Transcript Initial Therapy - MCE Conferences

Evaluation and Treatment
of Hypertensive Patients
Herbert L. Muncie, Jr., M.D.
Proper technique to
measure Blood Pressure (JNC VII)
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Sitting, back supported, arm at level of heart
Feet on floor, legs uncrossed
Rest at least five minutes
Proper cuff size (> 80% of arm with bladder)
Inflate & palpate radial pulse to approximate
BP – deflate cuff
 Inflate 20-30 mm above palpable systolic
 Measure Korotkoff I (onset sounds - systolic)
and V (disappearance sounds - diastolic)
WatchBP Office
Question
A 58 year old African American female with
three separate BP readings averaging
164/92. According to JNC VII, what is her
BP classification?
a)
b)
c)
d)
Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension
Classification of Blood
Pressure – JNC VII
Systolic
Normal
< 120
Prehypertension 120-139
Hypertension
Stage 1
140-159
Stage 2
> 160
And
Or
Or
Or
Diastolic
< 80
80-89
90-99
> 100
Highest value (systolic or diastolic) determines Stage
Treat Prehypertension?
 It is not a disease category (JNC VII)
 Treatment with ARB (candesartan) for
4 years
 Relative risk reduction of developing Stage
1 hypertension 15.6%
 Patients with prehypertension are not
candidates for drug therapy (JNC VII)
Lifetime Risk

For men or women who are
normotensive at age 55 or 65 and
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Who survive to age 80 - 85
90% will develop hypertension
Tests after Initial Diagnosis
 Target organ damage?
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ECG
Urinalysis
CBC
BUN & creatinine
 Secondary causes?
 Electrolytes, calcium
 Other cardiovascular risk factor?
 Lipid profile, glucose
Whom to consider evaluating for
2o causes
 Onset of hypertension before age 30 or
after age 55
 Initial diastolic BP is > 110 mm
 Patient with unexplained hypokalemia
 Patient with resistant or difficult to control
BP especially if initially good control
 Signs of Cushing’s disease
 Signs or symptoms of pheochromocytoma
Pheochromocytoma
 Measure plasma free
metanephrine (99% sensitive, 89%
specific)
 < 61 ng/L excludes diagnosis
 > 236 ng/L confirms diagnosis
 If 62 - 235 ng/L more testing
required

24 hour urine metanephrine alone
highly sensitive and specific, but
often incomplete collection
Renal artery stenosis
 Abdominal bruit suggestive often absent
 If high index of suspicion & normal renal
function [Hartman 2009]
 MRA
 CTA
 If high index of suspicion & diminished renal
function
 MRA
 Duplex Doppler ultrasonography
Primary hyperaldosteronism
 Screen with plasma aldosterone/renin ratio
(cutoff > 25)
 β-blockers & DHCCBs stop for 2 weeks
 Spironolactone & loop diuretics stop for 6 weeks
 Plasma aldosterone should be > 20 ng/dL to
make the diagnosis (Nl – 2 – 16 ng/dL –
supine)
 Renin – nl 12 – 79 mu/dL (supine)
Cushing Syndrome
 24 hr urine free cortisol useful screening
(cutoff > 90 mcg/day)
 Sensitivity 41 – 70%
 Specificity – almost 100%
 Overnight dexamethasone suppression
test equally sensitive, less specific
 1 mg dexamethasone midnight – plasma
cortisol next morning (cutoff > 100 nmol)
What if you find a
o
2
Cause?
 Renal artery stenosis
 For atherosclerotic etiology
 Medical therapy is cornerstone [Dworkin 2009]
 Stenting no better than medical but more
complications
 May be helpful with recurrent CHF or pulmonary
edema
 For fibromuscular dysplasia – balloon
angioplasty is worthwhile
White coat hypertension
 White coat hypertension
 Elevated office BP but normal outside office
 Normal would be either 24-hour BP with mean
< 125/79 or home BP < 132/82
 If out of office BP consistently < 130/80 & no
evidence of target organ damage
 24 hour monitoring or drug therapy can be avoided
(JNC VII)
 Increased risk of progressing to sustained
hypertension [Mancia 2009]
Masked hypertension
 Masked hypertension
 Normal office BP but elevated outside office
 Suspect if patient with normal office BP has
cardiovascular event
 Increased risk of cardiovascular events
 Pharmacotherapy is indicated
 Deserves “an aggressive diagnostic &
therapeutic approach” [Messerli 2007]
Mrs. Jones
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Mrs. Jones is a 58 year old white
female treated for hypertension for the
past 6 years. Her BP today in the
office is 168/94.
Which number should you focus on in
deciding on modifying treatment?
a)
b)
Systolic BP
Diastolic BP
Treatment of Patients > 50 y.o.
 Patients > 50 years old achieve diastolic
goal when systolic goal achieved
 Focus on systolic control for patients > 50
years old because:
 Systolic BP continues to rise with age
 Diastolic BP levels off around age 50 & will
remain at that level or fall after age 50
Non-pharmacologic Therapy
 Weight reduction alone reduces BP
 Regardless of weight - DASH diet
helpful in lowering BP
 Increase potassium (6-8 fruits or
vegetables a day)
 Increase fiber with whole grains
(breads, cereals)
 Increase calcium intake (low fat dairy)
 Decrease salt (DASH-low Na)
 No added salt
Non-pharmacologic Therapy
 Stage 1 can be treated with lifestyle only
(JNC VII)
 For one year if no other risk factors
 For 6 months with other risk factors
 You do not have to start medication
immediately with Stage 1 (BP < 160/100)
Audience Question
Patients who successfully lose 3 - 9% of
their body weight with lifestyle changes can
expect to see their average BP decrease
how many mm?
a)
b)
c)
d)
3
5
7
10
Weight loss & BP - EBM
 Dieting to lose weight may lower BP in
overweight people but the effects are modest &
dieting may not be effective alone
 Cochrane Review
 18 randomized trials found weight loss of 3-9%
 Associated with decreases of roughly 3 mmHg
systolic & diastolic
 http://www.chochrane.org/reviews/en/ab000484.html
Lifestyle changes
 Combining intensive lifestyle counseling &
physician feedback was not successful longterm (18 month) in achieving BP control
[Svetkey 2009]
 Some early success (6 months) faded over time
 Dietary choices influence control success
 Salt restriction is central especially in those
requiring intensive pharmacotherapy
 Increase fresh fruits & vegtables
 Maximum 1 restaurant meal/week
Question
A 50 yo African American male with BP 155/95
(avg.) requires initiating drug therapy.
What would be your initial choice of medication
class for this patient?
a)
b)
c)
d)
e)
Thiazide diuretic
Calcium channel blocker (CCB)
Beta blocker
Angiotensin-converting enzyme inhibitor (ACE)
Angiotensin receptor blocker (ARB)
Initial Therapy
 JNC VII – a thiazide-type diuretic should be
initial therapy unless compelling indication
 Most patients with Stage 1 will experience
better BP control & lower CVD risk when taking
a thiazide-type diuretic
 Most patients with Stage 2 disease will
experience better BP control & lower CVD risk
when taking a multidrug regimen that includes
a thiazide-type diuretic
Initial Therapy
 No treatment alters the natural progression
of the disease
 BP will continue to rise as the patient ages
regardless of which medications are used
 Therefore, every patient will eventually need
for more than one medication to control their
BP
Initial Therapy
 Dr. Chobanian (Chair JNC VII) now
suggests flexibility in choice of initial drug
[Chobanian 2009] – he suggests
 Stage 1 – ACE, ARB, CCB or diuretic
 Stage 2 – two of those 4 drugs to start
 With exception of β-blockers after an MI &
CCBs effect on CVA risk, all drugs lowered
CVD events for a given reduction in BP
[Law 2009]
Initial Therapy
 To increase drug persistence & compliance
with therapy [Friedman 2010]
 Choose medications that will lower BP with few
complications & is taken less often
 Persistence is lower with more side effects
 Compliance is lower in males, lower SES
groups & in urban environments
Question
A 50 yo African American male with BP
155/95 (avg.) requires initiating drug therapy.
What would I choose?
a)
b)
c)
d)
e)
Thiazide diuretic
Calcium channel blocker (CCB)
Beta blocker
Angiotensin-converting enzyme inhibitor (ACE)
Angiotensin receptor blocker (ARB)
STITCH Therapy
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Simplified Treatment Intervention to
Control Hypertension (STITCH)
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STITCH vs Canadian Hypertension
Education Program guideline (CHEP)
 CHEP is similar to JNC VII approach
STITCH Treatment
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Initiate therapy with ½ tablet of low dose
combination - diuretic & ACEI or ARB
Increase that combination to highest dose
tolerated
Then add CCB & increase to highest tolerated
dose
Then add non-first-line agents
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Alpha-blocker
Beta-blocker
Spironolactone
STITCH Therapy
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At 6 months [Feldman 2009]
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64.7% controlled on STITCH
52.7% controlled on CHEP (P = 0.03)
Pharmacologic Efficacy
 Average reduction in BP for major classes
of drugs
 At standard dosage - 9.1 mm (SBP)/5.5 mm
(DBP) drop
 With half standard dosage 7.1 mm (SBP)/4.4 mm (DBP)
 When BP > 20 (SBP) or 10 mm (DBP) above
goal (Stage 2) start two medications initially
Question
A 52 year old African American female has not
achieved BP control on diuretics. You add an ACE
inhibitor to the regimen. You order electrolytes,
BUN and creatinine in 1 week. Her creatinine
increased from 0.9 baseline to 1.14 mg/dL, a 26.7%
increase. What should you do about her ACEI?
a.
b.
c.
d.
Discontinue the ACEI & add a different class
Reduce the ACEI dose 50%
Reduce the ACEI dose 25%
Make no change in the ACEI dosage
Initiating Therapy – Change
in Renal Function
 After initiating treatment, common to get
decline in renal function
 If ≤ 30% non-progressive increase in creatinine
 Represents a functional response (reduced
intraglomerular pressure) & no change in
treatment required
 This response is associated with long-term
renal protection
 If > 30% increase in creatinine, D/C medication
& choose another class
Question
A 52 year old African American female has not
achieved BP control on diuretics. You add an ACE
inhibitor to the regimen. You order electrolytes,
BUN and creatinine in 1 week. Her creatinine
increased from 0.9 baseline to 1.14 mg/dL, a 26.7%
increase. What should you do about her ACEI?
a.
b.
c.
d.
Discontinue the ACEI & add a different class
Reduce the ACEI dose 50%
Reduce the ACEI dose 25%
Make no change in the ACEI dosage
Diuretic - Classes
 Thiazide
 Hydrochlorothiazide (HCTZ) dosage best if
≤ 25 mg & preferably 12.5 mg
 Outcome benefits have not been established for
these dosages of HCTZ
 Increasing to 50 mg minimally lowers BP further
but significantly increases side effects
 Hyponatremia & hypokalemia more common in
women
 12 combinations with HCTZ available
Diuretic - Classes
 Thiazide
 Chlorthalidone 25 mg provided better 24 hr BP
control than HCTZ 50 mg
 Milligram for milligram twice as potent as HCTZ
 Outcome data available regarding reduced CV events
 Only 2 combinations available
 Chlorthalidone/clonidine (Clorpres®) – 15/0.1,0.2, 0.3
 Atenolol/chlorthalidone (Tenoretic®) – 25/50, 25/100
Diuretic - Classes
 Loop
 If only treating hypertension - use loop
diuretics only with renal insufficiency
(CrCl < 30 - 40 ml/min)
 Discontinue thiazides at this CrCl – not effective
 Dosage frequency for BP treatment
 Furosemide (Lasix®) – BID
 QD dosage may lead to reactive Na+ retention mediated by
renin/angiotensin system
 Torsemide (Demadex®) – QD
Diuretic - Classes
 Potassium sparing
 Combined with thiazide - reduces risk
sudden death and hypokalemia
 Do not combine with continuous K+
supplements or give with renal insufficiency
 Increased risk hyperkalemia
 Especially with ACE or ARB combination
 Should be stopped temporarily if diarrhea or
vomiting occurs
Selective aldosterone
receptor antagonist
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Eplerenone (Inspra®) first approved in new class
Primary focus in heart failure
Add-on to anti-hypertensive Rx
Side effects
 Hyperkalemia
 Contraindicated with hyperkalemia, creatinine > 1.8 men,
> 2.0 women, or creatinine clearance < 50 ml
 Caution in use with ACE or ARB
Diuretics – diabetes &
hyperlipidemia?
 Diuretics can raise glucose & lipid levels
short-term
 However, no long-term adverse effects in
diabetics
 Fasting glucose increases in older adults
regardless antihypertensive drug
 Diuretics may be safely used in patients
with diabetes or hyperlipidemia
Beta-Blockers
 Available evidence does not support their use
as 1st line treatment alone
 Weak effect in reducing CVA
 Absent effect on CAD [Wiysonge - Cochrane 2007]
 Lower heart rate with beta-blocker therapy associated
with increased risk CV events & death
 Compelling indications (JNC VII)
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Heart failure
Chronic stable angina
Post MI
Tachyarrhythmia
Beta-Blockers
 Side effects
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Increased risk developing type 2 DM
Decreased exercise tolerance
Increased risk of Raynaud’s phenomenon
Increased insomnia & risk of delirium
Abrupt withdrawal can precipitate myocardial
ischemia in at risk patients
Beta-Blockers & Diabetes
 In diabetics beta-blockers blunt heart rate
& BP response to hypoglycemia
 However, no increase in severe
hypoglycemia in Type 1 or Type 2 DM
 Do not worsen glycemic control when used
with ACE/ARB
 Carvedilol (Coreg®) & nebivolol
(Bystolic®) have neutral or even favorable
effect on CHO & lipid metabolism
Angiotensin-Converting
Enzyme (ACE) Inhibitors
 Compelling indications (JNC VII)
 Heart failure
 Post MI - systolic dysfunction
 Diabetics with proteinuria
 Reduce cardiovascular & all-cause mortality
 As effectively as diuretics, β-blocker or CCB
[SOR-A]
 Diabetics may retain sodium
 Add diuretic to enhance response
ACE Inhibitors
 Side effects
 Cough (5-15%) - women 2x men’s risk
 Angioedema (0.1-0.2%) – African Americans
and Asians 3 - 4 x risk increase
 Hyperkalemia with renal insufficiency
 If patient has bilateral renal artery stenosis
 Can cause renal insufficiency
 Measure creatinine initially & one week after
starting ACE
 If > 30% increase in creatinine or hyperkalemia
1st 2 months – D/C ACE
Angiotensin Receptor
Blocker (ARB)
 Three trials found ARBs effective in reducing
CV events (LIFE, SCOPE, VALUE)
 But not as effectively as ACE
 Reduce the risk end-stage renal disease in
diabetics
 No evidence reduce mortality in diabetics with
renal disease
 Reserve for patients who cannot tolerate ACE
Angiotensin Receptor
Blocker (ARB)
 Low incidence of dizziness or other side
effects
 Cough not a problem
 Caution with renal insufficiency or K+
supplements
Angiotensin Receptor
Blocker (ARB)
 Less effective if high salt intake
 Measure serum creatinine initially & 1 week
after starting drug
 Can worsen renal failure
 Not proven to improve survival post MI
 ACE & ARB should not be used in
pregnancy
Combining ACE & ARB
 CHARM-Added trial found combination
reduced CV events & mortality in patients
with heart failure
 However, in patients without heart failure
 Combination lowered BP without CV benefit
over ACE alone (ONTARGET)
 But did increase hypotension, syncope & renal
dysfunction
Ca-Channel Blockers (CCB)
 More effective in African Americans than
diuretic or ACE as initial therapy
 ALLHAT – if African American cannot take
diuretic – CCB preferred initial drug
 Greater risk CVA, CHD, CVD, angioedema with
ACE
 Combination of benazepril/amlodipine was
more effective slowing progression of renal
disease than benazepril/HCTZ
(ACCOMPLISH trial)
Ca-Channel Blocker Risks
 CCB & diuretics are associated with best
stroke prevention
 Could be due to less visit-to-visit variability
 Caution combining non-dihydropyridine
CCB (diltiazem; verapamil) with beta
blocker
 Potential additive negative inotropic effect
 Can cause heart failure or complete heart
block
Direct Renin Inhibitor
 Aliskiren (Tekturna®)
 Monotherapy or combined
 Modestly lowers BP
 High fat meals decrease absorption
 Older hypertensive medications should be
considered 1st (Medical Letter 2007)
Alpha Adrenergic Blockers
 Peripheral sympatholytics
 Do not produce tachycardia & palpitations
 Not initial drug of choice
 Associated with increased risk of MI
Alpha Adrenergic Blockers
 Side effects
 Marked hypotension especially with first dose
 Careful in elderly, volume depleted patients, or
in patients taking other antihypertensive drugs
 Start with lowest dose at bedtime
 Not recommended for patients with CHF
regardless of BP status
 May benefit males with BPH symptoms
JNC VII Compelling Indications
Compelling Indic. Diuretic BB
CHF
X
Post MI
ACEI ARB CCB AlDO ANT
X
X
X
X
High CAD Risk
X
X
X
Diabetes Mellitus
X
X
X
Chronic Kidney
Disease
Recurrent CVA
Prevention
X
X
X
X
X
X
X
X
X
X
Treatment Goal
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For most patients goal BP is < 140/90
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Does a lower target (< 135/85) reduce risk?
Cochrane review found lower targets did not
change mortality, MI, CVA, CHF, major
cardiovascular events or ESRD [Arguedas 2009]
In the very old (> age 80) with CAD, a
suggestion of increased risk of adverse
outcomes with SBP < 140 & DBP < 70
[Denardo 2010]
Treatment Goal

For diabetics or patients with CKD
• ADA/AHA Goal BP is < 130/80
• INVEST trial of diabetics with CAD found tight
BP control did not improve CVD outcomes over
usual control
 Was associated with increase in all-cause mortality
 Emphasis should focus on maintaining SBP
between 130 – 139 mm Hg for these patients
Question
Your 52 y.o. African American female patient with
a 6 year history of hypertension comes in for a
routine office visit. No symptoms. BP 142/92.
No change in therapy. When would you want to
see her again for follow-up?
a) Two (2) weeks
b) One (1) month
c) Three (3) months
d) Six (6) months
Monitoring Treatment

No evidence based guidelines address the
frequency of monitoring treatment [Keenan
2009]
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Monitoring at short intervals increases
probability of false positives due to within
person variability
Longer intervals (years) increase probability
observed increase is real
Monitoring Treatment

Chance of detecting a true increase in BP is
better if:
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
Abnormal BP is signal for repeat readings at short
intervals
Using calibrated sphygmomanometer
Set times to measure BP in relation to drug therapy
Taking mean of several measurements
Or perhaps self-monitoring
Monitoring Treatment

What is the significance of visit-to-visit
(V2V) variability, maximum SBP and
episodic hypertension?
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
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V2V & maximum SBP are strong predictors of
stroke, independent of mean SBP (Rothwell 2010)
Interindividual variation is reduced with CCB &
non-loop diuretics but increased with ACE,
ARB and β-blockers
Does not yet prove a causal link
Telemonitoring & selftitration

Using automated BP measurement with
information sent to the office, patients on 2
meds without control [McManus 2010]

Having patients request additional medicine if
their BP remained uncontrolled for two
consecutive months resulted in lower SBP
difference of 3.7 mm (95% CI 0.8 – 6.6)
Combinations of Medications

Beyond studies of 2 drug combinations, little data
on the efficacy of 3 or more drugs



Advice largely empiric and/or anecdotal
Triple therapy amlodipine/valsartan/HCTZ (Tribenzor®)
better BP control than dual therapy [Calhoun 2009]
ASCOT study found ACE & DHPCCB better than
B blocker with diuretic


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In reducing CV mortality
In reducing new onset DM
In reducing incidence of fatal & nonfatal CVA
Combination therapy


Maximal dosage of one drug increases risk
of side effects
Using ½ standard dose resulted in decrease
of side effects




81% for CCBs (pedal edema)
80% for thiazides (hypokalemia)
27% for beta blockers (bradycardia/fatigue)
0 % for ACE/ARB (which are not dose related)
Combination therapy

Therefore, use lower dosages of two drugs
[Wald 2009]


Combining drugs from 2 classes will get 5 times
greater reduction in BP than doubling one drug
If appropriate consider fixed dose combinations

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May improve compliance
May reduce total costs
Some Combinations


Everything is combined with HCTZ
Amlodipine & benazepril (Lotrel®)


Slowed nephropathy more than benazepril &
HCTZ [Bakris 2010]
Amlodipine & an ARB


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With olmesartan (Azor®)
With telmisartan (Twynsta®)
With valsartan (Exforge®)
Persistence?

Do patients continue to take their
medication?



As many as 25% of patients stop taking their
medications by 6 months
Many variables influence this rate (side
effects, cost, patient’s understanding,
physician’s ability to explain, etc.)
One new variable is modification of dosage or
drug before the end of the 1st prescription –
more persistent if adjusted [Tamblyn R 2010]
Caution in Elderly
 What appears as refractory BP control
may be sclerotic arteries – ‘pseudo
hypertension’
 If radial artery palpable when brachial
artery is occluded with cuff
(Osler maneuver)
 Measure intra-arterial pressure
Hypertension and Elderly
 Criteria for diagnosis unchanged due to age
 Treatment reduced incidence CVA, CAD,
CHF and death from all causes
 Treatment initially proven beneficial up to age
80
 Treatment after age 80 is now proven
beneficial
Hypertension and Elderly
 Aggressiveness of treatment influenced by
patient's physiologic age and life expectancy
 Life expectancy should be at least as long as
time required to see a clinically meaningful
decrease in:
 Stroke - 3 years
 CHF - 4.5 years
 Heart attack - 7 years
Isolated Systolic Hypertension
 Treatment recommendations:
 Diuretics
 Long-acting dihydropyridine CCBs
 Strong evidence treatment helpful if > 160 mm
 Evidence less strong for 140 - 159 mm
 In oldest old males (> 85 yo) higher systolic BP
associated with lower mortality
Resistant Hypertension

BP remains above goal in spite of at least
3 medications at optimal dose


Ideally one of which should be a diuretic
Patients controlled on 4 or more
medications should be considered
resistant to treatment
Resistant Hypertension Treatment
 Restrict salt intake
 Increase dose of diuretic
 If CrCl is below 30-50 ml/min use loop diuretic
 Add aldosterone antagonist
 Since up to 20% - raised aldosterone/renin ratio
 Consider evaluating for 2o causes
 Future treatment?
 Radiofrequency ablation renal sympathetic nerve
 23 mm drop in systolic BP in 89% patients
Incidental Hypertension
 Elevated BP found incidentally during visit
 No consensus on how to evaluate or treat in
the acute care setting
 VA Cooperative Trial (1967) – 143 patients with
DBP 115 -130
 No adverse outcomes vs placebo initial 3 mo
 Close follow-up and perhaps treatment is all
that is required
Incidental Hypertension
 Prospective randomized trial of 64
asymptomatic patients with DBP 116 -139
 Oral clonidine load vs placebo then
maintenance oral clonidine
 No clinical difference in BP at 7 days
 No evidence demonstrating improved
morbidity or mortality with acute treatment of
BP in ED
Key Points – Lessons
from clinical trials




BP is the key driver of benefit from medications
Drugs that deliver less effective BP control
have never produced superior clinical
outcomes
The choice of initial treatment defines the initial
BP response to treatment & the longer term
quality of BP control usually requiring fewer
add-on drugs
Patients with treated hypertension remain at
higher risk of CVD
Key Points – Lessons
from clinical trials


If after formal estimate of global risk, their risk
of CVD is high, offer statin & ASA therapy
Treatment of pre-hypertension with lifestyle
changes might prevent development of severe
hypertension, target organ damage & diminish
risk of dementia
What Questions do
you have?