension compared with public-based values; 39 consultant
physicians, 39 general practitioners, 39 practice nurses, and
100 adult members of the public were asked by postal questionnaire
whether or not they would take drugs if one life would be saved for
every 12, 33, 50, 100, or 250 people treated for five years; number
needed to treat (NNT) thresholds were 100 for consultant
physicians, 50 for general practitioners and 33 for practice nurses
and the public (BMJ 2000 May 27;320(7247):1446), commentary
can be found in BMJ 2000 Oct 21;321(7267):1022
• Other management may include home blood pressure monitoring,
self-management programs, alcohol reduction, relaxation and
meditation and alternative therapies
Diet
• dietary salt restriction
• sodium restriction may not have substantial long-term benefits
(level 2 [mid-level] evidence); systematic review of randomized
trials of salt restriction in healthy persons lasting 6 months to 7
years; review included 3 trials in 2,326 normotensive people, 5 trials
in 387 patients with untreated hypertension, and 3 trials in 801
patients being treated for hypertension; 17 deaths and few
cardiovascular events reported overall with no significant differences
between groups; intensive interventions (not practical in primary
care) reduced blood pressure by mean 1.1/0.6 mm Hg at 13-60
months; sodium restriction may help patients taking
antihypertensives stop medication and maintain blood pressure
control; systematic review last updated 2003 Nov 26 (Cochrane
Library 2004 Issue 1:CD003656), earlier version published in BMJ
2002 Sep 21;325(7365):628full-text, commentary can be found in
Am Fam Physician 2003 Jan 15;67(2):410, commentary can be
found in BMJ 2003 Jan 25;326(7382):222full-text, commentary can
be found in Lancet 2003 Aug 2;362(9381):403, commentary can be
found in Evidence-Based Medicine 2003 Sep-Oct;8(5):139
• dietary changes can have modest effect in lowering blood pressure
• Dietary Approaches to Stop Hypertension (DASH) diet was healthy
diet specifically designed and tested for lowering blood pressure
• DASH diet is high in dietary fiber, moderate in total fat and protein,
and low in saturated fat, dietary cholesterol, and sodium
• DASH diet emphasizes increased fruits, vegetables, whole grains,
low-fat dairy products, legumes, nuts, seeds, and lean meats
• DASH diet reduces systolic blood pressure by about 8-14 mm Hg
and incidence of hypertension (level 3 [lacking direct] evidence),
based on randomized trials without clinical outcomes reported
• DASH diet reduces lipid levels and homocysteine levels (level 3
[lacking direct] evidence), based on randomized trials without
clinical outcomes
• see DASH diet for details
• slight reduction in saturated fat intake plus use of extra-virgin olive
oil significantly lowered daily antihypertensive dosage requirement
in randomized 6-month crossover study of 23 hypertensive patients
(Arch Intern Med 2000 Mar 27;160(6):837)
• weight loss if obese
• weight-reducing diets in overweight hypertensive persons can affect
modest weight loss of 3-9% body weight and are probably
associated with modest blood pressure decreases of about 3 mm
Hg systolic and diastolic, weight-reducing diets may decrease
dosage requirements of antihypertensive medications, clinical
outcomes not reported; systematic review last updated 1998 Jul 20
(Cochrane Library 1999 Issue 1:CD000484)
• net weight reduction of 5.1 kg (11.2 lbs) associated with blood
pressure reduction of 4.44/3.57 mm Hg; blood pressure reduction
proportional to weight loss at systolic blood pressure -1.05 mm Hg
per kg of weight loss and diastolic blood pressure -0.92 mm Hg per
kg of weight loss; based on meta-analysis of 25 randomized trials of
weight reduction for blood pressure lowering with 4,874 participants
(Hypertension 2003 Nov;42(5):878)
• weight loss associated with modest blood pressure reductions but
weight loss not generally maintained long-term; in one study,
diastolic blood pressure reduced 1.4 mm Hg for 2 lbs of weight loss,
but only 13% subjects maintained weight loss at 3 years (Ann Intern
Med 2001 Jan 2;134(1):1in BMJ 2001 Jan 13;322(7278):118 and in
QuickScan Reviews in Fam Pract 2001 May;26(3):3)
•
•
•
•
•
•
•
caffeine restriction not likely to improve BP among habitual coffee drinkers
with mild hypertension
short-term restriction of dietary caffeine not shown to reduce blood pressure
in patients with mild hypertension in crossover trial of 4 consecutive dietary
caffeine regimens for 2 weeks in patients consuming > 2 cups of coffee
daily (BMJ 1991 Nov 16;303(6812):1235)
no difference in BP between drinking vs. abstaining from filter- brewed,
caffeinated coffee in trial of 21 normotensive, habitual users over 2 months
(J Gen Intern Med 1990 May-Jun;5(3):211)
1-2 mm Hg decline in BP among 45 normotensive habitual users drinking
decaffeinated instead of caffeinated coffee over 6 weeks in randomized trial
(Hypertension 1989 Nov;14(5):563)
Reference - ACP J Club 1992 Mar-Apr;116(2):38
vitamin C 500 mg orally daily for 4 weeks reduced blood pressure from
142/84 mm Hg to 132/80 mm Hg in randomized placebo-controlled trial of
30 patients aged 45-70 with type 2 diabetes (Hypertension 2002
Dec;40(6):804)
partial substitution of carbohydrate with protein or monounsaturated
fat associated with improvements in blood pressure and lipid levels
(level 3 [lacking direct] evidence) in randomized crossover trial with 164
patients with prehypertension or stage 1 hypertension (JAMA 2005 Nov
16;294(19):2455), editorial can be found in JAMA 2005 Nov
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Dietary Alternatives
interventions which might reduce blood pressure based on randomized trials without
clinical outcomes (level 3 [lacking direct] evidence)
vitamin D
combination antioxidant vitamins
vitamin C
vitamin E
potassium
combination of potassium and magnesium
omega-6 fatty acids (olive oil)
dark chocolate
garlic
green coffee bean extract
guava fruit
sour milk (milk fermented with Lactobacillus helveticus, casein hydrosylate)
soy milk (but soy protein supplements had inconsistent results)
Abana
Balsamodendron mukul
grape seed polyphenol (but increased blood pressure when combined with vitamin C)
hawthorn extract
Hibiscus sabdariffa (sour tea)
stevia
L-arginine
coenzyme Q10
melatonin (but increased blood pressure with concomitant nifedipine)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
interventions which appear ineffective for lowering blood pressure (level 3
[lacking direct] evidence)
calcium
calcium plus vitamin D
magnesium
combination of calcium plus magnesium
combination of calcium plus potassium
omega-3 fatty acids (fish oil)
tea
North American ginseng
intervention which may increase blood pressure (level 3 [lacking direct]
evidence)
low potassium diet
interventions with no direct evidence for treatment of hypertension
folic acid
glucomannan
olive leaf extract (insufficient evidence)
• hypertension treatment considerations for race and ethnicity
• limited evidence regarding effect of race on clinical response
(morbidity and mortality) to antihypertensives
– diuretics associated with lower rates of heart failure, stroke and
cardiovascular disease than multiple other drug classes
– thiazide-type diuretics suggested as initial drug of choice in black
patients (grade B recommendation [inconsistent or limited evidence]),
based on chlorthalidone having superior outcomes to amlodipine and
lisinopril in ALLHAT trial
• antihypertensive drugs reported to differ in efficacy for lowering
blood pressure in black patients (level 3 [lacking direct] evidence)
but insufficient evidence to determine effect on clinical outcomes
• National Institute for Clinical Excellence (NICE) guidelines
recommend first choice for initial therapy in hypertensive black
patients of any age should be either calcium-channel blocker or
thiazide-type diuretic
• see Hypertension treatment considerations for race and ethnicity for
details
• comorbidities
• diabetes - see Hypertension treatment in patients with
diabetes
• chronic kidney disease
– target blood pressure in patients with chronic kidney disease <
130/80 mm Hg
– most patients with chronic kidney disease should be treated with
combination of
• ACE inhibitor or angiotensin receptor blocker (ARB)
• diuretic (may need loop diuretic instead of thiazide diuretic if stages
4-5 chronic kidney disease)
– recommended parameters for stopping ACE inhibitor are
hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L]) or
rise in creatinine > 30% above baseline, even for patients with
elevated baseline creatinine > 1.4 mg/dL (123.8 mcmol/L) (grade
C recommendation [lacking direct evidence])
Diabetes
Types of Diabetes
•
•
•
•
Diabetes mellitus type 1
Diabetes mellitus type 2
Gestational diabetes (GDM)
Diabetes in pregnancy (diabetes that predates
the pregnancy)
• diabetes insipidus
– Nephrogenic diabetes insipidus
– Central diabetes insipidus
Prediabetes, diabetes prevention
and screening
•
•
•
•
Prediabetes
Risk factors for diabetes mellitus type 2
Diabetes mellitus type 2 screening
Diabetes mellitus type 2 prevention
treatment targets in patients with
diabetes
•
•
•
•
•
Glycemic goals in patients with type 1 diabetes
Glycemic goals in patients with type 2 diabetes
Glucose monitoring
Hypertension treatment in patients with diabetes
Lipid-lowering in patients with diabetes
nonpharmacologic management of
diabetes
• Dietary considerations for patients with type 2
diabetes
• Physical activity for type 2 diabetes
• Diabetes mellitus type 2 self-management
• Diabetes alternative treatments
Medications for diabetes
• Glucose lowering medications for type 2 diabetes
–
–
–
–
–
–
Metformin
Sulfonylureas (oral hypoglycemic agents)
Glitazones
Alpha-glucosidase inhibitors
Meglitinide analogs
Dipeptidyl peptidase IV (DPP-4) inhibitors (gliptins)
• Insulin management
• Insulin for type 2 diabetes with suboptimal glycemic
control
• Weight loss medications in patients with diabetes
• Diabetes alternative treatments
• Oral health care in persons with diabetes
Complications of diabetes
•
•
•
•
•
•
Diabetic foot ulcer
Diabetic nephropathy
Diabetic retinopathy
Diabetic neuropathy
Diabetic ketoacidosis (DKA) in adults
Diabetic ketoacidosis (DKA) in children and
adolescents
• Hyperosmolar hyperglycemic crisis
• Gastroparesis
Nephropathy
• Causes:
• hyperglycemia leads to diabetic glomerulosclerosis (usually follows
12-15 year latent period)
• many patients with diabetes with chronic renal insufficiency may
have renal parenchymal disease and not classic diabetic
glomerulosclerosis; study of 1,197 adults > 40 years old with
diabetes mellitus type 2, 171 (13%) had chronic renal insufficiency
defined as glomerular filtration rate < 60 mL/minute/1.73 m2 body
surface area; among these 171 subjects, 30% had neither diabetic
retinopathy nor albuminuria (including microalbuminuria), suggesting
causes other than diabetic glomerulosclerosis (JAMA 2003 Jun
25;289(24):3273), commentary can be found in JAMA 2003 Oct
8;290(14):1855; author reply 1855
• Pathogenesis:
• increased mesangial matrix and glomerular basement membrane,
hyaline arteriosclerosis of afferent and efferent arterioles,
immunoglobulin G (IgG) and albumin deposits lining tubular and
glomerular basement membranes
• hypotheses include protein glycosylation, activation of "polyol"
pathway, abnormalities of vascular endothelium and altered capillary
blood flow
•
•
•
•
Likely risk factors:
hypertension
poorly controlled diabetes
microalbuminuria
– microalbuminuria may be marker for increased
mortality and future nephropathy
• microalbuminuria as marker for increased mortality
– microalbuminuria associated with increased risk of
mortality
» based on systematic review without methodological
analysis
» 11 European cohort studies defined microalbuminuria as
albumin excretion 0.03-0.3 g/day
» consistent finding across studies showed that presence of
microalbuminuria associated with 2 times risk of all cause
and cardiovascular mortality
» unclear if treating microalbuminuria in type 2 diabetes
reduces risk
» Reference - Arch Intern Med 1997 Jul 14;157(13):1413 in J
Fam Pract 1997 Nov;45(5):379
• microalbuminuria associated with increased risks for overall
mortality, major cardiovascular events and hospitalization for
heart failure
• based on cohort study
• 5,545 persons > 55 years old with cardiovascular disease and 3,498
persons > 55 years old with diabetes followed for median 4.5 years
• Reference - JAMA 2001 Jul 25;286(4):421, commentary can be
found in ACP J Club 2002 Jan-Feb;136(1):34
• microalbuminuria and gross proteinuria associated with
increased risks for death from all causes, cardiovascular
causes, coronary heart disease or stroke
• cohort study of 840 patients with older-onset diabetes followed 12
years; 43% cardiovascular mortality in cohort, based on death
certificates
• increased risks significant after controlling for known cardiovascular
risk factors and diabetes-related variables
• relative risks were 1.68 to 2.2 for microalbuminuria and 2.33 to 2.73
for gross proteinuria
• Reference - Arch Intern Med 2000 Apr 24;160(8):1093
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
albumin-to-creatinine ratio > 30 mg/g in random urine specimens predicts
development of overt nephropathy
study of 439 Pima Indians with diabetes aged 25-84 years with no overt nephropathy
at baseline
mean follow-up 4.2 years
overt nephropathy defined as protein-to-creatinine ratio > 1 g/g
at baseline, 140 patients had albumin/creatinine ratio > 30 mg/g and 299 had ratio <
30 mg/g
overt nephropathy developed in 34% with vs. 4% without albumin/creatinine ratio >
30 mg/g
other independent predictors of nephropathy were duration of diabetes and 2-hour
postload glucose concentration
albumin-to-creatinine ratio > 30 mg/g had 80% sensitivity, 76% specificity, 34%
positive predictive value and 96% negative predictive value
Reference - Arch Intern Med 1991 Sep;151(9):1761, commentary can be found in
ACP J Club 1992 Jan-Feb;116(1):19
microalbuminuria associated with increased risk for diabetic nephropathy but
most patients with microalbuminuria do not develop nephropathy
based on prospective cohort study
23 patients with diabetes with persistent microalbuminuria and 209 patients with
diabetes without microalbuminuria followed for 7 years
microalbuminuria regressed in 56% of those with it and developed in 16% of those
without it
microalbuminuria had 43% positive predictive value and 77% negative predictive
value for diabetic nephropathy
Reference - Diabetes Care 2001 Sep;24(9):1560
Complications and Associated
Conditions of Nephropathy
• Complications:
• avoid contrast material (intravenous pyelogram [IVP],
computed tomography [CT] dye) especially if creatinine
> 2, else prior hydration is extremely important
• papillary necrosis
• chronic interstitial nephritis
• Associated conditions:
• arteriosclerotic disease
• parallel development of retinopathy
•
•
Diagnosis of Nephropathy
measuring kidney function
serum creatinine
– high serum creatinine implies poor kidney function
– low or normal serum creatinine does not always imply good kidney function
– small or elderly patients may not generate as much creatinine due to smaller
muscle mass
•
creatinine clearance
– measured level more accurate but requires 24-hour urine collection
– common ways to estimate creatinine clearance include
• Cockcroft-Gault equation (based on serum creatinine, age, weight and gender)
• Modification of Diet in Renal Disease (MDRD) calculator (recommended by National
Kidney Foundation for evaluating renal function in patients with chronic kidney disease)
• Reference - Prescriber's Letter 2005 Jul;12(7):38
– MDRD appears more accurate than Cockcroft-Gault formula in elderly
patients with diabetes
• based on diagnostic cohort study
• 69 patients > 72 years old with diabetes and wide range of renal function (serum
creatinine 54-367 mcmol/L) had measured glomerular filtration rate (GFR) compared
with MDRD equation (4-variable version) and Cockcroft-Gault estimation
• chronic kidney disease defined as measured GFR < 60 mL/minute/1.73 m2
• MDRD had 98% sensitivity and 61% specificity for chronic kidney disease
• Cockcroft-Gault estimation had 82% sensitivity and 44% specificity for chronic kidney
disease
• Reference - J Am Geriatr Soc 2006 Jun;54(6):1007
• Rule out:
• other causes of renal failure, see
– Acute renal failure - differential diagnosis
– Chronic kidney disease
• other causes of elevated serum creatinine (blood urea nitrogen
[BUN]/creatinine ratio usually < 8)
–
–
–
–
–
acute upper gastrointestinal bleeding
malnutrition
liver disease
rhabdomyolysis
laboratory artifact (chemical interference with creatinine determination
due to presence of ketones, proteins, sugars)
– medication-induced inhibition of tubular secretion of creatinine
•
•
•
•
cimetidine
pyrimethamine
trimethoprim
acetoacetate
– Reference - Arch Intern Med 1998 Dec 7-21;158(22):2509
• causes of falsely elevated serum creatinine
–
–
–
–
medications (for example, cefoxitin)
toxic ingestion such as methanol poisoning or nitromethane ingestion
ketoacidosis, such as diabetic ketoacidosis (DKA)
see Acute renal failure - differential diagnosis for details
•
•
Testing to consider:
initial testing
– blood urea nitrogen, creatinine
– urine dipstick
– random urine albumin (or protein):creatinine ratio
•
confirmatory testing
– 24-hour urine collection for albumin (or protein) and creatinine
– renal biopsy
•
•
•
for all adults with diabetes regardless of degree of urine albumin excretion,
measure serum creatinine at least annually for estimation of glomerular
filtration rate (grade C recommendation [lacking direct evidence])
Pathology tests:
renal biopsy - 2 patterns
– diffuse glomerulosclerosis - eosinophilic thickening of mesangium and basement
membrane
– 50% nodular glomerulosclerosis (Kimmelstiel-Wilson syndrome) - round nodules
with homogeneous center and layering of nuclei, specific for diabetes
Prognosis of Nephropathy
•
•
disease process accelerated by
hypertension (inconsistent evidence)
– systolic blood pressure stronger predictor than diastolic blood pressure of
renal outcomes
•
•
•
•
based on randomized trial
1,513 patients with nephropathy, hypertension and type 2 diabetes
doubling of serum creatinine, end-stage renal disease, or death
Reference - Arch Intern Med 2003 Jul 14;163(13):1555, commentary can be found in
Arch Intern Med 2004 Jan 26;164(2):223; author reply 223
– hypoalbuminemia, proteinuria, and black race (but not blood pressure,
glycohemoglobin or serum cholesterol) were independent predictors of
progression of decline in glomerular filtration rate
• based on cohort study
• 343 patients with type 2 diabetes, chronic kidney disease and mean blood pressure
138/72 mm Hg
• Reference -BMC Nephrol 2005 Jun 28;6(1):8 full-text
•
•
•
urinary obstruction
infection
nephrotoxic agents
– medication
– IV radiocontrast material
•
•
Treatment of Nephropathy
medications
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs)
–
–
–
–
•
combination therapy
–
–
–
•
ACE inhibitors appear to reduce mortality in diabetic nephropathy (level 2 [mid-level]
evidence) while ARBs have limited evidence for mortality outcome
ACE inhibitors decrease albuminuria and may delay onset of nephropathy (level 3 [lacking
direct] evidence)
ARBs slow progression of diabetic nephropathy and reduce risk for end-stage renal disease
(level 1 [likely reliable] evidence)
addition of ARB to ACE inhibitor may further reduce albuminuria (level 3 [lacking direct]
evidence)
combination of perindopril plus indapamide reduces mortality in patients with type 2 diabetes
(level 1 [likely reliable] evidence)
addition of avosentan to ACE inhibitor/ARB therapy associated with decrease in urine
albumin excretion in patients with diabetic nephropathy (level 3 [lacking direct] evidence
addition of aliskiren to losartan may reduce albumin-creatinine ratio in patients with type 2
diabetes and nephropathy (level 3 [lacking direct] evidence)
other medications
–
–
–
–
–
calcium channels blockers may be effective in treating diabetic nephropathy (level 3 [lacking
direct] evidence)
spironolactone may reduce albuminuria (level 3 [lacking direct] evidence)
sulodexide may reduce urinary albumin excretion in patients with diabetes (level 3 [lacking
direct] evidence)
EDTA chelation might reduce progression in patients with low-level environmental lead
exposure (level 3 [lacking direct] evidence)
high-dose B vitamin therapy associated with increased vascular events in patients with
diabetic nephropathy (level 2 [mid-level] evidence)
Dietary Recommendations
• in patients with any degree of chronic kidney disease, limit
protein intake to 0.8 g/kg/day to reduce risk of nephropathy
(ADA Grade B) (American Diabetes Association [ADA] 2010
position statement on standards of medical care in diabetes in
Diabetes Care 2010 Jan;33 Suppl 1:S11 full-text)
Medication for Nephropathy
• Angiotensin-converting enzyme (ACE) inhibitors:
• ACE inhibitors appear to reduce mortality in diabetic
nephropathy (level 2 [mid-level] evidence) while angiotensin
receptor blockers (ARBs) have limited evidence for mortality
outcome
• recommended parameters for stopping ACE inhibitor (grade B
recommendation [inconsistent or limited evidence])
• hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L])
• rise in creatinine > 30% above baseline (even for patients with
elevated baseline creatinine > 1.4 mg/dL
• Angiotensin II-receptor blockers (ARBs):
• angiotensin II receptor blockers (ARBs) slow
progression of diabetic nephropathy (level 1 [likely
reliable] evidence)
– based on 11 randomized trials
– irbesartan (Avapro) and losartan (Cozaar) are first drugs FDA
approved for kidney disease in patients with type 2 diabetes and
hypertension (Prescriber's Letter 2002 Oct;9(10):60)
– losartan slows progression of diabetic nephropathy and
reduces risk for end-stage renal disease (level 1 [likely
reliable] evidence)
• Other medications:
• treat hypertension aggressively (see Hypertension
treatment in patients with diabetes)
• spironolactone may reduce albuminuria (level 3
[lacking direct] evidence)
– based on 2 randomized trials without clinical outcomes
– spironolactone may reduce urine albumin-to-creatinine ratio
in patients taking lisinopril (level 3 [lacking direct] evidence)
• calcium channel blockers may be effective in treating
diabetic nephropathy (level 3 [lacking direct] evidence)
• angiotensin-converting enzyme (ACE) inhibitors and
calcium channel blockers may have similar efficacy
in reducing progression of type 2 diabetesassociated nephropathy
– based on small randomized trial without clinical outcomes
– 52 patients mean age 63 years with type 2 diabetes mellitus
randomized to lisinopril, calcium channel blocker (verapamil SR
or diltiazem SR), or atenolol and followed for mean of 63 months
– lisinopril vs. calcium channel blockers
• no significant difference in rate of decline of creatinine clearance
• no significant difference in reduction of proteinuria
– rate of decline of creatinine clearance greatest and reduction of
proteinuria least affected with atenolol
– Reference -Kidney Int 1996 Nov;50(5):1641
• Surgery:
• transplantation or dialysis within 3 years if renal failure
depending on other complications
• pancreas transplantation can reverse lesions of diabetic
nephropathy, but reversal requires > 5 years of
normoglycemia, clinical outcomes (need for dialysis,
mortality) not assessed, based on serial biopsies of 8
patients with diabetes type 1 (N Engl J Med 1998 Jul
9;339(2):69)
Prevention of Nephropathy
• National Kidney Foundation recommendations for
preserving renal function in adults with hypertension
and diabetes:
• blood pressure (BP) goal < 130/80 mm Hg in patients
with diabetes
• first-line therapy is combination of angiotensin-converting
enzyme (ACE) inhibitor and thiazide diuretic
• additional therapies if BP > 145/90 mm Hg include
calcium channel blocker (verapamil or diltiazem if
proteinuria), beta blocker (if heart rate > 84
beats/minute), alpha blockers
• angiotensin receptor blockers may be substituted for
ACE inhibitors if adverse effects
• Reference - Am J Kidney Dis 2000 Sep;36(3):646
• Multiple risk factor management:
• intensive management of multiple risk factors may
reduce microvascular and macrovascular
complications in patients with type 2 diabetes and
microalbuminuria
• Antihypertensive treatment:
• ACE inhibitors
– ACE inhibitors decrease albuminuria and may delay onset
of nephropathy (level 3 [lacking direct] evidence)
• angiotensin receptor blockers (ARBs)
• angiotensin II receptor blockers (ARBs) slow progression
of diabetic nephropathy (level 1 [likely reliable] evidence)
-- see Treatment section
• ARBs may be beneficial in preventing nephropathy in
patients with type 2 diabetes
– irbesartan and losartan have been shown to reduce
microalbuminuria and slow progression of established renal
disease
– valsartan has been shown to reduce microalbuminuria
– no data to recommend ARBs over ACE inhibitors
– Reference - Prescriber's Letter 2001 Jul;8(7):41
• antihypertensive treatments for patients with
diabetes intolerant to ACE inhibitors and ARBs
• non-dihydropyridine calcium channel blockers (such as
verapamil and diltiazem) preferred for pateints with
diabetes and proteinuria (grade A recommendation
[consistent high-quality evidence])
• diuretics effective for reducing risk for cardiovascular
disease
• sustained-release indapamide (a diuretic) appears
effective for first-line treatment in of hypertension in
patients with diabetes and proteinuria (grade B
recommendation [inconsistent or limited evidence])
• atenolol may be as effective as captopril for reducing risk
of microvascular and macrovascular complications
(grade B recommendation [inconsistent or limited
evidence])
• controlling blood pressure in diabetes appears more
important than which antihypertensive agents are used
• Reference - J Fam Pract 2005 Aug;54(8):711
• Reviews:
• Clinical Evidence Concise review (search date 2004 Nov) can be
found in Am Fam Physician 2005 Dec 1;72(11):2299
• review of early screening for microalbuminuria can be found in Mayo
Clin Proc 2008 Dec;83(12):1373 full-text
• review can be found in Am Fam Physician 2005 Jul 1;72(1):96
• review can be found in Postgrad Med 2003 May;113(5):35
• review can be found in Arch Fam Med 1996 Jun;5(9):513
• review can be found in N Engl J Med 1999 Oct 7;341(15):1127
(summarized in Am Fam Physician 2000 Mar 1;61(5):1486),
commentary can be found in N Engl J Med 2000 Feb 10;342(6):441
• review can be found in N Engl J Med 2002 Apr 11;346(15):1145,
commentary can be found in N Engl J Med 2002 Sep
19;347(12):947
• review can be found in Lancet 1998 Jul 18;352(9123):213,
summarized in Am Fam Physician 1998 Nov 15;58(8):1845
• review can be found in J Fam Pract 1998 Jan;46(1):21
• review can be found in Mayo Clin Proc 2000 Jan;75(1):49
• editorial review can be found in BMJ 2002 Jul 13;325(7355):59
• American Diabetes Association (ADA) literature review on diabetic
nephropathy can be found in Diabetes Rev 1995;3:510
• Guidelines:
• American Diabetes Association (ADA) 2010 position statement on
standards of medical care in diabetes can be found in Diabetes Care
2010 Jan;33 Suppl 1:S11 full-text
– ADA grades of evidence for clinical practice recommendations
• Grade A - clear evidence from well-conducted, generalizable, randomized
controlled trials that are adequately powered
• Grade B - supportive evidence from well-conducted cohort studies
• Grade C - supportive evidence from poorly controlled or uncontrolled studies
• Grade E - expert consensus or clinical experience
• policy statement on nephropathy in diabetes from American
Diabetes Association (ADA) can be found in Diabetes Care 2004
Jan;27 Suppl 1:S79full-text
• National Kidney Foundation recommendations for preserving renal
function in adults with hypertension and diabetes can be found in
Am J Kidney Dis 2000 Sep;36(3):646
Diabetic Neuropathy
•
•
•
•
Causes:
hyperglycemia
Pathogenesis:
glucose is converted by aldose reductase to sorbitol
which is toxic to endothelium
• advanced glycosylation end-products
• atherogenic plaques in vasa nervorum
•
•
•
•
•
•
Complications:
injury
infections
amputations
Associated conditions:
diabetic gastroparesis
• Chief Concern (CC):
• paresthesias and pain of feet > hands
(symmetric, bilateral, intense burning especially
at night)
• radiculopathy (lancinating pain in single
dermatome)
• mononeuropathy (cranial nerves or proximal
motor nerves)
• weakness
• erectile dysfunction
• urinary retention
• nocturnal diarrhea
• rarely constipation or diarrhea
• History of Present Illness (HPI):
• neuropathic sensory symptoms (numbness of the
feet) in patients with diabetes suggest
polyneuropathy but are not sensitive for detecting
polyneuropathy in patients with type 2 diabetes
– 588 patients with type 2 diabetes in 26 general practices in the
Netherlands had blinded comparison of neuropathic sensory
symptom questionnaire and neurologic exam
– score > 4 on 0-25 scale on neurologic exam implied diagnosis of
diabetic polyneuropathy
– 32% patients had diabetic polyneuropathy on exam
– neuropathic symptoms associated with diabetic polyneuropathy
were numbness of the feet, sensory alteration and symptoms of
pain
– for patients < 68 years old, numbness of feet had 28%
sensitivity, 93% specificity, positive likelihood ratio 4 and
negative likelihood ratio 0.77
– for patients > 68 years old, numbness of feet had 22%
sensitivity, 92% specificity, positive likelihood ratio 2.75 and
negative likelihood ratio 0.85
– Reference - Diabet Med 2000 Feb;17(2):105 in ACP J Club 2000
Nov-Dec;133(3):112
• Review of Systems (ROS):
• erectile dysfunction frequent in men with diabetes
(normal sexual desire, preserved ejaculation, erection
affected, rule out other causes)
• neurogenic bladder (hesitancy, weak stream, dribbling)
•
•
•
•
•
•
•
•
General Physical:
postural hypotension
HEENT:
diplopia, abnormal visual fields
Extremities:
neuropathic ulcers
Neuro:
decreased reflexes, loss of vibratory sense, loss of pain
and temperature sensation, decreased pinprick/light
touch/pain sensations, loss of proprioception (causes
ataxia), weakness, atrophy of interossei muscles, high
steppage gait
• screening for diabetic peripheral neuropathy
– Semmes-Weinstein monofilament exam appears specific for
diabetic peripheral neuropathy (level 2 [mid-level] evidence),
suggesting diagnosis if positive screen
– vibration testing with on-off method is specific for diabetic
peripheral neuropathy (level 1 [likely reliable] evidence)
Diagnosis of Neuropathy
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Rule out:
distal symmetric polyneuropathy of various etiologies
autonomic dysfunction (idiopathic, Shy-Drager, Riley-Day)
heavy metal poisoning
drugs
myasthenia gravis
Guillain-Barre syndrome
sarcoidosis
connective tissue disease
paraneoplastic syndrome
peripheral vascular disease
femoral neuropathy
tarsal tunnel syndrome
spinal stenosis
complex regional pain syndrome
lymphoma
multiple sclerosis
spinal tumor
alcoholic neuropathy
syphilisof
• Testing to consider:
• blood tests to consider
–
–
–
–
–
–
complete blood count
electrolytes
blood urea nitrogen (BUN), creatine
glucose
thyroid function tests
syphilis serology
• nerve conduction studies
• slowing of nerve conduction velocity
• segmental demyelination and axonal
degeneration
• point of care device for sural nerve function had
92% sensitivity, 82% specificity, 92% positive
predictive value, and 82% negative predictive
value for neuropathy on conventional nerve
conduction study in 72 patients with diabetes of
whom 50 (69%) had neuropathy (Diabetes Care
2006 Sep;29(9):2023)
• ankle/brachial index (ABI) > 0.90
Treatment of Neuropathy
• Treatment overview:
• drugs with efficacy for pain relief in diabetic neuropathy
include
– anticonvulsants (level 2 [mid-level] evidence) including
pregabalin (Lyrica) (level 1 [likely reliable] evidence)
– antidepressants (level 2 [mid-level] evidence)
– opioids (controlled-release oxycodone [OxyContin], tramadol
[Ultram]) (level 2 [mid-level] evidence)
– topical capsaicin (level 2 [mid-level] evidence)
• actovegin improves neuropathic symptoms and quality of
life in patients with symptomatic diabetic neuropathy
(level 1 [likely reliable] evidence)
• dietary supplements have limited evidence but
substances which may reduce pain include alpha-lipoic
acid and acetyl-L-carnitine (level 2 [mid-level] evidence)
• Medications:
• drugs with efficacy for pain relief in diabetic
neuropathy include
– anticonvulsants (level 2 [mid-level] evidence)
– antidepressants (level 2 [mid-level] evidence)
– opioids (controlled-release oxycodone, tramadol) (level 1
[likely reliable] evidence)
– topical capsaicin (level 2 [mid-level] evidence)
Neuropathy screening
• Screening:
• American Diabetes Association (ADA) recommendations
for foot care
– perform annual testing for loss of protective sensation (LOPS)
(10-g monofilament plus testing any one of (ADA grade B)
•
•
•
•
vibration using 128-hertz (Hz) tuning fork
pinprick sensation
ankle reflexes
vibration perception threshold
– Reference - American Diabetes Association (ADA) 2010 position
statement on standards of medical care in diabetes can be found
in Diabetes Care 2010 Jan;33 Suppl 1:S11 full-text
• Semmes-Weinstein monofilament exam appears
specific for diabetic peripheral neuropathy (level 2
[mid-level] evidence), suggesting diagnosis if
positive screen
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Reviews:
review can be found in Am Fam Physician 2005 Jun 1;71(11):2123
review can be found in Mayo Clin Proc 2006 Apr;81(4 Suppl):S3 and Mayo Clin Proc
2006 Apr;81(4 Suppl):S12, correction can be found in Mayo Clin Proc 2006
Jun;81(6):854
review of diabetic polyneuropathy can be found in JAMA 2009 Oct 7;302(13):1451,
commentary can be found in JAMA 2010 Feb 3;303(5):420
review of treatments for diabetic neuropathy can be found in J Fam Pract 2004
May;53(5):403
review can be found in Am Fam Physician 1996 Dec;54(8):2478
review of managing painful diabetic neuropathy can be found in Hosp Pract
(Minneap) 1999 Oct 15;34(11):79
review of diagnosis and management of neuropathic pain can be found in BMJ 2009
Aug 12;339:b3002, commentary can be found in BMJ 2009 Sep 1;339:b3502
review of neuropathic pain can be found in CMAJ 2006 Aug 1;175(3):265 full-text
review of neuropathic pain can be found in Cleve Clin J Med 2006 Aug;73(8):726
review of neuropathic pain can be found in New Zealand Fam Physician 2006
Oct;33(5):323 PDF
discussion of diabetic polyneuropathy can be found in JAMA 2003 Sep
10;290(10):1371
review of primary care management of neuropathic pain can be found in Mayo Clin
Proc 2004 Dec;79(12):1533 PDF
review of autonomic peripheral neuropathy can be found in Lancet 2005 Apr
2;365(9466):1259
American Diabetes Association (ADA) literature review on diabetic autonomic
neuropathy can be found in Diabetes Care 2003 May;26(5):1553
• Guidelines:
• American Diabetes Association (ADA) 2010 position statement on
standards of medical care in diabetes can be found in Diabetes Care
2010 Jan;33 Suppl 1:S11 full-text
– ADA grades of evidence for clinical practice recommendations
• Grade A - clear evidence from well-conducted, generalizable, randomized
controlled trials that are adequately powered
• Grade B - supportive evidence from well-conducted cohort studies
• Grade C - supportive evidence from poorly controlled or uncontrolled studies
• Grade E - expert consensus or clinical experience
• consensus guidelines from 11 pain specialists
– explicit methodology not described, all authors have financial relations
with pharmaceutical companies
– recommended first-line therapies are duloxetine, oxycodone controlledrelease, pregabalin, tricyclic antidepressants
– recommended second-line therapies are carbamazepine, gabapentin,
lamotrigine, tramadol, venlafaxine extended-release
– "honorable mention" agents include topical capsaicin, topical lidocaine,
bupropion, citalopram, methadone, paroxetine, phenytoin, topiramate
– Reference - Mayo Clin Proc 2006 Apr;81(4 Suppl):S12, correction can
be found in Mayo Clin Proc 2006 Jun;81(6):854
Diabetic Retinopathy
• Pathogenesis:
• increased capillary permeability, vascular occlusion, weakness of
supporting structures
• erythropoietin and vascular endothelial growth factor levels in
vitreous fluid independently associated with proliferative diabetic
retinopathy in study of 73 patients with proliferative diabetic
retinopathy and 71 patients with ocular disease but no diabetes (N
Engl J Med 2005 Aug 25;353(8):782), editorial can be found in N
Engl J Med 2005 Aug 25;353(8):839, commentary can be found in N
Engl J Med 2005 Nov 17;353(20):2190
• main risk factor is duration of diabetes mellitus
• also poor glycemic control
• risk factors for diabetic retinopathy were duration of diabetes > 4
years and HbA1c level > 6.9% in study of 260 patients (median age
70 years) with type 2 diabetes (Br J Gen Pract 2002
Mar;52(476):214 in Am Fam Physician 2002 Jun 1;65(11):2349)
• worsens in 15% of pregnancies
•
•
•
•
•
•
•
•
•
•
high blood pressure may be associated with early diabetic retinopathy
in adolescents with normal albumin urinary excretion
based on prospective cohort of 1,025 adolescent patients with type 1
diabetes and albumin excretion rate < 7.5 mcg/minute followed for median
4.1 years
Reference - BMJ 2008 Aug 26;337:a918 full-text, editorial can be found in
BMJ 2008 Aug 26;337:a770
younger age at diabetes type 2 onset associated with increased risk
for retinopathy
based on cohort study
624 patients with diabetes type 2 for 20-30 years and 852 patients with
diabetes type 2 for 10-12 years analyzed for retinopathy outcomes
retinopathy prevalence and severity significantly higher with younger
diabetes onset
retinopathy risk highest in patients with mean HbA1c > 9%
Reference - Diabetes Care 2008 Oct;31(10):1985
review of hypertension as risk factor in ocular disease can be found in
Lancet 2007 Feb 3;369(9559):425, correction can be found in Lancet 2007
Jun 23;369(9579):2078
Retinopathy Complications
•
•
•
•
Complications:
20% of new blindness in adults, vitreal hemorrhages, fibrous scarring,
retinal detachment
impaired circulation in microvasculature can lead to ischemia of optic disk
and micro neuropathic damage to third, fourth, and sixth cranial nerves
insufficient evidence to support use of anti-vascular endothelial
growth factor in patients with diabetic retinopathy and macular edema
– based on Cochrane review
– systematic review of 4 randomized trials evaluating anti-vascular endothelial
growth factor in patients with diabetic macular edema
– clinical heterogeneity precluded meta-analysis for most comparisons
– 2 low quality trials reported short-term benefit with bevacizumab
• in patients with macular edema refractory to photocoagulation (compared to placebo)
• in previously untreated patients (compared to photocoagulation)
– Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD007419
•
•
•
•
Associated conditions:
increased frequency of cataracts and glaucoma with diabetes mellitus
retinal arteriolar narrowing associated with increased 20-year risk of lower
extremity amputation in cohort of 906 patients with diabetes (Arch Intern
Med 2003 Nov 10;163(20):2505)
25.7% of patients with diabetic retinopathy had significant stenotic
coronary artery disease
– based on cohort study of 214 patients with diabetic retinopathy
– Reference - J Thorac Cardiovasc Surg 2010 Jan;139(1):92
• on funduscopic exam - venous dilatation, exudates,
hemorrhages, microaneurysms; rarely preretinal or
vitreous hemorrhage may lead to clot retraction and scar
formation with retinal detachment
• microaneurysms generally first clinically detectable sign
of diabetic retinopathy
Prognosis of Retinopathy
•
•
•
•
•
•
•
•
nonproliferative retinopathy may improve with intensive multifactorial diabetes control
based on 63 patients ≥ 65 years with type 2 diabetes and nonproliferative retinopathy
11 (17%) worsened
23 (37%) improved
Reference - J Am Geriatr Soc 2007 Apr;55(4):541
diabetic retinopathy may worsen transiently with tighter glycemic control but
progresses more slowly in the long term (J Intern Med 1991 Aug;230(2):101, BMJ
1985 Mar 16;290(6471):811 in ACP J Club 1992 Jan-Feb;116(1):5)
black patients with diabetes have greater severity of retinopathy than white patients
with diabetes
high rate of progression of diabetic retinopathy among African American
patients with type 1 diabetes mellitus
–
–
–
–
–
–
cohort of 483 African American patients with type 1 diabetes mellitus who had 2 exams at
mean 6 years apart
among 195 without diabetic retinopathy at baseline, 141 (72%) developed diabetic
retinopathy
among 419 at risk for progression of diabetic retinopathy at baseline, 235 (56%) had
progression of diabetic retinopathy and 63 (15%) had progression to proliferative diabetic
retinopathy
among 434 without macular edema at baseline, 69 (16%) developed macular edema
among 393 without vision-threatening diabetic retinopathy at baseline, 85 (22%) developed
vision-threatening diabetic retinopathy
Reference - Arch Ophthalmol 2006 Sep;124(9):1297
Treatment of Retinopathy
•
American Diabetes Association (ADA) recommendations(2)
– promptly refer to an ophthalmologist experienced in managing diabetic
retinopathy any patient with (ADA Grade A)
• any level of macular edema
• severe nonproliferative diabetic retinopathy (NPDR)
• any proliferative diabetic retinopathy (PDR)
– laser photocoagulation therapy indicated to reduce risk of vision loss in patients
with any of (ADA Grade A)
• high-risk PDR
• clinically significant macular edema
• some cases of severe NPDR
– aspirin does not increase the risk of retinal hemorrhage and retinopathy is not a
contraindication to aspirin use for cardioprotection (ADA Grade A)
•
interventions with strong supporting evidence(1)
–
–
–
–
•
glycemic control
blood pressure control
pan-retinal laser photocoagulation
focal laser photocoagulation
interventions with some supporting evidence(1)
– lipid-lowering therapy
– surgical vitrectomy
– intravitreal steroids
•
•
•
laser therapy
laser beam photocoagulation for proliferative retinopathy (obliterates new
vessels, reduces rate of vision loss by 50%)
macular laser coagulation may improve visual acuity after intravitreal
triamcinolone (level 2 [mid-level] evidence)
– 86 eyes of 74 patients with diffuse diabetic macular edema were treated with
intravitreal injection of triamcinolone acetonide 4 mg then randomized to macular
grid laser photocoagulation 3 weeks later vs. no laser
– visual acuity significantly better in laser group at 3 and 6 months
– Reference - Arch Ophthalmol 2006 May;124(5):653
•
panretinal photocoagulation in 1 sitting may be as effective as in 4
sittings for diabetic macular edema (level 2 [mid-level] evidence)
– based on nonrandomized trial
– 155 patients with diabetic macular edema had panretinal photocoagulation in
either 1 vs. 4 sittings
– no significant differences in visual acuity or central subfield thickness at 34
weeks
– Reference - Arch Ophthalmol 2009 Feb;127(2):132
•
•
vitrectomy may be necessary for complications
rapid preoperative glycemic control may increase risk of postoperative
progression of diabetic retinopathy and maculopathy (level 2 [midlevel] evidence), based on observational study of 87 patients with type 2
diabetes who had monocular phacoemulsification cataract surgery (Arch
Ophthalmol 2006 Jan;124(1):38)
Prevention and Screening for
Retinopathy
•
•
•
•
control diabetes, hypertension
no smoking
vitamin B6
intensive management of multiple risk
factors reduces microvascular complications
in patients with microalbuminuria
•
•
Screening:
American Diabetes Association (ADA) recommendations(2)
– adults and children aged ≥ 10 years old with type 1 diabetes should have an
initial dilated and comprehensive eye examination by an ophthalmologist or
optometrist ≤ 5 years after onset of diabetes (ADA Grade B)
– patients with type 2 diabetes should have an initial dilated and comprehensive
eye examination by an ophthalmologist or optometrist soon after the diagnosis of
diabetes (ADA Grade B)
– once started, patients should have annual examinations by an ophthalmologist or
optometrist (ADA Grade B)
• less frequent exams (every 2-3 years) may be considered after one or more normal eye
exams
• if retinopathy progressing, more frequent examinations needed
– high-quality retinal fundus photography may serve as a screening tool for
retinopathy (ADA Grade E)
• interpretation of the images should be performed by a trained eye care provider
• not a substitute for a comprehensive eye exam
– women with preexisting diabetes who are planning pregnancy or who have
become pregnant should have (ADA Grade B)
• comprehensive eye examination in the first trimester
• counselling on the risk of development and/or progression of diabetic retinopathy
• close follow-up throughout pregnancy and for 1 year postpartum
– Reference - Diabetes Care 2010 Jan;33 Suppl 1:S62 PDF
• family physician screening using PanOptic ophthalmoscope may be
acceptable for patients who fail to obtain ophthalmologist screening
• based on case series
• 11 family physicians assessing 28 standardized patients with
diabetes mellitus using PanOptic ophthalmoscope in nonmydriatic
exam
• mean 87% sensitivity and 57% specificity and moderate overall
agreement
• Reference - Ann Fam Med 2004 May-Jun;2(3):218
• use of mydriatic eye drops for pupil dilation for funduscopy
associated with increased detection of diabetic retinopathy and
extremely small risk of acute glaucoma (BMJ 2006 Jan
7;332(7532):3), commentary can be found in BMJ 2006 Jan
21;332(7534):179
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Reviews:
review of screening eye exams in type 2 diabetes can be found in J Fam Pract 2004
Sep;53(9):732
Clinical Evidence 2003 Jan review (search date 2002 Sep) can be found in BMJ 2003 May
10;326(7397):1023
review can be found in N Engl J Med 2004 Jan 1;350(1):48, commentary can be found in N Engl J
Med 2004 Jun 10;350(24):2525
review can be found in BMJ 2003 Apr 26;326(7395):924
review can be found in Adv Stud Med 2003 Apr;3(4):214
review can be found in Practitioner 2000 Aug;244(1613):696 (Am Fam Physician 2001 Feb
15;63(4):765)
review can be found in N Engl J Med 1999 Aug 26;341(9):667 (author may have conflict of interest
[N Engl J Med 2000 Feb 24;342(8):586])
discussion can be found in Australian Fam Physician 1997 Apr;26(4):373 in Am Fam Physician
1997 Sep 15;56(4):1208)
review of systemic management of diabetic retinopathy can be found in BMJ 2009 Feb
12;338:b441
review of ocular emergencies can be found in Am Fam Physician 2007 Sep 15;76(6):829 full-text
review of management of the visually impaired patient can be found in Am Fam Physician 2008
May 15;77(10):1431, commentary can be found in Am Fam Physician 2009 Oct 1;80(7):668
review of vision loss in older persons can be found in Am Fam Physician 2009 Jun 1;79(11):963
review of age-related eye disease and medication safety in elderly can be found in Annals of
Long-Term Care 2009 Jun;17(6):17
review of common visual problems in elderly can be found in Annals of Long-Term Care 2005
Sep;13(9):41
review of common causes of vision loss in the elderly can be found in Am Fam Physician 1999
Jul;60(1):99
review of preventing visual loss from chronic eye disease in primary care can be found in JAMA
2004 Mar 24-31;291(12):1487, clinical commentary can be found in JAMA 2004 Mar 2431;291(12):1497
American Diabetes Association (ADA) literature review on diabetic retinopathy can be found in
Diabetes Care 1998 Jan;21(1):143 and Diabetic Care 2004 Oct;27(10):2540
•
•
•
•
Guidelines:
American Academy of Ophthalmology (AAO) guideline can be found at
National Guideline Clearinghouse 2009 Jun 8:13502
American Diabetes Association (ADA) recommendations for screening and
treatment of diabetic retinopathy can be found in Diabetes Care 2010
Jan;33 Suppl 1:S62 full-text
guideline for screening for retinopathy in pediatric patient with type 1
diabetes mellitus can be found in Pediatrics 2005 Jul;116(1):270 or at
National Guideline Clearinghouse 2005 Sep 12:7427, summary can be
found in Am Fam Physician 2005 Oct 1;72(7):1403, commentary can be
found in Pediatrics 2006 Feb;117(2):586
Hypertension treatment in patients
with diabetes
Antihypertensive medications overview
–
–
–
–
–
–
Thiazide-type diuretics
Beta blockers
Angiotensin-Converting Enzyme (ACE) inhibitors
Angiotensin II Receptor Blockers
Calcium Channel Blockers
Combination antihypertensives
• First-line therapy for hypertension
• Cardiovascular risk prediction
• DASH diet
• lifestyle modifications which may lower blood pressure include
• weight reduction
• Dietary Approaches to Stop Hypertension (DASH) diet (fruits,
vegetables, low-fat dairy, reduced fat)
• dietary sodium restriction
• aerobic physical activity
• moderate alcohol consumption
• most current guidelines recommend target blood pressure < 130/80
mm Hg in patients with diabetes
• diastolic blood pressure target < 75-80 mm Hg in patients with
diabetes associated with lower rates of mortality and cardiovascular
events (level 2 [mid-level] evidence)
• systolic blood pressure target < 120 mm Hg does not reduce
mortality or myocardial infarction but does reduce nonfatal stroke
compared to target < 140 mm Hg (level 1 [likely reliable] evidence)
• selection of antihypertensive agents
• guidelines vary but generally recommend angiotensin-converting
enzyme (ACE) inhibitor plus thiazide-type diuretic as initial
combination therapy or conclude insufficient evidence to
recommended specific regimen
• most patients will require 2 or more drugs to achieve target blood
pressure
• four major antihypertensive classes (diuretics, beta blockers, ACE
inhibitors, calcium channel blockers) appear to reduce
cardiovascular mortality and morbidity in hypertensive patients with
diabetes (level 2 [mid-level] evidence)
• angiotensin receptor blockers (ARBs) may not reduce
cardiovascular morbidity and mortality (level 2 [mid-level] evidence)
but reduce risk for end-stage renal disease (level 1 [likely reliable]
evidence)
• all major antihypertensive regimens (ACE inhibitors, angiotensin
receptor blockers, calcium channel blockers, diuretics, beta
blockers) appear to have similar short-term and medium-term effects
on major cardiovascular events (level 2 [mid-level] evidence)
• insufficient evidence to establish role for beta blockers as first-line
therapy for hypertension in patients with diabetes
• regimens with efficacy for renal outcomes
• ACE inhibitors appear to reduce all-cause mortality in diabetic
nephropathy (level 2 [mid-level] evidence) while angiotensin
receptor blockers (ARBs) have limited evidence for mortality
outcome – see Diabetic nephropathy
• angiotensin receptor blockers (ARBs) slow progression of diabetic
nephropathy and reduce risk for end-stage renal disease (level 1
[likely reliable] evidence)
• ACE inhibitors and calcium channel blockers each reported to be
effective in reducing progression of type 2 diabetes-associated
nephropathy (level 3 [lacking direct] evidence)
• effect of ACE inhibitors or ARBs on renal outcomes (doubling of
creatinine, end-stage renal disease) appears to result from blood
pressure lowering and does not clearly differ from other
antihypertensives (level 2 [mid-level] evidence)
• combination ACE inhibitor and ARB reported to be more effective
than monotherapy for reducing blood pressure and markers of
urinary albumin excretion in hypertensive patients with diabetes
(level 3 [lacking direct] evidence)
Lifestyle Modifications
• weight reduction can reduce blood pressure by 5-20 mm Hg per 10
kg lost
• Dietary Approaches to Stop Hypertension (DASH) diet (fruits,
vegetables, low-fat dairy, reduced fat) can reduce blood pressure by
8-14 mm Hg
• dietary sodium restriction can reduce blood pressure by 2-8 mm Hg
• aerobic physical activity 30 minutes/day can reduce blood pressure
by 4-9 mm Hg
• moderate alcohol consumption (1-2 drinks/day) can reduce blood
pressure by 2-4 mm Hg
• Reference - Seventh Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure (JNC
7) Reference Card, Express Report
• summary can be found in JAMA 2003 May 21;289(19):2560,
correction can be found in JAMA 2003 Jul 9;290(2):197,
considerable commentary can be found in JAMA 2003 Sep
10;290(10):1312
• summary can be found in Am Fam Physician 2003 Jul 15;68(2):376,
editorial can be found in Am Fam Physician 2003 Jul 15;68(2):228
Target Blood pressures
• American Diabetes Association (ADA) recommended
target levels for nonpregnant adults with diabetes
mellitus
• blood pressure < 130/80 mm Hg
• Reference - American Diabetes Association (ADA) 2010
position statement on standards of medical care in
diabetes (Diabetes Care 2010 Jan;33 Suppl 1:S11 fulltext)
• most current guidelines recommend target blood
pressure < 130/80 mm Hg in patients with diabetes
• Seventh Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood
Pressure (JNC 7) Reference Card, Express Report
• Evidence:
• diastolic blood pressure target < 75-80 mm Hg in patients with
diabetes associated with lower rates of mortality and
cardiovascular events (level 2 [mid-level] evidence)
•
•
3 trials compared target blood pressure levels
Hypertension Optimal Treatment (HOT) compared target diastolic blood pressure <
80 mm Hg vs. < 90 mm Hg
–
–
–
–
–
•
United Kingdom Prospective Diabetes Study (UKPDS) compared target blood
pressure < 150/85 mm Hg vs. < 180/105 mm Hg in patients with diabetes
–
–
–
–
•
subgroup analysis included patients with diabetes
drugs used were felodipine (Plendil), then angiotensin-converting enzyme (ACE) inhibitor or
beta blocker
5% absolute risk reduction in total cardiovascular events (NNT 20, 95% CI 12.5-50)
3% absolute risk reduction in total mortality (NNT 34, borderline statistical significance)
microvascular end points not reported
drugs used were captopril (Capoten) or atenolol (Tenormin)
statistically significant reduction in total cardiovascular events but absolute risk reduction not
reported
nonsignificant 4% absolute risk reduction in total mortality
5% absolute risk reduction in microvascular end points (NNT 20, 95% CI 11-100)
Appropriate Blood Pressure Control in Diabetes (ABCD) compared target diastolic
blood pressure 75 mm Hg vs. 80-89 mm Hg in patients with diabetes
–
–
–
–
drugs used were nisoldipine (Sular) or enalapril (Vasotec)
no significant difference in total cardiovascular events but absolute risk reduction not
reported
5% absolute risk reduction in total mortality (NNT 20, borderline statistical significance)
no significant difference in microvascular end points
• 3 trials compared drug vs. no drug and had subgroup analyses for
patients with diabetes
• Systolic Hypertension in the Elderly Program (SHEP) compared
thiazide diuretic vs. usual care
– 8% absolute risk reduction in total cardiovascular events (NNT 13, 95%
CI 7-100)
– nonsignificant 2% absolute risk reduction in total mortality
– microvascular end points not reported
• Systolic Hypertension in Europe (Syst-Eur) compared calcium
channel blocker vs. placebo
– 8% absolute risk reduction in total cardiovascular events (NNT 13, 95%
CI 8-34)
– nonsignificant 5% absolute risk reduction in total mortality
– microvascular end points not reported
• Heart Outcomes and Prevention Evaluation (HOPE) compared ACE
inhibitor vs. placebo
– 5% absolute risk reduction in total cardiovascular events (NNT 20, 95%
CI 14-50)
– 3% absolute risk reduction in total mortality (NNT 34, 95% CI 20-100)
– 3% absolute risk reduction in microvascular end points (NNT 34,
borderline statistical significance)
• 2 trials compared angiotensin II receptor blocker vs.
placebo in patients with diabetes (primary analysis)
• Reduction of Endpoints in NIDDM with the Angiotensin II
Antagonist Losartan (RENAAL) trial found nonsignificant
2% absolute risk reduction in total cardiovascular events,
no significant difference in total mortality, and 4%
absolute risk reduction in microvascular end points (NNT
25, borderline statistical significance)
• individualized predictive disease modeling (IPDM) trial
did not report total cardiovascular events or total
mortality, 10% absolute risk reduction in microvascular
end points (NNT 10, 95% CI 6-25)
• Reference - Ann Intern Med 2003 Apr 1;138(7):593 PDF
• National Kidney Foundation recommends lowering
blood pressure goal to < 130/80 mm Hg in patients
with diabetes
• based on consensus statement after review of 12
randomized trials lasting at least 2 years
• Reference - Am J Kidney Dis 2000 Sep;36(3):646 in
Prescriber's Letter 2000 Jul;7(7):37 and in QuickScan
Reviews in Fam Pract 2001 Feb;25(12):6
• systolic blood pressure target < 120 mm Hg does not
reduce mortality or myocardial infarction but does
reduce nonfatal stroke compared to target < 140 mm
Hg (level 1 [likely reliable] evidence)
Choice of Antihypertensive
• guidelines vary but generally recommend angiotensin-converting
enzyme (ACE) inhibitor plus thiazide-type diuretic as initial
combination therapy or conclude insufficient evidence to
recommended specific regimen
• most patients will require 2 or more drugs to achieve target blood
pressure
• four major antihypertensive classes (diuretics, beta blockers, ACE
inhibitors, calcium channel blockers) appear to reduce
cardiovascular mortality and morbidity in hypertensive patients with
diabetes (level 2 [mid-level] evidence)
• angiotensin receptor blockers (ARBs) may not reduce
cardiovascular morbidity and mortality (level 2 [mid-level] evidence)
but reduce risk for end-stage renal disease (level 1 [likely reliable]
evidence)
• all major antihypertensive regimens (ACE inhibitors, angiotensin
receptor blockers, calcium channel blockers, diuretics, beta
blockers) appear to have similar short-term and medium-term effects
on major cardiovascular events (level 2 [mid-level] evidence)
• Seventh Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure (JNC 7)
• most patients will require 2 medications to reach goal (< 130/80 mm
Hg)
• initial drug choices
– stage 1 hypertension (140-159/90-99 mm Hg) - thiazide-type diuretics
and/or angiotensin-converting enzyme (ACE) inhibitor; may consider
angiotensin receptor blocker (ARB), beta blocker, calcium channel
blocker
– stage 2 hypertension (160/100 mm Hg or higher) - 2-drug combination
using thiazide-type diuretic plus ACE inhibitor, ARB, beta blocker or
calcium channel blocker
• Reference - Seventh Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure (JNC
7) Reference Card, Express Report
– summary can be found in JAMA 2003 May 21;289(19):2560, correction
can be found in JAMA 2003 Jul 9;290(2):197, considerable commentary
can be found in JAMA 2003 Sep 10;290(10):1312
– summary can be found in Am Fam Physician 2003 Jul 15;68(2):376,
editorial can be found in Am Fam Physician 2003 Jul 15;68(2):228
• National Kidney Foundation recommends ACE inhibitor plus
thiazide diuretic
• based on consensus statement after review of 12 randomized trials
lasting at least 2 years
• recommended first-line therapy is combination of ACE inhibitor and
thiazide diuretic
• recommended additional therapies if blood pressure > 145/90 mm
Hg include calcium channel blocker (verapamil [Calan] or diltiazem
[Cardizem] if proteinuria), beta blocker if heart rate > 84
beats/minute, alpha blockers
• angiotensin receptor blockers may be substituted for ACE inhibitors
if adverse effects
• Reference - Am J Kidney Dis 2000 Sep;36(3):646 in Prescriber's
Letter 2000 Jul;7(7):37 and in QuickScan Reviews in Fam Pract
2001 Feb;25(12):6
•
•
•
•
•
•
•
•
•
•
Reviews:
review can be found in N Engl J Med 2006 Jul 27;355(4):385, commentary
can be found in N Engl J Med 2006 Nov 2;355(18):1934
review can be found in Arch Intern Med 2004 Sep 27;164(17):1850
review can be found in Adv Stud Med 2003 Jun;3(6):326
review can be found in Am Fam Physician 2002 Oct 1;66(7):1209, editorial
can be found in Am Fam Physician 2002 Oct 1;66(7):1151, correction can
be found in Am Fam Physician 2003 Mar 15;67(6):1195, commentary can
be found in Am Fam Physician 2003 Jul 1;68(1):41
review of pharmacologic management of hypertension in patients with
diabetes can be found in Am Fam Physician 2008 Dec 1;78(11):1277
review of treatment of hypertension in patients with diabetes can be found in
Mayo Clin Proc 1996 Jan;71(1):53
evidence-based discussion of treatment of hypertension in patients with
diabetes can be found in JAMA 2000 Jun 28;283(24):3177
review of calcium channel blockers and evidence for benefit and harm can
be found in Arch Intern Med 2001 May 13;161(9):1145
American Diabetes Association (ADA) literature review on hypertension in
adults with diabetes can be found in Diabetes Care 2002 Jan;25(1):134
•
•
Guidelines:
American Diabetes Association (ADA)
–
–
–
•
•
•
American Society of Hypertension position paper on treatment of hypertension in
patients with diabetes can be found in J Clin Hypertens (Greenwich) 2008
Sep;10(9):707
American Association of Clinical Endocrinologists (AACE) guidelines on management
of diabetes mellitus: hypertension management can be found in Endocr Pract 2007
May-Jun;13(Suppl 1):35 or at National Guideline Clearinghouse 2007 Nov 26:11095
American Heart Association/American College of Cardiology
–
–
•
•
•
2010 position statement on standards of medical care in diabetes can be found in Diabetes
Care 2010 Jan;33 Suppl 1:S11 full-text
policy statement on management of hypertension in adults with diabetes can be found in
Diabetes Care 2004 Jan;27 Suppl 1:S65 full-text
guidelines on prevention and management of diabetes complications in Diabetes Care 2007
Jan;30 Suppl 1:S4full-text or at National Guideline Clearinghouse 2008 Jun 2:12185
2007 scientific statement for primary prevention of cardiovascular diseases in people with
diabetes can be found in Circulation 2007 Jan 2;115(1):114 full-text
2006 guidelines for secondary prevention for patients with coronary and other atherosclerotic
vascular disease (endorsed by National Heart, Lung, and Blood Institute [NHLBI]) can be
found in Circulation 2006 May 16;113(19):2363 full-text or at National Guideline
Clearinghouse 2006 Oct 9:9373
American College of Physicians guidelines for treatment of hypertension in patients
with type 2 diabetes can be found in Ann Intern Med 2003 Apr 1;138(7):587,
supporting evidence-based review in Ann Intern Med 2003 Apr 1;138(7):593,
commentary can be found in Ann Intern Med 2004 Mar 16;140(6):487
Canadian Diabetes Association 2008 guideline on diabetes mellitus can be found at
CDA PDF
Seventh Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure can be found at JNC 7 Reference Card, Express
Report, summary can be found in JAMA 2003 May 21;289(19):2560 and Am Fam
Physician 2003 Jul 15;68(2):376
Lipid Management in Diabetes
• Overview:
• American Diabetes Association (ADA) guidelines and American
Heart Association/American College of Cardiology (AHA/ACC)
guidelines recommend LDL cholesterol target < 100 mg/dL (< 2.6
mmol/L)
– AHA/ACC also suggests optional target < 70 mg/dL (< 1.8 mmol/L)
– additional lipid targets recommended by ADA for non-pregnant adults
• triglycerides < 150 mg/dL (< 1.7 mmol/L)
• HDL cholesterol > 40 mg/dL (> 1.0 mmol/L) in men, or > 50 mg/dL (1.3
mmol/L) in women
• lipid-lowering therapy (primarily with statins) recommended for most
patients with diabetes (grade A recommendation [consistent highquality evidence])
– lipid-lowering drug therapy effective for primary and secondary
prevention of major coronary events in patients with and without
diabetes (level 1 [likely reliable] evidence)
– cholesterol and blood pressure lowering appear more effective than
glucose lowering for preventing cardiovascular events (level 2 [midlevel] evidence)
– lipid-lowering therapy in patients with diabetes with other cardiac risk
factors reduces risk of major cardiovascular events at ANY initial LDL
cholesterol level (level 1 [likely reliable] evidence)
•
•
Target lipid levels:
American Diabetes Association (ADA) recommended target levels for
non-pregnant adults with diabetes mellitus
– LDL cholesterol < 100 mg/dL (< 2.6 mmol/L)
– triglycerides < 150 mg/dL (< 1.7 mmol/L)
– HDL cholesterol > 40 mg/dL (> 1.0 mmol/L), or > 50 mg/dL (1.3 mmol/L) in
women
– Reference - American Diabetes Association (ADA) 2010 position statement on
standards of medical care in diabetes (Diabetes Care 2010 Jan;33 Suppl 1:S11
full-text)
•
2006 American Heart Association/American College of Cardiology
(AHA/ACC) secondary prevention guidelines recommend
– LDL cholesterol < 100 mg/dL (< 2.6 mmol/L) if 10-year risk of coronary heart
disease > 20%
– LDL cholesterol < 70 mg/dL (< 1.8 mmol/L) as an alternative goal
– Reference - Circulation 2006 May 16;113(19):2363
•
NO valid evidence found to support assumption that degree of LDL
cholesterol lowering with statins independently predicts cardiovascular risk
reduction in patients with LDL cholesterol levels < 130 mg/dL (3.36 mmol/L)
(Ann Intern Med 2006 Oct 3;145(7):520, full-text)
• cholesterol lowering could save 3-3.4 years of life in men and 1.62.4 years of life in women with type 2 diabetes, based on decision
analysis (Am J Med 2003 Aug 1;115(2):122), commentary can be
found in Am Fam Physician 2004 Jan 15;69(2):395, J Fam Pract
2004 Feb;53(2):102
• glycemic optimization reduced incidence of LDL cholesterol > 100
mg/dL (2.6 mmol/L) from 78% to 66% (NNT 9) in uncontrolled study
(Arch Intern Med 2000 Oct 9;160(18):2756), commentary can be
found in Arch Intern Med 2001 Jun 11;161(11):1461
• statin therapy recommended for all patients with type 2 diabetes
who have
• coronary artery disease (grade A recommendation [consistent
high-quality evidence])
• age > 40 years plus other cardiovascular risk factors and unable to
achieve LDL < 100 mg/dL (2.6 mmol/L) by lifestyle modification
(grade A recommendation [consistent high-quality evidence])
• no clear evidence to support routine use of statins in other patients
with type 2 diabetes (grade C recommendation [lacking direct
evidence])
• Reference - Am Fam Physician 2005 Sep 1;72(5):866
• Reviews:
• review can be found in J Fam Pract 2007 Aug;56(8):634,
commentary can be found in J Fam Pract 2007
Nov;56(11):886
• review can be found in J Fam Pract 2007 Apr;56(4):294
• review of cholesterol lowering in diabetes can be found
in Postgrad Med 2005 Apr;117(4):17
• review of management of dyslipidemia in patients with
type 2 diabetes mellitus can be found in Adv Stud Med
2005 Jan;5(1):28 PDF, commentary can be found in Adv
Stud Med 2005 Nov-Dec;5(10):546 PDF
• review of use of statins for prevention of coronary heart
disease can be found in Am Fam Physician 2001 Jan
15;63(2):309
•
•
•
•
•
•
Guidelines:
synthesis of 3 guidelines (UMHS 2009, USPSTF 2008, VA/DoD 2006) on
screening for lipid disorders in adults can be found at National Guideline
Clearinghouse 2010 Mar 8:LIPSCREEN7
American Diabetes Association (ADA) 2010 position statement on
standards of medical care in diabetes can be found in Diabetes Care 2010
Jan;33 Suppl 1:S11 full-text
Canadian Diabetes Association 2008 guideline on diabetes mellitus can be
found at CDA PDF
American Diabetes Association (ADA) guidelines on prevention and
management of diabetes complications in Diabetes Care 2007 Jan;30 Suppl
1:S4full-text or at National Guideline Clearinghouse 2008 Jun 2:12185
American College of Physicians evidence-based guideline on lipid control in
management of type 2 diabetes mellitus
– lipid-lowering therapy recommended for all patients with type 2 diabetes with
known coronary artery disease or other cardiovascular risk factors
– once lipid-lowering therapy started, patients with type 2 diabetes should be
taking at least moderate doses of a statin
– for patients with type 2 diabetes taking statins, routine monitoring of liver function
tests or muscle enzymes is not recommended except in specific circumstances
– Reference - Ann Intern Med 2004 Apr 20;140(8):644 full-text, supporting
systematic review can be found in Ann Intern Med 2004 Apr 20;140(8):650 fulltext, summary can be found in Am Fam Physician 2004 Aug 15;70(4):775,
commentary can be found in ACP J Club 2004 Nov-Dec;141(3):65, Am Fam
Physician 2005 Feb 1;71(3):588, Ann Intern Med 2005 Nov 1;143(9):673 PDF
Congestive Heart Failure
•
•
Congestive Heart Failure
Types:
American College of Cardiology/American Heart Association (ACC/AHA)
staging of development of heart failure(1,2)
– stage A - persons with risk factors that predispose toward development of heart
failure (coronary artery disease, hypertension, diabetes mellitus, prior treatment
with cardiotoxic drugs, rheumatic fever, or family history of cardiomyopathy) but
who do not yet have impaired left ventricular function, hypertrophy or geometric
chamber disorientation
– stage B - asymptomatic patients with left ventricular hypertrophy and/or impaired
left ventricular function
– stage C - patients with current or past symptoms of heart failure associated with
underlying structural heart disease
– stage D - patients with refractory heart failure
•
New York Heart Association (NYHA) functional classification(2)
– class I - symptoms of heart failure only at levels of exertion that would limit
normal individuals
– class II - symptoms of heart failure on ordinary exertion
– class III - symptoms of heart failure on less-than-ordinary exertion
– class IV - symptoms of heart failure at rest
•
Killip Classification of Heart Failure
–
–
–
–
Class I - no clinical heart failure
Class II - rales bilaterally up to 50% lung fields
Class III - pulmonary edema with rales in all lung fields
Class IV - pulmonary edema, cardiogenic shock, stuporous, SBP < 90 mm Hg,
cold clammy skin, decreased urine
•
•
•
•
•
•
•
•
•
•
types of left ventricular dysfunction
systolic dysfunction - primary impairment of pumping of left ventricle,
decrease in systolic wall motion, described in this topic
diastolic dysfunction - primary impairment of filling of left ventricle, elevated
end-diastolic pressure in chamber of normal size, not well understood, see
Diastolic heart failure
types of heart failure among 844 patients with initial diagnosis of heart
failure in Soweto, South Africa in 2006
dilated cardiomyopathy in 35%
hypertensive heart failure in 33%
right heart failure in 27%
ischemic cardiomyopathy in 9%
valvular heart failure in 8%
Reference - Lancet 2008 Mar 15;371(9616):915, editorial can be found in
Lancet 2008 Mar 15;371(9616):876
• Incidence/Prevalence:
• 400,000 new cases/year, affecting estimated 3 million Americans
• 200,000 deaths, nearly 1 million hospitalizations and costs > $7
billion/year
• incidence in US 3 per 1,000 person-years (Arch Intern Med 1999
Jan 11;159(1):29)
• CHF affects at least 4.8 million people in US, leading cause of
hospital admissions for patients > 65 years, annual mortality 5-30%
(Am J Cardiol 1999;83:2A in J Fam Pract 1999 Apr;48(4):247)
• incidence of heart failure in United States stable from 19701999
– 10,311 persons 28-62 years old without heart failure at baseline (1948)
were followed up to 50 years in Framingham cohort, 1,075 developed
heart failure
– age-adjusted incidence of heart failure for each decade higher in men
than women, and higher in 1950-1969 than 1970-1999 (statistically
significant only in women)
– age-adjusted incidence of heart failure in 1990-1999 was 564 per
100,000 person-years in men and 327 per 100,000 person-years in
women
– Reference - N Engl J Med 2002 Oct 31;347(18):1397, editorial can be
found in N Engl J Med 2002 Oct 31;347(18):1442, commentary can be
found in N Engl J Med 2003 Feb 13;348(7):660
•
•
•
•
•
•
•
•
•
•
•
•
20% lifetime risk for CHF
3,757 men and 4,472 women were followed over 25 years (124,262 personyears), 583 developed CHF
at age 40 years, lifetime risk for CHF was 21% for men and 20.3% for
women
at age 80 years, lifetime risk was 20.2% for men and 19.3% for women
lifetime risk for CHF increased with blood pressure > 160/100 mm Hg and
with myocardial infarction
Reference - Circulation 2002 Dec 10;106(24):3068, commentary can be
found in Am Fam Physician 2003 Mar 15;67(6):1339
about 3% of adults > 45 years old have heart failure
based on large representative sample of adults in England, 6,286 randomly
selected patients > 45 years from 16 randomly selected general practices,
3,960 (63%) participated
72 (1.8%) had left ventricular systolic dysfunction defined as ejection
fraction < 40% (95% CI 1.4-2.3%), 139 (3.5%) had borderline left ventricular
function defined as ejection fraction 40-50% (95% CI 3-4.1%)
124 (3.1%) had definite or probable heart failure (95% CI 2.6-3.7%)
definite heart failure in 92 patients associated with ejection fraction < 40%,
atrial fibrillation and valve disease
Reference - Lancet 2001 Aug 11;358(9280):439, editorial can be found in
Lancet 2001 Aug 11;358(9280):432
•
•
•
•
•
•
•
•
•
2.2% prevalence of congestive heart failure (CHF) based on clinical
criteria in study of 2,042 persons > 45 years old, 44% of whom had ejection
fraction (EF) > 50%
among this population, 6% had systolic dysfunction (EF < 50%), 2% had
moderate or severe systolic dysfunction (EF < 40%), 20.8% had mild
diastolic dysfunction (impaired relaxation without increased filling
pressures), 6.6% had moderate diastolic dysfunction (impaired relaxation
with moderately elevated filling pressures or pseudonormal filling), and
0.7% had severe diastolic dysfunction (advanced reduction in compliance or
restrictive filling)
systolic dysfunction and diastolic dysfunction each increased risk of CHF
but most patients with moderate or severe systolic or diastolic dysfunction
did not have CHF
Reference - JAMA 2003 Jan 8;289(2):194, commentary can be found in
ACP J Club 2003 Sep-Oct;139(2):51
higher prevalence with increasing age
study of 1,275 persons aged 60-86 years in Canberra, Australia who had
history and exam by cardiologist and echocardiography
6.3% had clinical heart failure (5.6% previously diagnosed, 0.6% previously
undiagnosed), persons aged 80-86 years had 4.4 times higher prevalence
of clinical heart failure than persons aged 60-64 years
75 persons (5.9%) had left ventricular systolic dysfunction, including 44
(3.5%) in preclinical stage of disease
Reference - Med J Aust 2006 Feb 20;184(4):151 full-text
• heart failure common among patients with coronary disease or
diabetes
• study of 1,062 patients with previous myocardial infarction, angina,
hypertension, or diabetes
• left ventricular systolic ejection fraction < 40% was found in 22.1%
patients with previous myocardial infarction, 8.1% patients with
angina, 1.8% patients with hypertension, and 5.8% patients with
diabetes
• heart failure (defined as dyspnea plus either systolic dysfunction,
atrial fibrillation or clinically significant valve disease) was found in
16% patients with previous myocardial infarction, 8.4% patients with
angina, 2.8% patients with hypertension, and 7.7% patients with
diabetes
• Reference - BMJ 2002 Nov 16;325(7373):1156
• Causes:
• coronary artery disease is most common cause ischemic cardiomyopathy, myocardial infarction
• systemic hypertension
• valvular heart disease including aortic stenosis, aortic
regurgitation, mitral regurgitation
• severe renal failure
• constrictive pericarditis
• other causes of heart failure include alcoholic
cardiomyopathy, dilated cardiomyopathy, hypertrophic
cardiomyopathy, restrictive cardiomyopathy, infiltrative
disorders (sarcoidosis, hemochromatosis, amyloidosis),
peripartum cardiomyopathy
• myocarditis
• infectious endocarditis
• arrhythmia
• tachycardia-induced heart failure
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
beriberi
chemotherapy
AIDS
muscular dystrophy
causes of right ventricular failure
#1 cause is left ventricular failure (right-sided failure usually late in
course)
mitral stenosis
pulmonary hypertension (COPD, pulmonary embolism)
right-sided infectious endocarditis
right ventricular infarction
high output cardiac failure - anemia, thyrotoxicosis, arteriovenous
fistula, Paget's disease
pheochromocytoma
other precipitating factors
noncompliance with medications - digitalis, diuretics, ACE inhibitor
excess dietary sodium
diastolic heart failure
• drugs
• alcohol, propanolol and other beta blockers, cardiotoxic drugs
(daunorubicin), NSAIDs, antiarrhythmics (disopyramide),
corticosteroids, androgens, estrogens, tricyclic antidepressants (for
example, nortriptyline), glitazones
• tumor necrosis factor antagonists (etanercept and infliximab)
associated with new or worsening heart failure in 47 cases reported
to US FDA Medwatch (Ann Intern Med 2003 May 20;138(10):807)
• imatinib (Gleevec) associated with occasional occurrence of severe
congestive heart failure and left ventricular dysfunction, mostly in
patients with history of cardiac disease (FDA MedWatch 2006 Oct
19); imatinib associated with severe congestive heart failure in 10
patients (Nat Med 2006 Aug;12(8):908)
• review of drug-induced heart failure can be found in J Am Coll
Cardiol 1999 Apr;33(5):1141 (QuickScan Reviews in Fam Pract
1999 Nov;24(8):7)
• high output states with increased metabolic demands - fever,
hypothyroidism, anemia, AV fistula, infections, pregnancy, cocaine
• bilateral renovascular disease may lead to fluid retention (BMJ 2003
Mar 1;326(7387):489 full-text)
• renal AV malformation in case report (Lancet 2009 Dec
5;374(9705):1944)
•
•
•
•
•
•
•
•
•
•
reversible causes of congestive heart failure - anemia, hyperthyroidism,
atrial myxoma, arteriovenous fistula, surgically correctable valvular heart
disease, surgically correctable congenital heart disease, cardiac
arrhythmias in otherwise normal heart, thiamine deficiency, alcohol,
cocaine, carnitine deficiency, hemochromatosis, hypocalcemia,
hypophosphatemia, infectious disease, pheochromocytoma, sarcoidosis,
uremia
hypocalcemia reported as cause of reversible cardiomyopathy with
ventricular tachycardia in case report (Ann Intern Med 2007 Apr
3;146(7):541)
causes of HF in children without congenital heart disease in United
Kingdom and Ireland
dilated cardiomyopathy
myocarditis
occult arrhythmia
anthracycline toxicity
metabolic disease
left ventricular noncompaction
Reference - based on cohort of 104 children in United Kingdom and Ireland
(Circulation 2008 Jan 1;117(1):79), editorial can be found in Circulation
2008 Jan 1;117(1):11, commentary can be found in Circulation 2008 Jun
10;117(23):e481
Pathogenesis of CHF
• impairment of ability to fill or empty left ventricle
• most cases are due to systolic dysfunction (low left ventricular
ejection fraction [LVEF]), usually left ventricular dysfunction for
example, post-MI, cardiomyopathy, myocarditis, valvular heart
disease
• some cases are due to diastolic dysfunction (normal LVEF), for
example, ischemic and infiltrative diseases, hypertensive
cardiovascular disease, valvular heart disease, restrictive
cardiomyopathy
– patients with diastolic heart failure have abnormal active relaxation
and high passive stiffness, based on prospective study comparing 47
such patients (heart failure signs and symptoms, normal ejection
fraction, and increased left ventricular end-diastolic pressure) with 10
controls (N Engl J Med 2004 May 6;350(19):1953), commentary can be
found in N Engl J Med 2004 Sep 9;351(11):1143, summary can be
found in Am Fam Physician 2005 Jan 15;71(2):374
• high-output failure is seen in chronic severe anemia, Paget's
disease, beriberi and arteriovenous fistulae
• symptoms due to
• congestion due to elevated ventricular filling
pressure
• fatigue and organ system dysfunction due to
inadequate cardiac output
• ventricular remodeling
• change in chamber volume and shape not
related to preload-mediated increase in
sarcomere length
• myocardium dilates and lowers ejection fraction
to avoid excess cardiac output
• does not cause symptoms directly, but data
suggests adverse effect on prognosis in patients
after myocardial infarction
• risk factors include hypertension, left ventricular hypertrophy,
smoking, hyperlipidemia, diabetes mellitus, microalbuminuria,
decreased vital capacity, higher resting heart rate, obesity and
asymptomatic left ventricular dysfunction (BMJ 1999 May
22;318(7195):1400 full-text)
• hypertension - especially elevated systolic blood pressure and
pulse pressure
• systolic blood pressure, pulse pressure, and body mass index
each associated with risk for incident heart failure
– based on cohort of 3,362 participants in Framingham Heart Study with
67,240 person-years of follow-up
– 518 developed heart failure
– Reference - Hypertension 2007 Nov;50(5):869
• systolic blood pressure and pulse pressure were each better
risk predictors than diastolic blood pressure for congestive
heart failure
– 2,040 persons in Framingham Heart Study followed for mean 17.4
years, 234 (11.8%) developed heart failure
– increasing SBP, DBP and pulse pressure were each associated with
increasing risk for heart failure after controlling for multiple variables
• several ECG findings associated with increased risk of CHF
• left ventricular hypertrophy on ECG associated with higher risk
of CHF in prospective study of 2,638 older persons (J Am Geriatr
Soc 1998 Oct;46(10):1280)
– ECG strain associated with further increased risk of CHF among
patients with left ventricular hypertrophy
• 8,696 patients with hypertension and left ventricular hypertrophy on ECG but
no CHF were randomized to atenolol-based vs. losartan-based
antihypertensive regimen for mean 4.7 years
• 923 (10.6%) had ECG strain at baseline defined as downsloping convex ST
segment with inverted asymmetrical T wave opposed QRS axis in lead V5 or
V6
• 265 (3%) had new-onset CHF, 26 had CHF-related death
• ECG strain predicted new-onset heart failure with hazard ratio 3.27 (95% CI
2.49-4.29) and adjusted hazard ratio 1.8 (95% CI 1.3-2.48)
• ECG strain predicted heart failure mortality with hazard ratio 4.74 (95% CI
2.11-10.64) and adjusted hazard ratio 2.78 (95% CI 1.02-7.63)
– Reference - Circulation 2006 Jan 3;113(1):67
• 5 ECG findings associated with > 2 times risk of incident CHF in 9year follow-up of 38,283 postmenopausal women in Women's
Health Initiative
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–
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wide QRS/T angle
STV5 depression
high TV1 amplitude
QRS non-dipolar voltage
myocardial infarction on ECG
Reference - Circulation 2006 Jan 31;113(4):481
•
•
•
•
•
•
increased left ventricular mass, especially eccentric left ventricular
hypertrophy on echocardiography, associated with increased risk of
new development of depressed left ventricular ejection fraction in
prospective study of 3,042 persons > 65 years old followed mean 5 years (J
Am Coll Cardiol 2004 Jun 16;43(12):2207 in J Watch Online 2004 Jul 30)
wall-motion abnormalities on echocardiography associated with
increased risk of cardiovascular events
based on prospective cohort study
2,864 patients (mean age 60 years) without clinically evident cardiovascular
disease at baseline followed for mean 8 years
on baseline echocardiography, 5% had focal hypokinesia and 1.5% had
wall-motion abnormalities
comparing patients with vs. without segmental wall-motion abnormalities
–
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•
42.1% vs. 18% had cardiovascular events
11.4% vs. 5.4% had myocardial infarction
4.3% vs. 2.4% had stroke
18.6% vs. 8.8% had coronary heart disease
11.4% vs. 4% had heart failure
18.6% vs. 5.6% had cardiovascular mortality
Reference - Circulation 2007 Jul 10;116(2):143
• chronic anemia associated with increased risk of
heart failure
• study of Medicare claims data for 1,179,700 persons >
65 years old in 1999 and 2000, 5% prevalence of chronic
anemia in 1999
• incidence of heart failure in 2000 (no heart failure in
1999) was 12.4% among patients with and 5.9% among
patients without chronic anemia in 1999
• Reference - AGS 2003 annual meeting in J Am Geriatr
Soc 2003 Apr;51(4 Suppl):S131,P262
• elevated atrial natriuretic peptide (ANP) level
associated with increased risk of developing
congestive heart failure in 7-month prospective study
of 256 nursing home patients aged 70-102 years without
history of CHF (J Am Geriatr Soc 1999 Apr;47(4):407)
•
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obesity associated with increased risk of heart failure
5,881 persons (mean age 55 years, 54% women) in Framingham Hearth Study
followed for mean 14 years, 496 (8.4%) developed heart failure
after adjustment for risk factors, risk of heart failure increased for each increment of 1
in body mass index
obese subjects had 2 times greater risk for heart failure compared to subjects with
normal body mass index
Reference - N Engl J Med 2002 Aug 1;347(5):305, editorial can be found in N Engl J
Med 2002 Aug 1;347(5):358, commentary can be found in N Engl J Med 2002 Dec
5;347(23):1887
waist circumference stronger risk factor for congestive heart failure than body mass
index in cohort of 2,435 persons aged 70-79 years followed median 6.1 years (J Am
Geriatr Soc 2006 Mar;54(3):413)
metabolic syndrome associated with increased risk for heart failure
2,314 men aged 50 years free from heart failure followed for 20 years
metabolic syndrome associated with adjusted hazard ratio 1.66 for heart failure
Reference - Heart 2006 Oct;92(10):1409
retinopathy associated with 2 times adjusted relative risk of congestive heart
failure (unadjusted rates 15.1% vs. 4.8%) in 7-year prospective follow-up of 11,612
US persons aged 49-73 years (JAMA 2005 Jan 5;293(1):63)
some medications may be associated with increased risk for CHF -- see History
section, Meds subsection
•
•
•
Possible risk factors:
higher dietary sodium intake may increase risk for CHF in overweight persons;
5,233 nonoverweight and 5,129 overweight persons followed mean 19 years, 413
nonoverweight and 679 overweight persons developed CHF based on medical
records and death certificates (Arch Intern Med 2002 Jul 22;162(14):1619),
commentary that underlying data is not valid can be found in Arch Intern Med 2003
Apr 14;163(7):851
egg consumption ≥ 1 per day may be associated with increased risk of heart
failure
–
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•
based on a prospective cohort study of 21,275 US male physicians
Reference - Circulation 2008 Jan 29;117(4):494
increased intake of eggs and high-fat dairy may be associated with increased
risk for heart failure
–
–
–
based on prospective cohort study of 14,153 African-American and white adults in United
States followed for mean 13 years
1,140 (8%) developed heart failure
incident heart failure associated with
•
•
–
increased egg intake (adjusted hazard ratio [HR] 1.23, 95% CI 1.08-1.41)
increased high-fat dairy intake (HR 1.08, 95% CI 1.01-1.16)
Reference - J Am Diet Assoc 2008 Nov;108(11):1881
• Complications:
• weak skeletal and respiratory muscles from heart failure
related myopathy (Eur Heart J 1999;20:1191 PDF in
BMJ 1999 Aug 28;319(7209):586)
• left ventricular failure associated with 2.1 times
increased risk for stroke in case-control study (J
Epidemiol Community Health 2002;56(suppl 1):i8 in BMJ
2002 Feb 9;324(7333):374)
• heart failure associated with increased risk of dementia
and Alzheimer disease in community-based cohort of
1,301 persons > 75 years old in Sweden followed for up
to 9 years (mean 5 years) (Arch Intern Med 2006 May
8;166(9):1003), commentary can be found in Arch Intern
Med 2006 Nov 13;166(20):2286
• hypoxic liver injury (Mayo Clin Proc 2006
Sep;81(9):1232)
•
•
Associated conditions:
depression
–
clinically significant depression reported in 21.5% of heart failure patients
•
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–
heart failure associated with depression
•
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•
based on prospective cohort study
1,006 patients ≥ 18 years old with heart failure and ejection fraction ≤ 35% were followed for mean 2.7 years
30% of patients depressed (Beck Depression Inventory ≥ 10)
24.2% taking antidepressants
mortality 42.7%
depression independently associated with increased mortality (odds ratio 1.34, 95% CI 1.08-1.68)
neither use of any antidepressant nor use of SSRI antidepressants associated with increased mortality after adjustment for
depression and other confounders
Reference - Arch Intern Med 2008 Nov 10;168(20):2232
depression common in heart failure and associated with worsening health status at 6 weeks
•
•
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cross-sectional study of 6,125 persons > 70 years old
criteria for syndromic depression were met by 11% of 199 persons with self-reported heart failure, 4.8% of 1,856 persons
with other heart conditions, and 3.2% of 4,070 persons with no heart conditions
Reference - J Am Geriatr Soc 2002 Dec;50(12):2003
depression but not antidepressant use associated with increased mortality in patients with heart
failure
•
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based on systematic review of 36 studies
prevalence was 19.3% in studies using diagnostic interview and 33.6% in studies using questionnaires
prevalence ranged from 11% in NYHA class I to 42% in NYHA class IV heart failure
Reference - J Am Coll Cardiol 2006 Oct 17;48(8):1527, commentary can be found in Am Fam Physician 2007 Jun
1;75(11):1711
prospective cohort study of 460 outpatients with heart failure and left ventricular ejection fraction < 30%, 30% had
depression at baseline
at 6 weeks, depressed patients had declines in health status, physical status (6-minute walk distance), social status and
quality of life
Reference - J Am Coll Cardiol 2003 Nov 19;42(10):1811 in QuickScan Reviews in Fam Pract 2004 Dec 6;30(6):20
depression associated with risk of death or cardiovascular hospitalization over 3 years
•
•
•
based on cohort of 204 outpatients with heart failure and ejection fraction 40% or lower who were followed for median 3
years
Beck Depression Inventory score at baseline associated with risk of death or cardiovascular hospitalization (p < 0.001)
Reference - Arch Intern Med 2007 Feb 26;167(4):367
• cognitive impairment associated with congestive
heart failure
• based on case-control study
• 62 patients with congestive heart failure were compared
to 53 controls with cardiovascular disease but not heart
failure (cardiac controls) and 43 healthy controls
• cognitive impairment in
–
–
–
–
25% of patients with congestive heart failure
15% of cardiac controls
4% of healthy controls
differences statistically significant (p = 0.04)
• patients with congestive heart failure had pattern of
general cognitive impairment including impairment in
executive function, memory, language, attention and
mental speed
• Reference - J Am Geriatr Soc 2007 Nov;55(11):1764
•
•
sleep-disordered breathing
sleep apnea associated with congestive heart failure
–
based on study of 81 patients with stable heart failure
•
•
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–
41 (51%) met criteria for sleep apnea
patients with sleep apnea had higher resting PO2 levels, oxygen desaturations during sleep (average
low level 76%), lower average ejection fractions (22% vs. 27%), higher prevalence of atrial fibrillation
(22% vs. 5%) and higher rate of nocturnal ventricular tachycardia (51% vs. 37%)
Reference - Circulation 1998 Jun 2;97:2154 full-text in J Watch 1998 Jul 1;18(13):103
untreated obstructive sleep apnea (OSA) associated with increased mortality in heart
failure
•
•
based on prospective study of 164 heart failure patients with left ventricular ejection fraction 45% or
lower followed for up to 7.3 years (mean 2.9 years)
death rate was
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•
•
8.7 per 100 patient-years in 37 patients with untreated OSA (apnea-hypopnea index at least 15/hour of sleep)
4.2 per 100 patient-years in 113 patients with mild or no OSA (apnea-hypopnea index < 15/hour of sleep)
0 in 14 patients with OSA treated with continuous positive airway pressure (CPAP)
Reference - J Am Coll Cardiol 2007 Apr 17;49(15):1625
review of sleep apnea and congestive heart failure can be found in Minerva Med 2004
Aug;95(4):257
see also Cardiovascular disease and obstructive sleep apnea
nocturnal desaturation common in patients with treated heart failure, low ejection
fraction related to dip frequency (Heart 1998;79:394 full-text in Mayo Clin Proc 1998
Oct;73(10):963)
sleep-disordered breathing occurs in about 60% patients with heart failure
–
–
–
–
manifesting as Cheyne-Stokes respiration in 36%, obstructive sleep apnea in 12% and
combination of central and obstructive abnormal breathing in 12%
studies of prognostic value of nocturnal Cheyne-Stokes respiration have been contradictory
but recent studies suggest poor prognosis
clinical trials of CPAP should be conducted, home pulse oximetry may be cheap screening
test for selection of trial participants
Reference - Lancet 1999 Aug 14;354(9178):531
• bundle branch block on ECG may be a marker of
myocardial progressive degenerative disease and
associated with congestive heart failure, in study of
855 men > 50 years old followed for 30 years 10% (82)
developed bundle branch block (BBB), 36% with BBB vs.
14% controls had congestive heart failure (Circulation
1998;98:2494 full-text in Family Practice Alert 1999
Feb;2(10):74)
•
•
•
risk for any orthopedic fracture, and hip fracture specifically, may be increased in patients
with heart failure
based on 2 cohort studies
cohort study of 31,936 Swedish twins born from 1914 to 1944 and followed up to age 50 years
–
–
hip fracture after age 50 years diagnosed in 1,442 twins
crude absolute rate of hip fractures (per 1,000 person-years)
•
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multivariable-adjusted hazard ratio of hip fracture
•
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•
12.6 after diagnosis of heart failure
12.6 after stroke
6.6 after diagnosis of peripheral atherosclerosis
5.2 after diagnosis of ischemic heart disease
1.2 for patients without cardiovascular disease diagnosis
4.4 (95% CI 3.43-5.63) after diagnosis of heart failure
5.09 (95% CI 4.18-6.2) after stroke
3.2 (95% CI 2.28-4.5) after diagnosis of peripheral atherosclerosis
2.32 (95% CI 1.91-2.84) after ischemic heart disease event
increased risk of hip fracture in identical twins without heart failure or stroke if their co-twins had either
respective disease
Reference - JAMA 2009 Oct 21;302(15):1666, commentary can be found in JAMA 2010 Feb 24;303(8):731
population-based cohort study of 16,294 consecutive patients ≥ 65 years old presenting to
emergency room with cardiovascular disease from 1998 to 2001 evaluated for orthopedic fracture
in first year after emergency room visit
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2,041 patients newly diagnosed with heart failure
14,253 patients had non-heart failure cardiovascular diagnosis
comparing patients with heart failure vs. non-heart failure cardiovascular patients
•
•
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–
orthopedic fracture occurred in 4.6% vs. 1% (p < 0.001)
hip fracture occurred in 1.3% vs. 0.1% (p < 0.001)
heart failure independently associated with increased risk for any orthopedic fracture (adjusted odds ratio 4
[95% CI 2.9-5.3]) and hip fracture (adjusted odds ratio 6.3 [95% CI 3.4-11.8])
Reference - Circulation 2008 Nov 4;118(19):1946
• risk for any orthopedic fracture, and hip fracture specifically,
may be increased in patients with heart failure
• based on 2 cohort studies
• cohort study of 31,936 Swedish twins born from 1914 to 1944 and
followed up to age 50 years
– hip fracture after age 50 years diagnosed in 1,442 twins
– crude absolute rate of hip fractures (per 1,000 person-years)
•
•
•
•
•
12.6 after diagnosis of heart failure
12.6 after stroke
6.6 after diagnosis of peripheral atherosclerosis
5.2 after diagnosis of ischemic heart disease
1.2 for patients without cardiovascular disease diagnosis
– multivariable-adjusted hazard ratio of hip fracture
•
•
•
•
4.4 (95% CI 3.43-5.63) after diagnosis of heart failure
5.09 (95% CI 4.18-6.2) after stroke
3.2 (95% CI 2.28-4.5) after diagnosis of peripheral atherosclerosis
2.32 (95% CI 1.91-2.84) after ischemic heart disease event
– increased risk of hip fracture in identical twins without heart failure or
stroke if their co-twins had either respective disease
– Reference - JAMA 2009 Oct 21;302(15):1666, commentary can be
found in JAMA 2010 Feb 24;303(8):731
• Chief Concern (CC):
• dyspnea, orthopnea, paroxysmal nocturnal dyspnea, nocturia,
edema, lethargy, nocturnal angina, fatigue, decreased exercise
tolerance, congestion
• some medications which may worsen heart failure include
• anti-inflammatory medications - corticosteroids (case series),
NSAIDs (case series)
• cardiovascular medications - class I and III antiarrhythmics
(randomized trials), calcium channel blockers (randomized trials),
minoxidil (randomized trial)
• diabetes medications - metformin (case series), thiazolidinediones
(open-label trial)
• hematologic medications - anagrelide (randomized trial), cilostazol
(randomized trial)
• neuropsychiatric medications - amphetamines (randomized trial),
carbamazepine (anecdotal), clozapine (case series), ergot alkaloids
(case reports), pergolide (case reports), tricyclic antidepressants
(case reports)
• miscellaneous - beta-2 agonists (case series), itraconazole (case
series), licorice (open-label trial)
• Reference - Arch Intern Med 2004 Apr 12;164(7):709, correction can
be found in Arch Intern Med 2004 Jul 12;164(13):1464, commentary
can be found in Arch Intern Med 2005 Jan 10;165(1):118
•
•
•
•
Family History (FH):
parental heart failure associated with increased risk of heart failure in crosssectional study of 1,497 participants in Framingham Offspring Study and
prospective study of 2,214 offspring (N Engl J Med 2006 Jul 13;355(2):138)
Social History (SH):
smoking and/or alcohol use associated with increased risk for multiple
hospital admissions for heart failure
– retrospective case-control study comparing 533 patients with 1 hospital
admission for heart failure to 220 patients with multiple heart failure admissions
over a 2-year period at a veterans hospital
– smoking associated with 2 times risk and alcohol use associated with 5 times risk
for multiple admissions
– Reference - Am J Cardiol 2000 Dec 15;86:1339 in Am Fam Physician 2001 Jun
15;63(12):2449
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•
Review of Systems (ROS):
anorexia (correlates with hepatic congestion and right heart failure)
thorough history should address physical functioning, mental health, sleep
disturbance, sexual function, cognitive function and ability to perform usual
work and social activities, grade B evidence in AHCPR clinical practice
guideline (J Am Geriatr Soc 1998 Apr;46(4):525)
ileus present in 14% of older CHF patients in study of 109 patients (mean
age 74 years) admitted with CHF compared to 3% of 114 controls admitted
with hip fracture (J Am Geriatr Soc 1999 Feb;47(2):258)
• General Physical:
• tachycardia, tachypnea (LHF), Cheynes-Stokes respiration, dyspnea
with rapid shallow breathing, pink frothy sputum
• elderly often present without typical findings (discussion in J Am
Geriatr Soc 1997 Sep;45(9):1128), commentary can be found in J
Am Geriatr Soc 1998 Aug;46(8):1053
• technique to differentiate between cardiac and pulmonary disease in
acute dyspnea
– Valsalva maneuver with BP cuff inflated to 15 mm Hg over SBP (with
auscultation in antecubital fossa)
– normal response is disappearance of Korotkoff sounds during sustained
Valsalva maneuver with reappearance after release
– patients with chronic heart disease have abnormal response with lack of
reappearance of Korotkoff sounds after release of Valsalva maneuver or
maintenance of beats throughout maneuver
– 80-85% sensitive, 86-91% specific
– Reference - Chest 1990;97:772
• increased Valsalva blood pressure response may be an early
warning sign of recurrent CHF after furosemide withdrawal, based
on very small study of older CHF patients (J Am Geriatr Soc 1998
Sep;46(9):S71,P219, J Am Geriatr Soc 1999 Nov;47(11):1384)
•
•
Neck:
jugular venous distension (JVD)
– suggests right heart failure
– jugular venous distension approximates right atrial pressure, add 4 cm to height
above angle of Louis (i.e. junction of manubrium and body of sternum), normal is
0-6 cm
– anecdotal suggestion to use dorsal hand veins to estimate jugular venous
pressure when jugular venous pulses not visible (Cortlandt Forum 1997
Sep;10(9):146,115-37)
– jugular venous distention has 55-65% sensitivity and 74-80% specificity for
increased filling pressure; based on review of 11 studies (JAMA 1997 Jun
4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)
– elevated jugular venous pressure and third heart sound are each
independently associated with adverse outcomes in patients with heart
failure
• retrospective study of 2,479 patients with symptomatic heart failure or history of
symptomatic heart failure enrolled in SOLVD trial which randomized them to enalapril
vs. placebo, mean follow-up 32 months
• 280 (11%) had elevated jugular venous pressure at entry, this group had increased risk
of hospitalization for heart failure (relative risk [RR] 1.32, 95% confidence interval [CI]
1.08-1.62), death or hospitalization for heart failure (RR 1.3, 95% CI 1.11-1.53), and
death from pump failure (RR 1.37, 95% CI 1.07-1.75)
• 597 (24%) had third heart sound at entry, this group had similar increased risks
• Reference - N Engl J Med 2001 Aug 23;345(8):574, editorial can be found in N Engl J
Med 2001 Aug 23;345(8):612, commentary can be found in N Engl J Med 2001 Dec
27;345(26):1912
•
•
•
hepatojugular reflux (RHF)
Chest:
bilateral breast swelling due to congestive heart failure in case report (BMJ
2007 Sep 8;335(7618):520)
• Cardiac:
• palpation of precordial apical impulse
– palpation of precordial apical impulse in left lateral decubitus
position for point of maximal impulse (PMI)
– localized, sustained, outward thrust suggests hypertrophy
– displaced, diffuse heave suggests dilatation
– abnormal apical impulse has 31-36% sensitivity and 89-95%
specificity for ejection fraction < 40%, based on review of 12
studies assessing systolic dysfunction (JAMA 1997 Jun
4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)
• S3 and S4 heart sounds
• S3 ventricular gallop (third heart sound)
– found in left heart failure, most reliable sign in patients > 40, may
also be found in young healthy athletes
– elevated jugular venous pressure and third heart sound are
each independently associated with adverse outcomes in
patients with heart failure
• retrospective study of 2,479 patients with symptomatic heart failure
or history of symptomatic heart failure enrolled in SOLVD trial which
randomized them to enalapril vs. placebo, mean follow-up 32
months
• 280 (11%) had elevated jugular venous pressure at entry, this group
had increased risk of hospitalization for heart failure (relative risk
[RR] 1.32, 95% confidence interval [CI] 1.08-1.62), death or
hospitalization for heart failure (RR 1.3, 95% CI 1.11-1.53), and
death from pump failure (RR 1.37, 95% CI 1.07-1.75)
• 597 (24%) had third heart sound at entry, this group had similar
increased risks
• Reference - N Engl J Med 2001 Aug 23;345(8):574, editorial can be
found in N Engl J Med 2001 Aug 23;345(8):612, commentary can be
found in N Engl J Med 2001 Dec 27;345(26):1912
• S4 atrial gallop (fourth heart sound, may also be caused
by decreased left ventricular compliance with age)
• S2 paradoxical splitting or increased P2 intensity
• murmurs (AS, AR, MR)
• all patients with angina and/or congestive heart failure
with a systolic murmur should be suspected of having
significant aortic stenosis, aortic stenosis can present
without left ventricular hypertrophy on ECG and no
history of syncope, patients will often have atrial
fibrillation (Am J Cardiol 1995 Oct 1;76:728 in QuickScan
Reviews in Fam Pract 1996 Mar;10)
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•
Lungs:
rales (pulmonary edema in LHF)
Abdomen:
ascites (RHF), hepatomegaly (RHF, distended liver from passive
congestion)
ileus present in 14% of older CHF patients in study of 109 patients
(mean age 74) admitted with CHF compared to 3% of 114 controls
admitted with hip fracture (J Am Geriatr Soc 1999 Feb;47(2):258)
Extremities:
edema (RHF, lower extremity and presacral)
Beau's lines - transverse nail ridging or depressions of nail plates
– usually bilateral from temporary cessation of growth during severe
systemic illness
– picture can be found in N Engl J Med 1997 Jul 17;337(3):168 full-text
– picture can be found in BMJ 2002 Aug 31;325(7362):502, dissenting
commentary can be found in BMJ 2003 Jan 11;326(7380):105
• Terry's nails are proximal white nail beds with distal pink transverse
band; associated with cirrhosis, diabetes mellitus type 2, congestive
heart failure and chronic renal failure (Am Fam Physician 2004 Jun
15;69(12):2903 full-text)
• case report of elephantiasis nostras verrucosa can be found in
CMAJ 2008 Sep 23;179(7):673
• Making the diagnosis:
• see acute heart failure for diagnostic considerations in patients
presenting with acute symptoms
• chest x-ray findings of cardiomegaly and pulmonary congestion
• capillary wedge pressure > 20 (normal 12)
• left ventricular systolic dysfunction (LVSD) difficult to diagnose
based on history and physical exam alone
– study of 259 adult British patients with suspected congestive heart
failure referred by general practitioner to assess whether they would be
candidates for treatment with ACE inhibitor
– each patient underwent complete history and physical exam by single
examiner then echocardiography by blinded cardiologist, some patients
were already treated empirically at time of study
– LVSD defined as fractional shortening < 25% or systolic function
"significantly impaired" when quantitative measures unobtainable;
echocardiogram revealed LVSD in 16%
– absence of dyspnea on exertion effectively ruled out LVSD, while
displaced cardiac apical impulse and S3 gallop strongly supported
diagnosis of LVSD; presence of jugular veinous distension, history of
diabetes mellitus and history of myocardial infarction predicted LVSD
– given pretest probability in this study of LVSD of 16%, positive predictive
values were 64% for JVD, 77% for S3 gallop, 75% for displaced cardiac
apical impulse and 89% for combination of prior MI and displaced
cardiac apical impulse
– Reference - QJM 1997 May;90(5):335 in J Fam Pract 1997
Sep;45(3):197, commentary can be found in BMJ 2004 Jul
24;329(7459):209
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history, physical, ECG and chest x-ray all have low predictive value in
differentiating normal from decreased systolic function in patients
with CHF
225 consecutive patients hospitalized with CHF were evaluated, 104 (46%)
had normal left ventricular systolic function defined as ejection fraction (EF)
> 45% and 121 (54%) had EF < 45% on echocardiogram
rales had 89% sensitivity, 20% specificity, 57% positive predictive value and
62% negative predictive value
electrocardiographic left ventricular hypertrophy had 42% sensitivity, 78%
specificity, 69% positive predictive value and 54% negative predictive value
cephalization of blood flow on chest x-ray had 91% sensitivity, 21%
specificity, 13% positive predictive value and 57% negative predictive value
Reference - Am J Med 2002 Apr 15;112(6):437 in QuickScan Reviews in
Fam Pract 2002 Jul;27(6):5
history and physical exam alone has low predictive value for heart
failure
study of 5,434 Portuguese patients attending 365 primary care centers,
echocardiography done in 1,058 patients who met study screening criteria,
551 (10%) had cardiac dysfunction at rest
history findings with high positive likelihood ratios (high specificity for heart
failure) had sensitivity < 36% and included prior use of digoxin, prior use of
diuretics, history of coronary artery disease, history of pulmonary edema,
current paroxysmal nocturnal dyspnea, current orthopnea, and current
breathlessness when walking on the flat
physical exam findings with high positive likelihood ratios had sensitivity <
10% and included jugular pressure > 6 cm with hepatic enlargement, edema
of lower limbs, ventricular gallop, heart rate > 110 bpm, and pulmonary rales
Reference - Eur J Heart Fail 2004 Oct;6(6):795
• possible prediction rule for diagnosing heart failure
in elderly patients with stable COPD
• rule derived in study of 405 patients at least 65 years old
with COPD, chronic bronchitis or emphysema
– 20.5% had heart failure based on expert consensus panel using
clinical findings and echocardiography
– no external validation study
• points for rule
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–
–
–
history of ischemic disease 2 points
body mass index > 30 kg/m2 3 points
laterally displaced apex beat 3 points
heart rate > 90 beats/minute 2 points
NT-proBNP > 14.75 pmol/L (125 pg/mL) 4 points
abnormal ECG (abnormal Q waves, left bundle branch block, left
ventricular hypertrophy, atrial fibrillation, ST and/or T wave
abnormalities, sinus tachycardia) 3 points
• risk interpretation
• very low risk if 0 points; 4 (5%) of 81 patients with 0 points had heart
failure
• low risk if 2-5 points
– 15 (11%) of 142 patients with 2-5 points had heart failure
– risk score 2 or higher had 95% sensitivity, 24% specificity, 24% positive
predictive value and 95% negative predictive value
• medium risk if 6-9 points
– 32 (25%) of 126 patients with 6-9 points had heart failure
– risk score 6 or higher had 77% sensitivity, 63% specificity, 35% positive
predictive value and 91% negative predictive value
• high risk if 10-14 points
– 32 (57%) of 56 patients with 10-14 points had heart failure
– risk score 10 or higher had 39% sensitivity, 93% specificity, 57%
positive predictive value and 85% negative predictive value
• Reference - BMJ 2005 Dec 10;331(7529):1379 full-text
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•
Testing to consider:
American College of Cardiology/American Heart Association (ACC/AHA)
guidelines on heart failure:
Initial assessment in patients presenting with heart failure:
thorough history and physical exam (ACC/AHA Class I, Level of Evidence C)
careful history of current and past use of alcohol, illicit drugs, "alternative therapies"
and chemotherapy drugs (ACC/AHA Class I, Level of Evidence C)
assessment of ability to perform routine and desired activities of daily living
(ACC/AHA Class I, Level of Evidence C)
exam including volume status, orthostatic blood pressure changes, weight, height and
calculation of body mass index (ACC/AHA Class I, Level of Evidence C)
laboratory evaluation (ACC/AHA Class I, Level of Evidence C)
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–
•
complete blood count
electrolytes including calcium and magnesium
blood urea nitrogen
serum creatinine
fasting blood glucose
glycohemoglobin (HbA1c)
lipid profile
liver function tests
thyroid-stimulating hormone (TSH)
urinalysis
measurement of natriuretic peptides (BNP and NT-proBNP) (ACC/AHA Class IIa,
Level of Evidence A)
–
–
–
useful in urgent care setting if clinical diagnosis of heart failure uncertain
useful in risk stratification
see Brain natriuretic peptide (BNP) testing for details
• screening or diagnostic testing for specific conditions in
selected patients (ACC/AHA Class IIa, Level of Evidence
C)
• hemochromatosis
• sleep-disturbed breathing (obstructive sleep apnea
(OSA))
• human immunodeficiency virus (HIV infection)
• rheumatologic diseases
• amyloidosis
• pheochromocytoma
• 12-lead electrocardiogram (ACC/AHA Class I,
Level of Evidence C)
• chest x-ray (posterior to anterior [PA] and lateral)
(ACC/AHA Class I, Level of Evidence C)
• 2-dimensional echocardiography with Doppler
(ACC/AHA Class I, Level of Evidence C)
• to assess left ventricular ejection fraction, left
ventricular size, wall thickness and valve
function
• radionuclide ventriculography can be done to
assess left ventricular ejection fraction and
volumes
•
measurement of left ventricular ejection fraction can be done by
–
–
–
•
echocardiography
equilibrium radionuclide angiocardiography (multiple gated acquisition scanning [MUGA])
ventriculography
consider ECG before echocardiography, may make echocardiography unnecessary
–
–
use of EKG may be reasonable as a screening test to determine if an
echocardiography is indicated; in a study of 534 patients who underwent echo for
suspected left ventricular dysfunction, a normal EKG would reduce the number of echo's
performed by about 50% without missing any of the 96 patients with left ventricular systolic
dysfunction seen on echo (BMJ 1996 Jan 27;312(7025):222 in J Watch 1996 Mar 1;16(5):39)
study suggests that normal ECG reduces likelihood of left ventricular systolic
dysfunction to 2%
•
•
•
•
–
•
2,158 patients > 40 years old were screened, 126 with any past or present signs or symptoms of heart
disease were studied, 15 (12%) had left ventricular systolic dysfunction
Reference - BMJ 2000 Jan 22;320(7229):220, commentary can be found in BMJ 2000 Jul
8;321(7253):111, ACP J Club 2000 Nov-Dec;133(3):114
only 1 of 60 patients with normal ECG had systolic dysfunction (J Watch 2000 Mar 15;20(6):50)
with only 126 patients actually studied, validity for clinical application questionable (DynaMed
commentary)
in series of 300 inpatients referred for echocardiographic assessment of left ventricular
function, 124 (41%) had left ventricular systolic dysfunction (LVSD) defined as ejection
fraction < 45%, only 2 patients with LVSD (1.6%) had a normal electrocardiogram (Am Heart
J 2000 Mar;139(3):394), editorial can be found in Am Heart J 2000 Mar;139(3):388,
commentary can be found in J Fam Pract 2000 Jul;49(7):655
American College of Radiology (ACR) Appropriateness Criteria for suspected cardiac
origin in shortness of breath can be found at National Guideline Clearinghouse 2006
Aug 21:9591, previous version can be found in Radiology 2000 Jun;215 Suppl:23
• Blood tests:
• ABG may show respiratory and metabolic acidosis (but may have
respiratory alkalosis initially) - decreased PaO2, increased PCO2,
decreased pH
• increased uric acid, may be due to increased proximal tubule
resorption as nephron perceives hypovolemic state (Cortlandt
Forum 1996 Jan;9(1):109,95-30)
• brain natriuretic peptide (BNP) levels potentially useful in primary
care for ruling out heart failure
– N-terminal pro-BNP improved diagnostic accuracy in primary care by
ruling out heart failure in 1 randomized trial
– see Brain natriuretic peptide (BNP) testing for details
• chest x-ray (CXR)
• may show pulmonary venous congestion (fluffy perihilar infiltrates in
early stages, Kerley-B lines), cardiomegaly, pleural effusions
• radiographic redistribution has 10-58% sensitivity and 79-100%
specificity for increased filling pressure; based on review of 11
studies (JAMA 1997 Jun 4;277:1712 in Evidence-Based Medicine
1998 Jan/Feb;3(1):22)
• radiographic cardiomegaly or redistribution has 4-33% sensitivity
and 87-100% specificity for ejection fraction < 40%, based on review
of 12 studies assessing systolic dysfunction (JAMA 1997 Jun
4;277:1712 in Evidence-Based Medicine 1998 Jan/Feb;3(1):22)
• cardiothoracic ratio on CXR not useful for estimating left ventricular
ejection fraction in study of 7,476 CHF patients, although weak
negative correlation exists (Arch Intern Med 1998 Mar 9;158(5):501)
•
•
•
•
echocardiogram
especially useful to show mitral valve disease
use of Doppler to evaluate VHD or intracardiac shunts
bedside thoracic ultrasound alone or in combination with Nterminal pro-brain-type natriuretic peptide (NT-ProBNP) may
help differentiate CHF from COPD in dyspneic adults in the
emergency department (level 2 [mid-level] evidence)
– based on prospective convenience sample of 100 adults seeking
emergency department care for shortness of breath
– positive thoracic ultrasound
• positive likelihood ratio 3.88 (p < 0.05)
• negative likelihood ratio 0.5 (p < 0.05)
– NT-ProBNP had
• positive likelihood ratio 2.3 (p < 0.05)
• negative likelihood ratio 0.24 (P < 0.05)
– Reference - Acad Emerg Med 2009 Mar;16(3):201
• review of stress echocardiography in heart failure can be found in
Cardiovascular Ultrasound 2004 Jul 30;2:11
• review of basic transthoracic echocardiography can be found in BMJ
2005 Jun 18;330(7505):1432
• ACC/AHA/ASE 2003 guideline for clinical application of
echocardiography can be found in J Am Coll Cardiol 2003 Sep
3;42(5):954, J Am Soc Echocardiogr 2003 Oct;16(10):1091,
Circulation 2003 Sep 2;108(9):1146
• see Cardiac stress testing for additional information
• review of cardiovascular MRI can be found in CMAJ
2006 Oct 10;175(8):911 full-text
• coronary angiography - cardiac catheterization most
accurate but invasive
• American College of Radiology (ACR) Appropriateness
Criteria for congestive heart failure can be found at
National Guideline Clearinghouse 2006 Sep 4:9604
• EKG:
• almost always abnormal if substantial left ventricular dysfunction;
frequently nonspecific but may detect ischemia, arrhythmia,
infarction or hypertrophy
• anterior Q waves has 32-44% sensitivity and 89% specificity for
ejection fraction < 40%, based on review of 12 studies assessing
systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based
Medicine 1998 Jan/Feb;3(1):22)
• left bundle branch block has 18% sensitivity and 95% specificity for
ejection fraction < 40%, based on review of 12 studies assessing
systolic dysfunction (JAMA 1997 Jun 4;277:1712 in Evidence-Based
Medicine 1998 Jan/Feb;3(1):22)
• American College of Cardiology/American Heart Association
guidelines for ambulatory ECG can be found in Circulation 1999 Aug
24;100(8):886 full-text or J Am Coll Cardiol 1999 Sep;34(3):912
(summarized in Am Fam Physician 2000 Feb 1;61(3):884)
• T wave alternans on ECG may be predictive of future arrhythmic
events, based on study of 107 CHF patients (Lancet 2000 Aug
19;356(9230):651)
Prognosis of CHF
• 7-item risk score may predict mortality in elderly patients
• based on prospective cohort of 282 elderly (mean age 79 years)
with heart failure followed for up to 14 years
• 269 patients (95%) died with median survival 894 days
• risk score based on 1 point each for
–
–
–
–
–
–
–
age > 75 years
sodium < 135 mEq/L
coronary artery disease
dementia
peripheral vascular disease
systolic blood pressure < 120 mm Hg
serum urea nitrogen 30 mg/dL or higher
• all-cause mortality stratified by risk score
– 0-1 point (89 patients) - mortality 8% at 6 months, 9% at 1 year, 57% at
5 years
– 2-3 points (153 patients) - mortality 10% at 6 months, 22% at 1 year,
79% at 5 years
– 4-7 points (137 patients) - mortality 59.5% at 6 months, 73% at 1 year,
100% at 5 years
• Reference - Arch Intern Med 2006 Sep 25;166(17):1892
• 7-item risk score may predict mortality in elderly patients
• based on prospective cohort of 282 elderly (mean age 79 years)
with heart failure followed for up to 14 years
• 269 patients (95%) died with median survival 894 days
• risk score based on 1 point each for
–
–
–
–
–
–
–
age > 75 years
sodium < 135 mEq/L
coronary artery disease
dementia
peripheral vascular disease
systolic blood pressure < 120 mm Hg
serum urea nitrogen 30 mg/dL or higher
• all-cause mortality stratified by risk score
– 0-1 point (89 patients) - mortality 8% at 6 months, 9% at 1 year, 57% at
5 years
– 2-3 points (153 patients) - mortality 10% at 6 months, 22% at 1 year,
79% at 5 years
– 4-7 points (137 patients) - mortality 59.5% at 6 months, 73% at 1 year,
100% at 5 years
• Reference - Arch Intern Med 2006 Sep 25;166(17):1892
• asymptomatic left ventricular dysfunction with ejection fraction <
35% had 30% 3-year risk of symptomatic heart failure in Studies of
Left Ventricular Dysfunction (SOLVD) Prevention Trial (N Engl J Med
1992 Sep 3;327(10):685, correction in N Engl J Med 1992 Dec
10;327(24):1768)
• risk factors for exacerbation of heart failure
• based on prospective study of 768 patients with ejection fraction <
40% participating in 2 randomized trials over 43 weeks
• noncompliance with salt restriction (22% episodes)
• other noncardiac causes (20%, especially pulmonary infectious
processes)
• use of antiarrhythmic agents in prior 48 hours (15%)
• arrhythmias (13%)
• calcium channel blockers (13%)
• inappropriate reductions in heart failure therapy (10%)
• Reference - Arch Intern Med 2001 Oct 22;161(19):2337
Treatment of CHF
• American College of Cardiology and American Heart Association
(ACC/AHA) guidelines on heart failure in adults
• recommendations for patients with symptomatic heart failure (Stage
C) and reduced left ventricular ejection fraction
– follow all Class I recommendations for Stage A and Stage B (patients at
risk but without symptomatic heart failure)
• treat risk factors in accordance with contemporary guidelines
– control systolic and diastolic hypertension (ACC/AHA Class I, Level of Evidence
A)
– treat lipid disorders (ACC/AHA Class I, Level of Evidence A)
– control blood sugar in patients with diabetes (ACC/AHA Class I, Level of Evidence
C)
– provide secondary prevention measures for patients with known atherosclerotic
vascular disease (ACC/AHA Class I, Level of Evidence C)
• counsel patients to avoid behaviors that may increase risk of heart failure
(such as smoking, excessive alcohol consumption and illicit drug use)
(ACC/AHA Class I, Level of Evidence C)
• control ventricular rate or restore sinus rhythm in patients with
supraventricular tachyarrhythmias (ACC/AHA Class I, Level of Evidence B)
• treat thyroid disorders in accordance with contemporary guidelines
(ACC/AHA Class I, Level of Evidence C)
• evaluate periodically for signs and symptoms of heart failure (ACC/AHA
Class I, Level of Evidence C)
•
•
medications
diuretics and salt restriction indicated in patients who have evidence of fluid
retention (ACC/AHA Class I, Level of Evidence C)
– furosemide (Lasix) 20-40 mg once or twice daily initially, maximum 600 mg/day
– bumetanide (Bumex) 0.5-1 mg once or twice daily initially, maximum 10 mg/day
– torsemide (Demadex) 10-20 mg/day initially, maximum 200 mg/day
•
ACE inhibitors recommended for all patients unless contraindicated
(ACC/AHA Class I, Level of Evidence A)
– captopril (Capoten) 6.25 mg three times daily initially, maximum 50 mg three
times daily
– enalapril (Vasotec) 2.5 mg twice daily initially, maximum 10-20 mg twice daily
– fosinopril (Monopril) 5-10 mg/day initially, maximum 40 mg/day
– lisinopril (Prinivil, Zestril) 2.5-5 mg/day initially, maximum 20-40 mg/day
– perindopril (Aceon) 2 mg/day initially, maximum 8-16 mg/day
– quinapril (Accupril) 5 mg twice daily initially, maximum 20 mg twice daily
– ramipril (Altace) 1.25-2.5 mg/day initially, maximum 10 mg/day
– trandolapril (Mavik) 1 mg/day initially, maximum 4 mg/day
•
beta blockers proven to reduce mortality (bisoprolol, carvedilol or sustained
release metoprolol succinate) recommended for all stable patients unless
contraindicated (ACC/AHA Class I, Level of Evidence A)
– start at very low doses and increase gradually as tolerated
– bisoprolol (Zebeta) 1.25 mg/day initially, maximum 10 mg/day
– carvedilol (Coreg) 3.125 mg twice daily initially, maximum 25 mg twice daily
(maximum 50 mg twice daily if > 85 kg)
– metoprolol extended release (Toprol XL) 12.5-25 mg/day initially, maximum 200
mg/day
• angiotensin II receptor blockers (ARBs)
• recommended in patients who are ACE inhibitorintolerant (ACC/AHA Class I, Level of Evidence A)
• ARBs are reasonable to use as alternatives to ACE
inhibitors as first-line therapy for patients with mild to
moderate heart failure, especially for patients taking
ARBs for other indications (ACC/AHA Class IIa, Level of
Evidence A)
• addition of ARB may be considered in persistently
symptomatic patients on conventional therapy
(ACC/AHA Class IIb, Level of Evidence B)
• specific ARBs may include
– candesartan (Atacand) 4-8 mg/day initially, maximum 32 mg/day
– losartan (Cozaar) 25-50 mg/day initially, maximum 50-100
mg/day
– valsartan (Diovan) 20-40 mg twice daily initially, maximum 160
mg twice daily
•
•
•
•
•
addition of aldosterone antagonist recommended in selected patients with
moderately severe to severe symptoms of heart failure who can be carefully
monitored for preserved renal function and normal potassium concentration
(ACC/AHA Class I, Level of Evidence B)
maintain creatinine ≤ 2.5 mg/dL (221 mcmol/L) in men and ≤ 2 mg/dL (176.8
mcmol/L) in women
maintain potassium < 5 mEq/L (5 mmol/L)
risks may outweigh benefits in patients where monitoring for hyperkalemia
or renal dysfunction is not feasible
risk for hyperkalemia increased with
– risk increases progressively when serum creatinine > 1.6 mg/dL (141.4
mcmol/L), or creatinine clearance < 30 mL/minute
– concomitant use of higher doses of ACE inhibitors (captopril 75 mg/day, enalapril
or lisinopril 10 mg/day or higher doses)
– nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors
– potassium supplements
•
•
•
initial dose of spironolactone 12.5 mg or eplerenone 25 mg recommended,
dose may then increase to spironolactone 25 mg or eplerenone 50 mg if
appropriate
closely monitor serum potassium, check at 3 days and 1 week after initiation
of therapy and at least monthly for first 3 months
emergently address diarrhea or other causes of dehydration
• combination of hydralazine plus nitrates
• recommended for patients self-described as AfricanAmericans with moderate-severe symptoms on optimal
therapy with ACE inhibitors, beta blockers and diuretics
(ACC/AHA Class I, Level of Evidence B)
• reasonable addition for patients with persistent
symptoms despite taking an ACE inhibitor and betablocker (ACC/AHA Class IIa, Level of Evidence B)
• might be reasonable for patients who cannot take ACE
inhibitor or ARB because of drug intolerance,
hypotension or renal failure (ACC/AHA Class IIb, Level
of Evidence C)
• digitalis can be beneficial to decrease hospitalizations for
heart failure (ACC/AHA Class IIa, Level of Evidence B)
• avoid or withdraw drugs known to adversely affect
clinical status whenever possible (e.g. NSAIDs, most
antiarrhythmic drugs, most calcium channel blocking
drugs) (ACC/AHA Class I, Level of Evidence B)
• implantable cardioverter-defibrillator recommended
• as secondary prevention to prolong survival in patients with history
of cardiac arrest, ventricular fibrillation or hemodynamically
destabilizing ventricular tachycardia (ACC/AHA Class I, Level of
Evidence A)
• as primary prevention of sudden cardiac death to reduce mortality in
patients with nonischemic dilated cardiomyopathy or ischemic heart
disease at least 40 days post-myocardial infarction, left ventricular
ejection function ≤ 35%, New York Heart Association (NYHA)
functional Class II or III symptoms while undergoing chronic optimal
medical therapy and reasonable expectation of survival with good
functional status for > 1 year (ACC/AHA Class I, Level of Evidence
A)
•
•
•
•
cardiac resynchronization therapy (biventricular pacing or atriobiventricular
pacing)
recommended (with or without implantable cardioverter-defibrillator) (unless
contraindicated) for patients with left ventricular ejection fraction ≤ 35%,
sinus rhythm and NYHA functional Class III or ambulatory Class IV
symptoms despite recommended optimal medical therapy and who have
cardiac dyssynchrony (currently defined as QRS duration > 120
milliseconds) (ACC/AHA Class I, Level of Evidence A)
reasonable (with or without implantable cardioverter-defibrillator) for patients
with left ventricular ejection fraction ≤ 35%, QRS duration 0.12 seconds,
atrial fibrillation, and NYHA functional Class III or ambulatory class IV
symptoms despite recommended optimal medical therapy (ACC/AHA Class
IIa, Level of Evidence B)
reasonable for patients with left ventricular ejection fraction ≤ 35% and
NYHA functional Class III or ambulatory Class IV symptoms despite
recommended optimal medical therapy and who have frequent dependence
on ventricular pacing (ACC/AHA Class IIa, Level of Evidence C)
• reasonable to treat patients with atrial fibrillation with strategy to
maintain sinus rhythm or with strategy to control ventricular rate
alone (ACC/AHA Class IIa, Level of Evidence A)
• treatments NOT recommended
• routine combined use of ACE inhibitor, ARB and aldosterone
antagonist (ACC/AHA Class III, Level of Evidence C)
• calcium channel blockers as routine treatment (ACC/AHA Class III,
Level of Evidence A)
• long-term use of infusion of positive inotropic drug, except as
palliation for patients with end-stage disease who cannot be
stabilized with standard medical treatment (ACC/AHA Class III,
Level of Evidence C)
• use of nutritional supplements (ACC/AHA Class III, Level of
Evidence C)
• hormonal therapies other than to replete deficiencies (ACC/AHA
Class III, Level of Evidence C)
•
•
•
•
meticulous identification and control of fluid retention (ACC/AHA Class I,
Level of Evidence B)
referral to heart failure program with expertise in management of refractory
heart failure (ACC/AHA Class I, Level of Evidence A)
referral for cardiac transplantation in potentially eligible patients (ACC/AHA
Class I, Level of Evidence B)
absolute indications for cardiac transplantation in appropriate patients
– hemodynamic compromise due to heart failure
• refractory cardiogenic shock
• documented dependence on intravenous inotropic support
• peak oxygen consumption (VO2) < 10 mL/kg/minute with achievement of anaerobic
metabolism
– severe symptoms of ischemia that consistently limit routine activity and are not
amenable to revascularization
– recurrent symptomatic ventricular arrhythmias refractory to all therapeutic
modalities
•
relative indications
– peak VO2 11-14 mL/kg/minute (or 55% predicted) and major limitation of
patient's daily activities
– recurrent unstable ischemia not amenable to other intervention
– recurrent instability of fluid balance or renal function not due to patient
noncompliance
•
•
•
•
•
•
•
•
•
•
•
•
•
discuss options for end-of-life care with patient and family when severe
symptoms persist despite all recommended therapies (ACC/AHA Class I,
Level of Evidence C)
provide information about option to inactivate defibrillation in patients with
implantable defibrillators (ACC/AHA Class I, Level of Evidence C)
consider left ventricular assist device as permanent or "destination" therapy
for end-stage heart failure patients who (ACC/AHA Class IIa, Level of
Evidence B)
are not candidates for transplantation
do not respond to standard therapy
have predicted 1-year survival < 50%
considerations with insufficient evidence for guidance (ACC/AHA Class IIb,
Level of Evidence C)
pulmonary artery catheter placement to guide therapy in patients with
persistently severe symptoms
mitral valve repair or replacement for severe secondary mitral regurgitation
continuous intravenous infusion of positive inotropic agent for palliation of
symptoms
treatments NOT recommended
partial left ventriculectomy in patients with non-ischemic cardiomyopathy
(ACC/AHA Class III, Level of Evidence C)
routine intermittent infusions of vasoactive and positive inotropic agents
(ACC/AHA Class III, Level of Evidence A)
• Diet:
• Fluid restriction:
• fluid restriction not advisable unless hyponatremia present, grade C
evidence (i.e. expert opinion with no evidence) in AHCPR clinical
practice guideline (J Am Geriatr Soc 1998 Apr;46(4):525)
• Sodium restriction:
• normal sodium diet with high diuretic doses and fluid intake
restriction associated with reduced readmission rate for
patients with compensated heart failure (level 2 [mid-level]
evidence)
– based on randomized trial without blinding
– 410 patients aged 53-86 years with NYHA class II-IV (compensated)
heart failure randomized to 8 different levels of fluid/sodium intake and
diuretic doses; followed for 180 days
– patients taking 1,000 mL fluid per day, 120 mmol sodium per day,
furosemide 250 mg twice daily had 7.69% readmission rate compared
to other groups with readmission rate range 29.4% to 78.4% (p < 0.001)
– Reference - Am J Cardiol 2009 Jan 1;103(1):93
• Alcohol:
• reduction of alcohol intake to < 60 g daily may be associated
with significant improvement in ejection fraction in men with
alcoholic cardiomyopathy (level 3 [lacking direct] evidence)
– based on prospective cohort study without clinical outcomes
– 55 men with history of alcohol consumption > 100 g daily for at least 10
years and known alcoholic cardiomyopathy followed prospectively for 4
years
– mean improvements of ejection fractions after 1 year of observation
• complete abstinence 0.131 (95% CI 0.069-0.193)
• < 60 g ethanol daily 0.125 (95% CI 0.082-0.168)
– most patients who consumed > 80 g of ethanol/day had significant
decrease in ejection fraction
– trend of improvement continued after 4 years of observation for subjects
who abstained or had moderate alcohol consumption; all patients with
continued heavy alcohol consumption were dead by the end of the fouryear observation period
– Reference - Ann Intern Med 2002 Feb 5;136(3):192 PDF
• Nutrition:
• heart failure patients may need to increase protein intake
– prospective study of 57 nonobese heart failure patients and 49 age- and
BMI-matched sedentary controls using 7-day food diaries, urine and
blood samples, and calorimetry
– 31 (54%) heart failure patients had malnutrition, 22 with protein
malnutrition and 9 with combined protein-calorie malnutrition
– heart failure patients had more nutritional deficits than controls despite
similar calorie intake, nitrogen intake and total energy expenditure
– heart failure patients on average had negative calorie balance and
negative nitrogen balance, while controls had positive calorie balance
and positive nitrogen balance
– Reference - J Am Coll Cardiol 2003 Oct 1;42(7):1218 in J Watch Online
2003 Nov 14
• see also nutritional supplements (below)
• Activity:
• exercise training safe in patients with heart failure
(level 1 [likely reliable] evidence)
– systematic review of 81 controlled comparisons of exercise
training vs. no exercise training in patients with ejection fraction
< 40%
– no exercise-related death reported with > 60,000 hours of
exercise training in 2,387 patients
– 30 parallel-group randomized trials included 1,197 patients,
follow-up ranged from 4 weeks to 192 weeks, no significant
differences in adverse events or all-cause mortality, nonsignificant trend (p = 0.06) toward reduction in all-cause mortality
with exercise
– exercise training increased maximum oxygen uptake by 17% in
57 trials
•
•
•
•
•
•
•
•
•
•
•
•
Medications:
Angiotensin-converting enzyme (ACE) inhibitors:
indicated for all patients with reduced left ventricular ejection fraction
regardless of symptomatic state, unless ACE inhibitors contraindicated or
not tolerated (grade A recommendation [consistent high-quality evidence])
ACE inhibitors can improve symptoms, exercise tolerance and enhance
functional status, usually takes 4-12 weeks; early circulatory instability does
not preclude long-term benefit
contraindicated with hyperkalemia, hypotension, elevated creatinine, severe
aortic stenosis
start at low doses and increase gradually
ACE inhibitors lower rates of mortality, myocardial infarction, and hospital
admission for heart failure in patients with left ventricular dysfunction or
heart failure (level 1 [likely reliable] evidence)
ACE inhibitors may be ineffective in black patients and in patients with
creatinine > 2 mg/dL (176.8 mol/L) (level 2 [mid-level] evidence)
side effects include hypotension, azotemia, hyperkalemia, cough, and
angioneurotic edema
severe hyperkalemia can occur with concomitant spironolactone
different ACE inhibitors appear to have similar rates of mortality and hospital
admission for heart failure (level 2 [mid-level] evidence)
see ACE inhibitors for heart failure for details
•
•
•
•
•
Angiotensin receptor blockers (ARB):
angiotensin II receptor blockers (ARBs) also called angiotensin II inhibitors
established role of ARBs is substitution of ACE inhibitor for patients intolerant of ACE
inhibitors, for example, cough or angioneurotic edema
ARBs reduce mortality and heart failure hospitalization compared with placebo, no
differences compared with ACE inhibitors (level 1 [likely reliable] evidence)
addition of ARBs to ACE inhibitors
–
–
•
•
•
reduces heart failure hospitalization but not mortality (level 1 [likely reliable] evidence)
increases rate of medication discontinuation due to adverse effects, symptomatic
hypotension and worsening renal function compared to ACE inhibitor alone (level 1 [likely
reliable] evidence)
SEVERE HYPERKALEMIA can occur when spironolactone given with ACE inhibitors
or angiotensin receptor blockers for heart failure
see Angiotensin II inhibitors for heart failure for details
combination of ACE inhibitor and angiotensin receptor blocker reduces
hospitalization rate but not mortality compared to ACE inhibitor alone
–
–
–
–
based on MEDLINE search for randomized trials and meta-analyses
addition of ARB to ACEI did not affect mortality in meta-analysis of 6 trials with nearly 6,000
patients or more recent trial with 2,548 patients, addition of ARB to ACEI in these studies
reduced hospitalization rates (NNT 21 over 2 years)
limited number of studies evaluated symptoms, exercise capacity, functional capacity or
quality of life with larger trials finding no benefit
Reference - Am Fam Physician 2003 Nov 1;68(9):1795, commentary can be found in Am
Fam Physician 2004 Jul 15;70(2):261
• Beta blockers:
• useful in class II, III and IV congestive heart failure (CHF)
• beta blockers proven effective for heart failure include
– bisoprolol, a beta-1 selective blocker
– carvedilol, a nonselective beta-blocker and alpha-1 blocker
– sustained-release metoprolol, a beta-1 selective blocker
• choice of beta blocker not clear
– only carvedilol and sustained-release metoprolol FDA approved for CHF
– carvedilol improved survival compared to immediate-release metoprolol
in large randomized trial
– 4 small randomized trials have compared carvedilol vs. metoprolol, 2
found no difference, 2 found differences in ejection fraction or left
ventricular size favoring carvedilol
• adverse effects include worsening of heart failure, symptomatic
hypotension, bradycardia, heart block
• use not advised in patients with asthma or severe bradycardia
• starting with low doses and titrating dose based on tolerance can
reduce risk of side effects
• addition of carvedilol to digoxin may reduce symptoms in
patients with heart failure and atrial fibrillation (level 2 [midlevel] evidence)
• 47 patients with heart failure and persistent atrial fibrillation for at
least 1 month and were taking digoxin were randomized to add
carvedilol vs.placebo for 4 months
• carvedilol improved symptom control and left ventricular ejection
fraction and reduced heart rate
• Reference - J Am Coll Cardiol 2003 Dec 3;42(11):1944 in Am Fam
Physician 2004 Jul 15;70(2):386
•
•
Timing of starting beta blocker and ACE inhibitor:
starting beta blocker before ACE inhibitor and starting ACE inhibitor
before beta blocker may have similar outcomes (level 2 [mid-level]
evidence)
– 1,010 patients with mild to moderate CHF and ejection fraction 35% or lower
were randomized to open-label monotherapy with bisoprolol (target dose 10 mg
once daily) vs. enalapril (target dose 10 mg twice daily) for 6 months then
combined therapy for 6-24 months
– no significant difference sin all-cause mortality or hospitalization
– study underpowered to definitively demonstrate lack of clinically significant
differences
– Reference - Circulation 2005 Oct 18;112(16):2426
•
starting carvedilol before perindopril may improve symptoms (level 2
[mid-level] evidence)
– 78 patients with New York Heart Association (NYHA) functional class II or III
heart failure were randomized to open-label carvedilol vs. perindopril for 6
months then combination therapy, study drugs titrated to maximum tolerable
doses
– comparing carvedilol-first vs. perindopril-first groups at 12 months, carvedilol-first
associated with
•
•
•
•
higher tolerable dose of carvedilol achieved (43 mg vs. 33 mg, p = 0.03)
lower furosemide dose (p < 0.05)
better improvements in NYHA functional class (p < 0.002)
better improvements in ejection fraction (15% vs. 6%, p < 0.05)
– Reference - J Am Coll Cardiol 2004 Nov 2;44(9):1825
•
•
Diuretics:
for heart failure
–
–
–
–
diuretics recommended for patients with current or recent history of fluid overload, but not in
patients without fluid overload
strong evidence that diuretics relieve symptoms, reduce episodes of decompensation and improve
exercise capacity (level 1 [likely reliable] evidence)
weak evidence that diuretics reduce mortality and worsening heart failure compared to placebo
(level 2 [mid-level] evidence)
typical doses for recommended loop diuretics
•
•
•
–
•
–
•
addition of spironolactone to ACE inhibitor and loop diuretic shown to reduce mortality in patients
with severe heart failure
monitor electrolytes, BUN and creatinine
–
–
•
furosemide (Lasix) 20-40 mg once or twice daily initially, maximum 600 mg/day
bumetanide (Bumex) 0.5-1 mg once or twice daily initially, maximum 10 mg/day
torsemide (Demadex) 10-20 mg/day initially, maximum 200 mg/day
hypokalemia may require potassium supplements or potassium-sparing diuretics
hyperkalemia may occur with potassium-sparing diuretics, especially with concomitant ACE
inhibitors
excessive diuresis, particularly before or with ACE inhibitors, can potentiate hypotension or renal
insufficiency
loop diuretics (and possibly metolazone and indapamide) more effective than thiazides if
renal insufficiency
potassium-sparing diuretics include amiloride (Midamor) and triamterene (Dyrenium)
–
–
–
–
–
potassium-sparing diuretics which also have aldosterone antagonist activity include spironolactone
and eplerenone
used as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents to prevent
hypokalemia
rarely used alone due to weak diuretic and antihypertensive effects
contraindicated if anuria, acute or chronic renal insufficiency, or diabetic nephropathy
risk for hyperkalemia, especially with renal impairment or use of ACE inhibitors, angiotensin II
receptor antagonist, cyclosporine, or tacrolimus
•
•
•
•
•
•
Aldosterone antagonists:
Spironolactone:
aldosterone antagonist, potassium-sparing diuretic
available in generic or brand name Aldactone
addition of aldosterone antagonist recommended in selected patients with moderately
severe to severe symptoms of heart failure who can be carefully monitored for
preserved renal function and normal potassium concentration (grade B
recommendation [inconsistent or limited evidence])
addition of spironolactone to ACE inhibitor and loop diuretic shown to reduce mortality
in patients with severe heart failure based on Randomized Aldactone Evaluation
Study (RALES)
–
–
–
•
•
•
•
•
•
initial dose 25 mg orally once daily
increased to 50 mg/day after 8 weeks if progression of heart failure without hyperkalemia or
renal insufficiency
decreased to 25 mg every other day if hyperkalemia developed
US FDA Pregnancy Category C
contraindicated with hyperkalemia (potassium > 5.5 mEq/L [5.5 mmol/L]) or renal
impairment (creatinine > 2.5 mg/dL [221 µmol/L])
SEVERE HYPERKALEMIA can occur when spironolactone given with ACE inhibitors
or angiotensin receptor blockers for heart failure
avoid concomitant potassium-sparing diuretics, potassium supplements and lithium
gynecomastia occurred in 10% of men in RALES study
see Spironolactone for heart failure for details
•
•
•
•
•
Digoxin:
digoxin (Lanoxin) is inotropic but also vagotonic
limited value with mild heart failure and normal sinus rhythm
no increased survival if asymptomatic heart failure
beneficial if atrial fibrillation, severe heart failure, ejection fraction (EF) < 20%
–
–
–
•
•
can be added to diuretics and ACE inhibitors
digoxin loading dose 0.5 mg intravenously or orally then 0.25 mg every 4-6 hours for
4 doses then 0.125-0.25 mg orally once daily
–
–
–
–
–
•
•
dramatic effectiveness in symptomatic heart failure
withdrawal studies (digoxin replaced with placebo) have shown increased progression of
heart failure; PROVED and RADIANCE trials with and without ACE inhibitors ( J Am Coll
Cardiol 1993;22:955, N Engl J Med 1993;329:1, discussion in Cortlandt Forum 1996
Sep;9(9):69, 103-8)
can decrease symptoms, increase exercise tolerance and decrease hospitalization frequency
optimal dose unclear
most studies used 0.25-0.5 mg/day, but many physicians prescribe 0.125-0.25 mg/day as
initial and target dose
reduce dose in elderly and renal failure patients
monitor level (therapeutic 0.5-0.9 ng/mL); higher levels may increase mortality
digoxin toxicity more likely with quinidine, verapamil, hypokalemia, hypomagnesemia
adverse effects - conduction disturbances, cardiac arrhythmias, nausea, vomiting,
confusion, visual disturbances; risk of digitalis toxicity increased with hypokalemia or
renal insufficiency
Reference - Treatment Guidelines from The Medical Letter 2006 Jan;4(41):91
• Antiplatelet therapy/anticoagulants:
• role of aspirin for heart failure has not been established
– aspirin may increase hospitalization rates in patients with heart failure
(level 2 [mid-level] evidence)
– aspirin may increase heart failure hospitalization and non-fatal stroke
compared to warfarin in patients with heart failure (level 2 [mid-level]
evidence)
– aspirin may reduce efficacy of ACE inhibitors (based on surrogate
markers) in patients with heart failure (level 3 [lacking direct] evidence)
– see Aspirin use in patients with heart failure for details
• role of warfarin for heart failure has not been established
– warfarin decreases heart failure hospitalization and non-fatal
stroke compared to aspirin in patients with heart failure (level 1
[likely reliable] evidence)
•
•
•
Hydralazine plus isosorbide dinitrate (BiDil):
BiDil (hydralazine plus isosorbide dinitrate) FDA approved for heart failure in
self-identified black patients; hydralazine is an antihypertensive which
causes arterial vasodilation and reduced cardiac workload, isosorbide
dinitrate is an anti-anginal with venous and arterial vasodilation; neither
hydralazine alone nor isosorbide dinitrate alone is FDA approved for heart
failure (FDA Press Release 2005 Jun 23)
recommendations from The Medical Letter
– recommended for patients with persistent symptoms despite taking an ACE
inhibitor and a beta-blocker; consider in patients intolerant of an ACE inhibitor or
ARB
– no data available for use in addition to standard therapy in populations other than
black patients
– improves left ventricular ejection fraction
– dosing
• initial isosorbide dinitrate/hydralazine 20 mg/37.5 mg 3 times daily
• target dose isosorbide dinitrate/hydralazine 40 mg/75 mg 3 times daily
– avoid BiDil with concurrent phosphodiesterase inhibitors - sildenafil (Viagra,
Revatio), vardenafil (Levitra), or tadalafil (Cialis) because of risk of additive
hypotension
– adverse effects of BiDil include frequent headache and dizziness
– hydralazine alone can cause tachycardia, peripheral neuritis, and a lupus-like
syndrome
– Reference - Treatment Guidelines from The Medical Letter 2006 Jan;4(41):91
• Nitrates (nitroglycerin):
• transdermal nitroglycerin improves exercise
tolerance in some patients but no differences shown
in patient-oriented outcomes
– 29 patients with CHF and symptoms despite ACE inhibitor
therapy randomized to nitroglycerin 50-100 mg/day vs. placebo
as transdermal patches daily for 12 hours for 12 weeks in
crossover fashion with 4-week washout period, exercise
treadmill testing done every 4 weeks
– increase in exercise tolerance (by 38-117 seconds) occurred
with nitroglycerin but not with placebo
– most common adverse effects were headache and patch site
irritation, 23% nitroglycerin vs. 11% placebo discontinuation
rates, no differences in quality of life or need for additional
diuretics or hospitalizations for CHF
– Reference - Circulation 1999 May 25;99(20):2652 full-text
• Statins:
– atorvastatin may decrease all-cause mortality and hospitalization
for worsening heart failure (level 2 [mid-level] evidence), but these
benefits not found with simvastatin (level 2 [mid-level] evidence) or
rosuvastatin (level 1 [likely reliable] evidence)
• based on systematic review of trials with methodologic limitations
• systematic review of 10 randomized trials comparing statins to placebo in
10,192 patients with heart failure
• 3 trials of rosuvastatin, 1 trial of simvastatin, and 6 trials of atorvastatin
• trials had varied follow-up (3-47 months) and possible publication bias
• all individual trials had methodologic limitations affecting blinding, allocation
concealment, or sample size except one large rosuvastatin trial
• heterogeneity in overall analysis so meta-analysis combining statins not
appropriate
• in meta-analyses of atorvastatin
– significantly decreased all-cause mortality (odds ratio 0.39, p = 0.004) in analysis
of 6 trials with 471 patients
– significantly decreased hospitalization for worsening heart failure (odds ratio 0.3, p
< 0.00001) in analysis of 6 trials with 472 patients
– increase in left ventricular ejection fraction (weighted mean difference +5.49%, p <
0.0001) in analysis of 4 trials
• in meta-analyses of rosuvastatin
– no significant effect on all-cause mortality in analysis of 3 trials with 9,670 patients
– no significant effect on hospitalization for worsening heart failure in analysis of 3
trials with 9,670 patients
– decrease in left ventricular ejection fraction (mean difference -3.07%, p = 0.002) in
1 trial
• simvastatin trial had only 51 patients
• Reference - Am J Cardiol 2009 Dec 15;104(12):1708
• Dobutamine:
• long-term intermittent dobutamine infusion may improve
survival in refractory CHF (level 2 [mid-level] evidence)
– 30 patients with end-stage CHF refractory to standard medical therapy
who could be weaned from dobutamine after initial 72-hour infusion
were randomized to dobutamine 10 mcg/kg/minute vs. placebo IV for 8
hours every 14 days
– all patients received standard medical therapy and oral amiodarone 400
mg/day (800 mg/day if implanted defibrillator) starting at least 2 weeks
before randomization
– comparing dobutamine vs. placebo, 1-year survival 69% vs. 28% (NNT
3), 2-year survival 44% vs. 21% (NNT 5), median survival 574 vs. 144
days
– Reference - Chest 2004 Apr;125(4):1198 in Am Fam Physician 2004
Aug 15;70(4):756
• Medical therapy in patient subgroups:
• among the oldest old, ACE inhibitors appear beneficial while
digoxin may not be; retrospective study of 19,492 nursing home
residents > 85 years old with CHF taking ACE inhibitor or digoxin,
patients taking ACE inhibitor had lower mortality and lower rates of
functional decline than patients taking digoxin (Arch Intern Med 2000
Jan 10;160(1):53); comparison with entire group of 64,637 nursing
home residents > 85 years old with CHF would make data more
convincing (DynaMed commentary), commentary can be found in
Arch Intern Med 2000 Sep 11;160(16):2550
• limited evidence regarding treatment for heart failure patients
with renal failure
– ACE inhibitors reduce mortality if moderate renal insufficiency
(glomerular filtration rate 30-60 mL/minute/1.73 m2) but little evidence
for more severe renal failure
– beta blockers unlikely affected by renal function
– spironolactone associated with increased risk of hyperkalemia if renal
failure
– Reference - Ann Intern Med 2003 Jun 3;138(11):917 PDF, commentary
can be found in Ann Intern Med 2004 Apr 6;140(7):584, Ann Intern Med
2004 Jun 1;140(11):931
•
•
•
Iron/erythropoietin:
Iron:
intravenous iron (ferric carboxymaltose) improves quality of life and
functional status in patients with heart failure and iron deficiency even
if no anemia present (level 1 [likely reliable] evidence)
– based on randomized trial
– 459 patients with heart failure of NYHA functional class II-III, iron deficiency
(ferritin level < 100 mcg/L, or 100-299 mcg/L if transferrin saturation < 20%) and
hemoglobin level 9.5-13.5 g/dL were randomized to IV ferric carboxymaltose 4
mL (elemental iron 200 mg) vs. saline
– dosing was weekly until iron repletion achieved and then once every 4 weeks
(beginning at week 8-12)
– patients had left ventricular ejection fraction ≤ 40% (for patients with NYHA class
II) or ≤ 45% (for NYHA class III) at baseline
– withdrawal before 24-week follow-up in 6.9% with iron and 10.3% with placebo
– comparing iron vs. placebo
• self-reported "much or moderately improved" on Patient Global Assessment in 50% vs.
28% (p < 0.001, NNT 5)
• NYHA functional class I or II in 47% vs. 30% (p < 0.001, NNT 6)
– iron associated with improvements in 6-minute walk test and quality-of-life (p <
0.001)
– no significant differences in death, adverse events, or serious adverse events
– similar findings in subgroups of patients with or without anemia
– Reference - FAIR-HR trial (N Engl J Med 2009 Dec 17;361(25):2436), editorial
can be found in N Engl J Med 2009 Dec 17;361(25):2475
•
•
Erythropoietin:
erythropoietin treatment may reduce hospitalization but not mortality
in patients with anemia and chronic heart failure (level 2 [mid-level]
evidence)
– based on systematic review of moderate quality trials
– systematic review of 7 randomized trials comparing the effect erythropoietin
stimulating proteins vs. placebo or usual care in 650 patients with anemia and
heart failure
– erythropoietin stimulating proteins associated with reduced heart failure
hospitalization (relative risk 0.59, 95% CI 0.41-0.86)
– no significant difference between treatments in mortality risk (relative risk 0.69,
95% CI 0.39-1.23)
– Reference - Heart 2009 Aug;95(16):1309, editorial can be found in Heart 2009
Aug;95(15):1278
•
treatment of mild anemia with subcutaneous erythropoietin and
intravenous iron associated with marked improvement in patients with
severe CHF
– based on small randomized trial
– 32 patients with moderate to severe CHF (NYHA class III-IV), ejection fraction <
40% despite maximal medical therapy and hemoglobin 10-11.5 g/dL were
randomized to subcutaneous erythropoietin and intravenous iron to attain
hemoglobin 12.5 g/dL vs. no treatment of anemia
– comparing erythropoietin and iron vs. no treatment at mean follow-up 8 months
•
•
•
•
•
0 vs. 25% death from CHF-related causes
ejection fraction increased 5.5% vs. decreased 5.4%
NYHA class improved vs. worsened
need for furosemide decreased vs. increased
number of days of hospitalization decreased vs. increased
– Reference - J Am Coll Cardiol 2001 Jun 1;37(7):1775 in Prescriber's Letter 2001
Jul;8(7):38
•
•
•
•
Estrogen:
estrogen use associated with reduced mortality in RETROSPECTIVE study;
retrospective study of 1,134 women > 50 years old with symptomatic CHF and left
ventricular ejection fraction < 30%; comparing estrogen users vs. nonusers, 15% vs.
27% overall mortality (J Am Coll Cardiol 2000 Aug;36:529 in Am Fam Physician 2001
Feb 15;63(4):728)
Testosterone:
testosterone replacement therapy may improve symptoms in men (level 2 [midlevel] evidence)
–
76 men with heart failure were randomized to testosterone replacement therapy (Androderm
5 mg) vs. placebo with maximum follow-up of 12 months
•
•
–
–
–
•
42 (55%) completed 12 months of follow-up
19 (25%) dropped out due to skin reaction
exercise capacity significantly improved with testosterone therapy
13 (35%) testosterone vs. 3 (8%) placebo group improved symptoms by at least 1 functional
class (NNT 4)
Reference - Eur Heart J 2006 Jan;27(1):57
long-acting testosterone therapy may improve metabolic parameters in men
with chronic heart failure (level 3 [lacking direct] evidence)
–
–
–
–
–
based on randomized trial without clinical outcomes
70 men with stable chronic heart failure (median age 70 years) were randomized to
testosterone undecanoate 1,000 mg vs. placebo intramuscularly every 6 weeks for 12 weeks
91% completed trial
testosterone associated with improvements in body mass index, aerobic capacity, peak work
load, 6-minute walking test, maximal voluntary contraction, isokinetic power torque,
ventilation/carbon dioxide output and insulin sensitivity (all p < 0.05)
Reference - J Am Coll Cardiol 2009 Sep 1;54(10):919, commentary can be found in J Am
Coll Cardiol 2009 Sep 1;54(10):928
• Additional medications:
• morphine has been suggested for late-stage, refractory, severely
symptomatic CHF (Mayo Clin Proc 1998 Feb;73(2):194)
• theophylline may reduce apnea and oxygen desaturation
during sleep in patients with stable heart failure who have
central apnea
• study of 15 men with compensated heart failure, EF < 45%, and
baseline polysomnograms showing periodic breathing with > 10
episodes of apnea and hypopnea per hour
• crossover study of theophylline orally 2 times daily for 5 days vs.
placebo
• episodes with theophylline, placebo and baseline were 18, 37 and
47, number of episodes of central apnea (cessation of inspiratory
flow for 10 seconds, without rib cage or abdominal excursions) were
6, 26 and 26
• theophylline also reduced % sleep time with O2 saturation < 90%
• alternative treatment of nasal oxygen mentioned as safest approach
but somewhat inconvenient
• Reference - N Engl J Med 1996 Aug 22;335(8):562
• sildenafil (Viagra)
• sildenafil may improve exercise capacity and quality of life in
patients with symptomatic heart failure and pulmonary
hypertension (level 2 [mid-level] evidence)
– based on small randomized trial
– 34 patients with symptomatic heart failure and pulmonary hypertension
randomized to oral sildenafil (25-75 mg 3 times/day) vs. placebo for 12
weeks
– comparing sildenafil vs. placebo
• 29-meter improvement in 6-minute walking distance (p = 0.047)
• improved quality of life score (p = 0.01)
• decreased pulmonary vascular resistance and increased cardiac output with
exercise (p < 0.05)
– Reference - Circulation 2007 Oct 2;116(14):1555
• sildenafil may improve breathlessness scores in stable CHF
patients (level 2 [mid-level] evidence)
– based on small randomized trial
– 23 stable CHF patients randomized to sildenafil 50 mg vs. placebo twice
daily for 6 months
– breathlessness score reduced from baseline at 3 and 6 months in
sildenafil group (p < 0.01) but not in placebo group
– Reference - J Am Coll Cardiol 2007 Nov 27;50(22):2136
•
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Nutritional supplements:
Omega-3 (n-3) fatty acids:
n-3 polyunsaturated fatty acids reduce all-cause mortality in patients with
chronic heart failure (level 1 [likely reliable] evidence)
–
–
–
–
–
–
based on randomized trial in 357 cardiology or internal medicine centers in Italy
7,046 patients (mean age 67 years) with chronic heart failure (New York Heart Association
[NYHA] class II-IV) randomized to n-3 polyunsaturated fatty acids 1 g vs. placebo once daily
n-3 polyunsaturated fatty acids 1 g contains 850-882 mg of eicosapentaenoic acid plus
docosahexaenoic acid as ethyl esters in average ratio 1.2:1
median follow-up 3.9 years
71 (1%) patients from 1 site not analyzed due to inadequate data
comparing n-3 polyunsaturated fatty acids vs. placebo
•
•
•
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–
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–
–
death from any cause in 27.3% vs. 29.1% (p = 0.041, NNT 56)
death from cardiovascular cause in 20.4% vs. 22% (p = 0.045, NNT 63)
hospital admission for cardiovascular reasons in 46.8% vs. 48.5% (p = 0.026, NNT 59)
no significant differences in rates of sudden cardiac death, myocardial infarction, or
admission for heart failure, but non-significant trends toward reduced rates with n-3
polyunsaturated fatty acids
no significant differences in rates of stroke
similar rate of patients no longer taking study drug by trial end (29% with treatment vs. 30%
with placebo)
gastrointestinal disorders reported as most frequent adverse reaction (3% in both groups)
Reference - GISSI-HF trial (Lancet 2008 Oct 4;372(9645):1223) (correction in Lancet 2009
Jan 31;373(9661):382), editorial can be found in Lancet 2008 Oct 4;372(9645):1195, Ann
Intern Med 2009 Jan 20;150(2):JC1
DynaMed commentary -- study funded by drug manufacturer, drug used in study appears
similar to (but not same as) prescription drug with brand name Lovaza
•
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•
Coenzyme Q10:
may be beneficial as adjunctive therapy, but should not replace conventional therapy
coenzyme Q10 also called ubiquinone or Co-Q10
coenzyme Q10 beneficial in most rigorous randomized, placebo-controlled trial
–
–
651 patients with NYHA class III or IV heart failure given coenzyme Q10 2 mg/kg/day vs.
placebo for 1 year
comparing coenzyme Q10 vs. placebo
•
•
•
–
–
•
23% vs. 37% hospitalization (NNT 7)
6% vs. 30% pulmonary edema (NNT 4)
30% vs. 61% cardiac asthma (NNT 3)
no adverse effects found
Reference - Clin Investig 1993;71(8 Suppl);S134
coenzyme Q10 might improve symptoms in end-stage heart failure (level 2
[mid-level] evidence)
–
–
–
–
–
32 patients with end-stage heart failure awaiting heart transplantation were randomized to
Ultrasome--CoQ10 60 mg/day vs. placebo for 3 months
27 patients (84%) completed the study
no significant differences in echocardiography parameters, or atrial natriuretic factor or tumor
necrosis factor levels
intervention group had significant improvement in 6-minute walk test and decreases in
dyspnea, nocturia, fatigue and NYHA classification
Reference - Clin Cardiol 2004 May;27(5):295
• Phosphodiesterase inhibitors:
• phosphodiesterase inhibitors include amrinone, milrinone,
vesnarinone
• phosphodiesterase inhibitors increase mortality in chronic
heart failure (level 1 [likely reliable] evidence)
– systematic review of 21 randomized placebo-controlled trials with 8,408
patients followed at least 3 months
– phosphodiesterase inhibitors also increase risk of cardiac death, sudden
death, arrhythmias and vertigos
– Reference - systematic review last updated 2004 Jul 20 (Cochrane
Library 2005 Issue 1:CD002230)
• long-term oral milrinone increases morbidity and mortality in
severe congestive heart failure
– patients with dyspnea and left ventricular ejection fraction < 35%
despite conventional therapy (diuretics, digoxin and ACE inhibitor at
least 4 weeks) given milrinone 10 mg orally 4 times daily vs. placebo
– lack of functional improvement, increased hospitalization and increased
mortality in milrinone group resulted in early termination of trial
• Medical therapies which appear ineffective for chronic heart
failure:
• calcium channel blockers
– calcium channel blockers not associated with significant effect on
mortality
• based on systematic review of 18 randomized trials with 3,128 patients with
moderate to advanced heart failure
• Reference - Am J Cardiol 2001 Feb 15;87(4):487
– amlodipine (Norvasc) studied in PRAISE-1 trial
• amlodipine may be safe in severe heart failure but efficacy not shown
– based on trial of 1,153 chronic heart failure patients given amlodipine (5 mg orally
once daily for 2 weeks then 10 mg orally once daily) vs. placebo for 6-33 months,
all patients given ACE inhibitor
– no significant negative inotropy, no effects on conduction
– trend toward mortality reduction from 38.3% to 33.2% (p = 0.07), no adverse
effects
– no trend in patients with ischemic cardiomyopathy
– 421 patients with non-ischemic (idiopathic) cardiomyopathy had statistically
significant decrease in all-cause mortality from 34.9% to 21.5% (p = 0.001),
decrease in fatal or nonfatal cardiovascular events from 37% to 28%, decrease in
cardiovascular mortality from 31% to 18%
– amlodipine increased incidence of pulmonary edema from 10% to 15% (mainly on
chest x-ray and not clinically significant)
– Reference - N Engl J Med 1996 Oct 10;335(15):1107, commentary in N Engl J
Med 1997 Apr 3;336(14):1023
•
•
•
•
Surgery:
Left ventricular assist device (LVAD) :
general information
left ventricular assist device improves survival and quality of
life in advanced heart failure in patients ineligible for cardiac
transplantation
– based on randomized trial
– 129 patients with end-stage heart failure (NYHA class IV) who were
ineligible for cardiac transplantation randomized to left ventricular assist
device (LVAD) vs. optimal medical management
– comparing LVAD vs. medical management
• 1-year survival 52% vs. 25% (p = 0.002, NNT 4)
• 2-year survival 23% vs. 8% (p = 0.09, NNT 6.7)
• quality of life significantly improved in device group at 1 year
– device use associated with increased serious adverse events including
infection, bleeding, and device malfunction; rate of serious adverse
events 6.45 vs. 2.75 per patient-year
– Reference - N Engl J Med 2001 Nov 15;345(20):1435, editorial can be
found in N Engl J Med 2001 Nov 15;345(20):1490, commentary can be
found in N Engl J Med 2002 Mar 28;346(13):1023, ACP J Club 2002
May-Jun;136(3):88
• left ventricular assist device placement before heart
transplant not associated with increased survival
• based on retrospective cohort study
• 2,786 adults ≥ 18 years old in status 1A or 1B had heart
transplantation
• 1,354 patients (48.6%) received left ventricular assist
device prior to transplantation
• no significant difference in survival with or without left
ventricular assist device (even after data stratified by
propensity score)
• Reference - BMJ 2010 Feb 10;340:c392 full-text
• device approvals
• HeartMate left ventricular assist device FDA approved
for use as bridge to heart transplant and for permanent
use in certain terminally ill patients ineligible for heart
transplant (FDA Press Release 2002 Nov 6)
• HeartMate II left ventricular assist system FDA approved
as
– first compact heart assist device (FDA Press Release 2008 Apr
21)
– support for severe heart failure patients not acceptable as
candidates for heart transplantation (FDA Press Release 2010
Jan 20)
• DeBakey VAD Child is first ventricular assist device FDA
approved for children ages 5-16 years awaiting heart
transplant (FDA Talk Paper 2004 Feb 26
• Cardiac transplantation:
• consider in class III-IV, age < 65 years, no major
medical problems
• post-transplant survival rates 85-87% at 1 year,
65-75% at 5 years, median survival 7-8 years;
survival has improved with use of cyclosporine
•
•
•
•
•
•
•
•
•
•
•
Consultation and referral:
Structured management and education:
heart failure-specific patient education and postdischarge follow-up after
hospitalization for heart failure reduces readmission rates but not mortality
(level 1 [likely reliable] evidence)
comprehensive discharge planning with postdischarge support reduces
readmission rates in heart failure patients (level 1 [likely reliable] evidence)
self-management may reduce readmission rate after hospitalization for
heart failure (level 2 [mid-level] evidence)
nurse-based case management has inconsistent evidence
multidisciplinary disease management programs may reduce mortality and
hospitalizations (level 2 [mid-level] evidence)
collaborative care including pharmacist (but not pharmacist-directed care)
may reduce all-cause and heart failure hospitalizations (level 2 [mid-level]
evidence)
telephonic case management or support for heart failure may reduce
mortality and hospital admission rates (level 2 [mid-level] evidence)
home nurse visits after hospital discharge may reduce readmission rates
(level 2 [mid-level] evidence)
see Heart failure structured management and education for details
• Reviews of pacing for heart failure:
• review of pacing for heart failure can be found in Lancet
2001 Apr 21;357(9264):1277
• review of ventricular pacing in congestive heart failure
can be found in Mayo Clin Proc 2001 Aug;76(8):803
• review of pacemaker therapy can be found in Am Fam
Physician 2005 Apr 15;71(8):1563
• review of cardiac pacing can be found in Lancet 2004
Nov 6;364(9446):1701
• review of pacing for heart failure can be found in BMJ
2003 May 17;326(7398):1073
• Implanted cardioverter-defibrillator (ICD):
• implanted cardioverter-defibrillator (ICD) may prevent sudden
cardiac death in multiple patient populations
– single-lead, shock-only ICD reduces mortality in patients with NYHA
class II heart failure, and in patients with class III heart failure and
ejection fraction < 31% (level 1 [likely reliable] evidence)
– ICD reduces mortality in patients with prior myocardial infarction and left
ventricular ejection fraction < 30%
– ICD reduces risk of sudden death from arrhythmia in nonischemic
dilated cardiomyopathy, left ventricular ejection fraction < 36% and
premature ventricular complexes (at least 10 in 24 hours) or
nonsustained ventricular tachycardia (3-15 beats > 120/minute) (level 1
[likely reliable] evidence)
– ICD may reduce mortality in patients prone to ventricular fibrillation
based on electrophysiologic testing (level 2 [mid-level] evidence)
– implantable cardioverter-defibrillator (ICD) appears superior to
antiarrhythmic drugs for increasing survival (level 2 [mid-level] evidence)
for patients with history of ventricular fibrillation or sustained ventricular
tachycardia (spontaneous or induced)
– see Implantable cardioverter-defibrillator (ICD) for details
• Hospice care:
• 4-item risk score may predict 6-month mortality in
older patients with heart failure (level 2 [mid-level]
evidence)
–
–
–
–
based on derivation cohort study without validation
282 patients > 70 years old admitted to hospital with heart failure
43 (15%) died within 6 months
4 independent risk factors for 6-month mortality
•
•
•
•
serum urea nitrogen (BUN) ≥ 30 mg/dL
systolic blood pressure < 120 mm Hg
peripheral arterial disease
serum sodium < 135 mEq/L
– 6-month mortality
•
•
•
•
3.7% with 0 risk factors
16.3% with 1 risk factor
41% with 2 risk factors
66.7% with 3-4 risk factors
– Reference - J Am Geriatr Soc 2008 Jun;56(6):1111
smoking cessation
– retrospective study of > 6,700 patients in trials found
that current smoking was associated with increased
risks for overall mortality and combined endpoint of
death, myocardial infarction or recurrent
hospitalization for heart failure compared with neversmokers or ex-smokers
– increased risk disappeared within 2 years after
quitting smoking
– Reference - J Am Coll Cardiol 2001 May;37(6):1677
in J Watch 2001 Jul 1;21(13):105, editorial can be
found in J Am Coll Cardiol 2001 May;37(6):1683
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•
Continuous positive airway pressure (CPAP):
CPAP does not prevent mortality or hospitalization in heart failure
patients with central sleep apnea (level 1 [likely reliable] evidence)
– 258 patients with heart failure (mean ejection fraction 24.5%) and central sleep
apnea (mean 40 apnea and hypopnea episodes per hour of sleep) were
randomized to continuous positive airway pressure (CPAP) vs. no CPAP for
mean 2 years
– CPAP (vs. no CPAP) improved multiple intermediate outcomes
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mean reductions in hourly apnea and hypopnea episodes 21 vs. 2 (p < 0.001)
mean nocturnal oxygen saturation increased 1.6% vs. 0.4% (p < 0.001)
mean ejection fraction increased 2.2% vs. 0.4% (p = 0.02)
mean six-minute walk distance increased 20 vs. -0.8 meters (p = 0.016)
– CPAP did not significantly affect most important outcomes
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number of hospitalizations
quality of life
overall survival
survival without heart transplantation
– Reference - N Engl J Med 2005 Nov 10;353(19):2025, editorial can be found in N
Engl J Med 2005 Nov 10;353(19):2070, (correction can be found in N Engl J Med
2005 Dec 8;353(23):2523), commentary can be found in N Engl J Med 2006 Mar
9;354(10):1086
• Follow-up:
• Monitoring:
• routine echocardiography or maximal exercise testing for monitoring
not recommended, grade B evidence in AHCPR clinical practice
guideline (J Am Geriatr Soc 1998 Apr;46(4):525)
• patients should record daily weights and call practitioner if
unexplained weight gain of 3-5 lbs, grade C evidence (i.e. expert
opinion with no evidence) in AHCPR clinical practice guideline (J Am
Geriatr Soc 1998 Apr;46(4):525)
• implantable hemodynamic monitoring (Chronicle IHM System)
not clearly shown to reduce health care utilization (level 2 [midlevel] evidence)
– based on systematic review of limited evidence
– remote monitoring for ambulatory heart failure patients transmits data
from implantable device for continuous assessment
– 5 prospective observational studies funded by Medtronic suggest
reduced hospitalizations with right ventricle implantable hemodynamic
monitoring
– 1 randomized trial in 277 patients (COMPASS-HF) did not show
significant reduction in composite outcome of hospital admissions,
emergency department or urgent clinic visits
– Reference - Canadian Agency for Drugs and Technologies in Health
(CADTH) Health Technology Assessment 2008 Jan PDF
Prevention and Screening of CHF
• Prevention:
• American College of Cardiology/American Heart
Association (ACC/AHA) guidelines on heart failure in
adults
– for patients with risk factors (hypertension, coronary artery
disease, diabetes, prior treatment with cardiotoxic drugs,
rheumatic fever, or family history of cardiomyopathy)
• treat hypertension and lipid disorders (ACC/AHA Class I, Level of
Evidence A)
• control blood sugar in patients with diabetes (ACC/AHA Class I,
Level of Evidence C)
• secondary prevention measures if known atherosclerotic vascular
disease (ACC/AHA Class I, Level of Evidence C)
• avoid smoking, excessive alcohol consumption and illicit drug use
(ACC/AHA Class I, Level of Evidence C)
• control ventricular rate or restore sinus rhythm if supraventricular
tachyarrhythmia (ACC/AHA Class I, Level of Evidence B)
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additional recommendations for asymptomatic patients with cardiac
structural abnormalities or remodeling (for example, reduced left ventricular
ejection fraction)
if recent or remote history of myocardial infarction
– add beta blockers (ACC/AHA Class I, Level of Evidence A ) and ACE inhibitors
(ACC/AHA Class I, Level of Evidence A)
– angiotensin II receptor blockers may be beneficial if low left ventricular ejection
fraction and intolerant of ACE inhibitor (ACC/AHA Class I, Level of Evidence B)
•
if reduced left ventricular function
– add beta blockers (ACC/AHA Class I, Level of Evidence C ) and ACE inhibitors
(ACC/AHA Class I, Level of Evidence A)
– angiotensin II receptor blockers may be beneficial if intolerant of ACE inhibitor
(ACC/AHA Class IIa, Level of Evidence C)
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if hypertension and left ventricular hypertrophy - ACE inhibitors or
angiotensin II receptor blockers (ACC/AHA Class IIa, Level of Evidence B)
implantable cardioverter-defibrillator reasonable in patients with ischemic
cardiomyopathy who are at least 40 days post-myocardial infarction, have
left ventricular ejection fraction ≤ 30%, are New York Heart Association
functional Class I on chronic optimal medical therapy and have reasonable
expectation of survival with good functional status for > 1 year (ACC/AHA
Class IIa, Level of Evidence B)
• antihypertensives associated with reduced incidence of
heart failure
• diuretic treatment of elderly patients with isolated systolic
hypertension may reduce incidence of heart failure (level
2 [mid-level] evidence)
• beta blockers similar to other antihypertensive agents for
prevention of heart failure in hypertensive patients (level
2 [mid-level] evidence)
• ACE inhibitors appear effective for prevention of heart
failure (level 2 [mid-level] evidence)
• angiotensin receptor blockers (ARBs) may not be
effective for prevention of heart failure (level 2 [mid-level]
evidence)
• calcium channel blockers (CCBs) may not be as
effective as other antihypertensives for prevention of
heart failure (level 2 [mid-level] evidence)
• Screening:
• current evidence inadequate to support communitywide screening for asymptomatic left ventricular
systolic dysfunction, either with echocardiography or
with natriuretic peptide assays; estimated prevalence
3%-6%, prognosis of mild disease in community settings
not established (Ann Intern Med 2003 Jun
3;138(11):907)
• plasma natriuretic peptides not useful for general
population screening
– study of 3,177 subjects from Framingham cohort
– neither brain natriuretic peptide (BNP) nor N-terminal proatrial
natriuretic peptide (NT-ANP) had adequate sensitivity for
elevated left ventricular mass or left ventricular systolic
dysfunction to be useful for screening
– Reference - JAMA 2002 Sep 11;288(10):1252
• BNP may be sensitive enough for screening if use limited to
high-risk patients, based on high blood pressure or abnormal
ECG
• random sample of 1,257 persons age 25-74 years from general
population in Glasgow had blood pressure measurement, ECG,
BNP measurement and echocardiography
• 140 subjects with symptomatic heart disease had 19% prevalence of
left ventricular systolic dysfunction and 71% had BNP > 8 pg/mL,
BNP had 92% sensitivity with 95.1% negative predictive value, 34%
specificity with 24% positive predictive value
• 269 subjects with blood pressure > 160/95 mm Hg or abnormal ECG
had 6% prevalence of left ventricular systolic dysfunction and 64%
had BNP > 8 pg/mL, BNP had 94% sensitivity with 99% negative
predictive value, 38% specificity with 8.7% positive predictive value
• 823 subjects with no risk factors had 0.7% prevalence of left
ventricular systolic dysfunction and 41% had BNP > 8 pg/mL, BNP
had 83% sensitivity with 99.8% negative predictive value, 59%
specificity with 1.5% positive predictive value
• Reference - J Am Coll Cardiol 2003 Jan 1;41(1):113 in Am Fam
Physician 2003 Jun 15;67(12):2599
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•
General references used:
1. Jessup M, Abraham WT, Casey DE, et al. Focused Update: ACCF/AHA Guidelines for the
Diagnosis and Management of Heart Failure in Adults. A Report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation
2009 Apr 14;119(14):1977 PDF
2. Hunt SA; American College of Cardiology; American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management
of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic
heart failure in the adult: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines
for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005 Sep 20;46(6):e182. PDF or Circulation 2005 Sep 20;112(12):e154 full-text (correction can be found in Circulation
2006 Apr 4;113(13):e684) or at National Guideline Clearinghouse 2005 Dec 5:7664
American College of Cardiology/American Heart Association (ACC/AHA) guideline
classification:
Classification of Recommendations:
Class I - evidence and/or general agreement that procedure or treatment is beneficial, useful and
effective and should be done
Class II - conflicting evidence and/or divergence of opinion about usefulness or efficacy of
procedure or treatment
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–
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•
Class IIa - weight of evidence or opinion in favor of usefulness or efficacy, so reasonable to do
Class IIb - usefulness or efficacy less well established by evidence or opinion, so may be considered
Class III - evidence and/or general agreement that procedure or treatment is not useful or
effective, and may be harmful, so should not be done
Level of Evidence:
Level of Evidence A - data derived from multiple randomized trials or meta-analyses
Level of Evidence B - data derived from single randomized trial or non-randomized studies
Level of Evidence C - only consensus opinion of experts, case studies or standard of care
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•
General reviews:
review can be found in Lancet 2009 Mar 14;373(9667):941
Clinical Evidence Concise review (search date 2005 Feb) can be found in Am Fam
Physician 2006 Aug 1;74(3):467
review can be found in Lancet 2005 May 28;365(9474):1877
review can be found in N Engl J Med 2003 May 15;348(20):2007, commentary can
be found in N Engl J Med 2003 Sep 4;349(10):1002, Am Fam Physician 2004 Jan
15;69(2):405
review based on new ACC/AHA guidelines can be found in Adv Stud Med 2003
Jan;3(1):14 PDF
review can be found in Postgrad Med 2003 Mar;113(3):36
Clinical Evidence review can be found in Am Fam Physician 2002 Jan 1;65(1):99
review can be found in BMJ 2002 Aug 24;325(7361):422
review of systolic heart failure can be found in N Engl J Med 2010 Jan 21;362(3):228
review of advanced heart failure can be found in JAMA 2002 Feb 6;287(5):628,
commentary can be found in JAMA 2002 May 1;287(17):2209
review can be found in Am Fam Physician 2000 Mar 1;61(5):1319
review can be found in BMJ 2000 Mar 4;320(7235):626
multiple articles on heart failure can be found in Lancet 1998 Aug 29;352(suppl 1);
summary of review article can be found in Am Fam Physician 1999 Jan 15;59(2):443
review can be found in Am Fam Physician 1996 Jul;54(1):245, commentary can be
found in Am Fam Physician 1997 Apr;55(5):1561
review of CHF in elderly patients can be found in Mayo Clin Proc 1997 May;72(5):453
(summary in Am Fam Physician 1997 Oct 1;56(5):1448 or in J Am Geriatr Soc 1997
Oct;45(10):1252), commentary can be found in J Am Geriatr Soc 1998
Aug;46(8):1053
review of diastolic ventricular dysfunction in the elderly can be found in J Am Geriatr
Soc 1995 Sep;43(9):1035
review of diastolic heart failure can be found in Postgrad Med 2003 Mar;113(3):51
• Diagnosis reviews:
• review of evaluation of chronic dyspnea can be found in
Am Fam Physician 2005 Apr 15;71(8):1529
• review of diagnosis of heart failure in adults can be found
in Am Fam Physician 2004 Dec 1;70(11):2145
• Applied Evidence review of evaluation of suspected left
ventricular systolic dysfunction can be found in J Fam
Pract 2002 May;51(5):466
• review of clinical features and complications can be
found in BMJ 2000 Jan 22;320(7229):236
• case-based discussion of heart failure can be found in
JAMA 1999 Jun 23/30;281(24):2321, commentary can
be found in JAMA 2000 Feb 23;283(8):1054
• review of pulmonary artery wedge pressure can be found
in Am Fam Physician 1996 Sep 1;54(3):1039, correction
can be found in Am Fam Physician 1996 Dec;54(8):2377
• Treatment reviews:
• Applied Evidence review of outpatient treatment can be found in J
Fam Pract 2002 Jun;51(6):519
• review of management strategies can be found in BMJ 2000 Feb
26;320(7234):559
• review of outpatient treatment of systolic heart failure can be found
in Am Fam Physician 2004 Dec 1;70(11):2157, commentary can be
found in Am Fam Physician 2005 Oct 1;72(7):1172
• review of treatment can be found in Am Fam Physician 2001 Apr
15;63(8):1593, editorial can be found in Am Fam Physician 2001 Apr
15;63(8):1483, correction can be found in Am Fam Physician 2002
Jan 15;65(2):172
• review of treatment checklist for advanced heart failure in elderly
can be found in Annals of Long-Term Care 2007 Aug;15(8):21,
commentary can be found in Annals of Long-Term Care 2008
Jan;16(1):17
• review of treatment of edema can be found in Am Fam Physician
2005 Jun 1;71(11):2111, commentary can be found in Am Fam
Physician 2006 Feb 15;73(4):589
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Pharmacological:
review with focus on drug therapy can be found in Arch Intern Med 2001
Feb 12;161(3):342
review of drug treatment can be found in Adv Stud Med 2005 Feb;5(2):81
PDF
review of newer drug therapy can be found in Arch Intern Med 1999 Jun
14;159(11):1177
review of drug treatment can be found in BMJ 2000 Apr 29;320(7243):1188,
correction can be found in BMJ 2000 Jul 15;321(7254):161, commentary
can be found in BMJ 2000 Sep 16;321(7262):706
review of pharmacotherapy for chronic heart failure can be found in Ann
Intern Med 2005 Jan 18;142(2):132
review of pharmacologic management of heart failure caused by systolic
dysfunction can be found in Am Fam Physician 2008 Apr 1;77(7):957,
commentary can be found in Am Fam Physician 2009 Mar 15;79(6):454
review of diuretics, ACE inhibitors and nitrates can be found in BMJ 2000
Feb 12;320(7232):428
review of inotropes, beta blockers, antithrombotics and antiarrhythmics can
be found in BMJ 2000 Feb 19;320(7233):495
• Non-pharmacological:
• review of nutrition and heart failure can be found in Nutr Clin Pract
2009 Feb-Mar;24(1):60
• review of nonpharmacologic treatment can be found in BMJ 2000
Feb 5;320(7231):366
• review of non-pharmacologic therapy for chronic heart failure can be
found in Adv Stud Med 2006 Jan;6(1):16 PDF
• review of surgery for chronic heart failure can be found in Postgrad
Med 2001 Mar;109(3):61
• Palliative:
• review of palliative care for heart failure patients can be found in
JAMA 2004 May 26;291(20):2476, follow-up can be found in JAMA
2004 Oct 13;292(14):1744
• review of palliative care in heart failure can be found in Adv Stud
Med 2003 Sep;3(8):456 PDF, commentary can be found in Adv Stud
Med 2003 Nov-Dec;3(10):580 PDF
• review of integrating palliative care into heart failure care can be
found in Arch Intern Med 2005 Feb 28;165(4):374
• Guidelines:
• synthesis of 3 guidelines (HFSA 2006,
NHFA/CSANZ 2006, SIGN 2007) on diagnosis
and evaluation of chronic heart failure can be
found at National Guideline Clearinghouse 2009
May 18:CHF1
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United States guidelines:
American College of Cardiology/American Heart Association (ACC/AHA)
heart failure guidelines
– American College of Cardiology Foundation/American Heart Association
(ACCF/AHA) 2009 focused update on guidelines for diagnosis and management
of heart failure in adults can be found in Circulation 2009 Apr 14;119(14):1977
PDF or J Am Coll Cardiol 2009 Apr 14;53(15):e1
– ACC/AHA 2005 guideline update for diagnosis and management of chronic heart
failure in the adult can be found in J Am Coll Cardiol. 2005 Sep 20;46(6):e1 PDF
or Circulation 2005 Sep 20;112(12):e154 full-text (correction can be found in
Circulation 2006 Apr 4;113(13):e684) or at National Guideline Clearinghouse
2005 Dec 5:7664, summary can be found in Am Fam Physician 2007 Mar
1;75(5):742 full-text
– updates ACC/AHA 2001 guidelines for evaluation and management of chronic
heart failure in adult which can be found in J Am Coll Cardiol 2001;38:2101 fulltext, summary can be found in J Am Geriatr Soc 2003 Jan;51(1):123
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American College of Cardiology/American Heart Association/European
Society of Cardiology (ACC/AHA/ESC) 2006 guidelines for management of
patients with ventricular arrhythmias and prevention of sudden cardiac
death can be found in J Am Coll Cardiol 2006 Sep 5;48(5):e247 full-text or
at National Guideline Clearinghouse 2007 Jun 25:9725
Advisory Council to Improve Outcomes Nationwide in Heart Failure
(ACTION HF) guidelines published in Am J Cardiol 1999 Jan 21 can be
found in Am Fam Physician 1999 Jun;59(11):3265 or in J Am Geriatr Soc
2000 Nov;48(11):1521
University of Michigan Health System guidelines on heart failure- systolic
dysfunction can be found at National Guideline Clearinghouse 2007 Feb
5:10179
• The primary source of information, data
and links are from DynaMed medical
database