Transcript Hypertension - Dr Ted Williams

Evidence Based Treatment of
Hypertension
Harleen Singh
Pharm.D., Assistant Professor
Ted D. Williams
Pharm.D. Candidate
OSU/OHSU College of Pharmacy
P3 Year – Investing in your Education
Objectives
1.
2.
Describe the epidemiology of hypertension
Identify various physiologic systems that can contribute to the
development of elevated blood pressure.
3. Identify the complications of untreated hypertension.
4. Describe the classification of blood pressure in adults.
5. Identify appropriate blood pressure goals for patients with hypertension.
6. Know the disease states and other factors that increase the risk of
cardiovascular complications for a patient with hypertension.
7. Be able to identify secondary causes of hypertension, including drugs.
8. Summarize our current knowledge on the relative effectiveness of
antihypertensive therapy in preventing complications of hypertension.
9. Describe the role of non-pharmacologic management of hypertension
and various lifestyle changes that can be recommended.
10. Describe when drug therapy for hypertension is indicated.
Objectives
11. Be able to articulate the advantages, disadvantages,
effectiveness as monotherapy, side effects,
contraindications, relative cost, and monitoring parameters
for the following classes of antihypertensives:
A. Diuretics (Loop, Thiazide, Potassium Sparing)
B. Beta-blockers
C. Angiotensin-converting enzyme (ACE) inhibitors
D. Calcium blockers
E. Centrally-acting sympatholytics
F. Peripheral sympatholytics and arteriolar dilators
G. Alpha blockers
H. Angiotensin receptor blockers (ARBs)
I. Direct rennin inhibitors
Objectives
11. Describe differences among various agents in the same
antihypertensive class.
12. Identify antihypertensives that should not be abruptly
discontinued.
13. Taking into consideration demographics, socio-economic
factors, and medical disorders for a given hypertensive
patient, be able to develop an appropriate therapeutic
plan (recommend appropriate agent, patient education,
and monitoring).
14. Identify factors that can lead to a poor response to
antihypertensive therapy.
15. Describe the factors that can influence compliance with
antihypertensive therapy.
16. Be able to distinguish between true hypertensive
emergency and hypertensive urgency.
The Road Ahead
• Evidence Based Medicine (EBM) Primer
• Hypertension Defined, Epidemiology,
Complications
• Goals of Hypertension Therapy
• Hypertension Treatment Guidelines
• Non-Pharmacological Treatments of
Hypertension
• Pharmacology Review
• EBM for pharmacological treatment selection
Evidence Based Medicine
• Evidence-based medicine (EBM)
– EBM is the conscientious, explicit, and judicious
use of the current best evidence in making
decisions about the care of individual
patients.(Sackett 1998)
Pathophysiology, Pharmacology and
EBM
• Pathophysiology suggests where we can
intervene to improve outcomes
• Pharmacology helps predict likely targets
– Therapeutic Effects
– Adverse Effects
• Clinical Trials show what happens when we
treat 10,000 patients
– Evidence Based Medicine lives here
Types of Significance
• Statistical Significance
– Can we detect any difference
• Clinical Significance
– Do we care if there is a difference
• Patient Significance
– Blood Glucose level differences with Thiazide Diuretics
are significantly higher vs. placebo
– Increase in Blood Glucose 3-5mg/dL in non-diabetics
– Is this clinically significant?
EBM In Real Life
• Question : A patient is taking 25mg HCTZ QDay
with BP 140/95. What should the next step be?
• Answer from PharmD: “Continue HCTZ 25mg Q
Day and add Lisinopril 10mg Q Day, titrating to
40mg Q Day”
• Response: “Why not increase HCTZ to 50mg Q
Day. Micromedex says the max daily dose is
100mg”
• PharmD: ???
JNC-7
• The Seventh Report of the Joint National
Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood
Pressure
• Gold Standard EBM in Hypertension diagnosis
and treatment
• Express and Full Version
Case
• JD is a pleasant 56 yo female with
– Hypertension (HTN)
– type 2 diabetes
– occasional gout attacks.
• Her last three home BP readings were 145/95mmHg,
153/98mmHg, and 143/92mmHg.
• Today in the clinic she had a BP of 142/89mmHg.
• Her last Lipid panel was 2 months ago: LDL 153mg/dL,
HDL 63mg/dL, triglycerides 121
• Lisinopril 40mg once daily
• Metformin 1000mg BID
Hypertension (HTN) Defined
• Elevated Blood Pressure (BP)
– Systolic Blood Pressure (SBP) >=140mmHg
– Diastolic Blood Pressure (DBP) >=90mmHg
• Why these values will be discussed later
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
Hypertensive Crisis
• Less than 1% of all hypertensive patients will
ever have a hypertensive crisis.
• Hypertensive crisis is defined as a diastolic
pressure above 120mm Hg.
• There are 2 types of hypertensive crisis:
– hypertensive emergency
– hypertensive urgency
White Coat Hypertension
• Elevated blood pressure in a clinical setting
• Believed to be tied to anxiety
• Documented lower blood pressures at home
Epidemiology of Hypertension
• Approximately 50 million people in the U.S.
have hypertension.
• The risk of CVD beginning at 115/75 mmHg
doubles with each increment of 20/10 mmHg
• There is a strong correlation between blood
pressure and cardiovascular morbidity and
mortality.
– Systolic BP has a stronger correlation than
diastolic BP, but both are important
Epidemiology of Hypertension
• While 70% of hypertensives are aware of their
condition and 59% are being treated; only
34% are controlled.
Epidemiology of Hypertension
Prevalence Doubles
From 40s to 60s
Epidemiology of Hypertension
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
Definitions - Determinants of Blood
Pressure
• Arterial blood pressure is generated by the interplay of
cardiac output and total peripheral resistance: BP = CO
x TPR
• It reaches a peak during cardiac contraction (systolic
pressure) and a nadir at the end of cardiac relaxation
(diastolic pressure).
• Blood pressure is measured in millimeters of mercury
and recorded as systolic (SBP) over diastolic pressure
(DBP).
• The difference between the systolic and the diastolic
pressure is the pulse pressure (PP)
• Mean arterial pressure (MAP) = 1/3 PP + DBP.
Schematic of the Pathophysiology of
Hypertension
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004
Plasma
Volume
AT II
Renin
Pathophysiology of Hypertension
1. Increased Sympathetic Activation
2. Excessive vascular volume
3. Activation of the Renin Anginotensin
Aldosterone System
4. Peripheral Resistance
Causes of Hypertension
• Idiopathic
– 90-95% of cases have no known etiology
• Secondary
–
–
–
–
–
–
–
–
Renal Insufficiency
Coarcation of the aorta
Primary Aldosteronism
Thyroid/parathyroid disease
Cushing’s Syndrome
Pheochromocytoma
Sleep Apnea
Increased Intracranial pressure
• Look for secondary causes, but don’t be surprised if you
don’t find them
Hypertension as a Risk Factor
HTN
Hypertension as a Risk Factor
• Hypertension is a primary risk factor for multiple comorbidities
– Ischemic Heart Disease (IHD)
• aka Carotid Artery Disease (CAD), Coronary Heart Disease(CHD)
• Myocardial Infarction (MI)
• Angina (Stable and Unstable)
– Heart Failure (HF)
– Left Ventricular Hypertrophy or Dysfunction (LVH, LVD)
– Cerebrovascular Disease
• Stroke
• Transient Ischemic Attack (TIA)
– Chronic Kidney Disease (CKD)
– Retinopathy
Goals of Hypertensive Therapy
• Long Term
• Short Term
Long Term Goals of Hypertension
Therapy
• Direct Measures
– Reduced Mortality
– Reduced incidence of end organ damage
•
•
•
•
Cardiovascular
Cerebrovascular
Renal
Retinopathy
– Trailing indicators
Short Term Goals of Hypertension
Therapy
• Surrogate markers
– Blood Pressure
– Leading indicator
• Why is blood pressure a good surrogate
marker?
Hypertension and Ischemic Heart Disease
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
Hypertension and Stroke
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
Hypertension and Cardiovascular
Disease
• High Normal = 130-139/85-89mmHg
• Normal = 120-129/80-84mmHg
• Optimal <120/<80mmHg
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004
JNC-7 Hypertension Classifications
DBP = Diastolic Blood Pressure, SBP = Systolic Blood Pressure
*Treatment should be determined by the highest blood pressure
‡Treat patients with chronic kidney disease or diabetes
to BP goal of <130/80mmHg
JNC-7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. 2004
From JNC-7 to 2007 AHA Guidelines
Past Medical History
Primary
Prevention
Blood Pressure Goal
Framingham
Risk Score
<10%
<140/90 mmHg
>10%
Diabetes
Melitus
Chronic Kidney
Disease
<130/80 mmHg
CAD Risk
Equivalents
CAD
Left Ventricular
Dysfunction
<120/80 mmHg
Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008
Framingham Risk Factors and CAD
Equivalents
• Framingham Risk Factors
–
–
–
–
–
–
Age > 45
Total Cholesterol
Smoking
HDL Cholesterol
Systolic Blood Pressure
See ATP III Guidelines for scoring algorithm
• CAD Equivalents
–
–
–
–
Ischemic Stroke
Transient Ischemic Attack
Peripheral Arterial Disease
Abdominal Aortic Aneurysm
Therapy
• Therapeutic Lifestyle Changes (TLC)
– Weight
– Exercise
– Diet
– Smoking
– Caffeine
• Pharmacotherapy
Therapeutic Lifestyle Changes vs.
Pharmacotherapy
Therapeutic Intervention
Approximate SBP Reduction
Weight Reduction (5-10% or 10kg)
5-20mmHg
DASH Diet (Low sodium, low fat)
8-14mmHg
Single Antihypertensive
10mmHg (10 over 5 rule)
30 minutes exercise most days
4-9mmHg
Dietary Sodium Reduction
2-8mmHg
Reduce alcohol to <=2 drinks/day
2-4mmHg
Adapted From: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. 2004
Weight Reduction EBM
• Trials of Hypertension Prevention, Phases I and II
(TOHP I, TOHP II) Late 1980s, early 1990s
– Evaluated Multiple Non-Pharmacological Methods of
weight loss (weight reduction, sodium restriction,
mineral supplementation) in pre-hypertensive (DBP
83-89mmHg female, 80-89mmHg male) and BMI
approximately 25-35
– Sodium Restriction and Weight Loss were the most
effective methods for reducing both SBP and DBP
More Weight Reduction EBM
Rate(%) of Hypertension
Comparison of the 7 year cumulative incidence of hypertension
between active intervention and control groups for weight loss
and sodium reduction interventions.
45
40
35
30
25
20
15
10
5
0
Active
Control
Weight Loss p = 0.02
Sodium Reduction p=0.19
He, J et. al Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of
Hypertension. Hypertension 2000;35:544-549
DASH Diet & Sodium Restriction
DASH Diet & Sodium Restriction
•
•
•
•
•
•
Restricted Sodium
Low Fat
High Fiber
Emphasis on Fruits and Vegetables
High Potassium
High Calcium
EBM of DASH Diet & Sodium
Restriction
• 412 subjects randomized
to typical American diet
(control) or DASH diet
and to three different
sodium levels for 30 days
with a 2 week run in
period
– High 3.5g
– Intermediate 2.3g
(Recommended DASH)
– Low 1.2g
• Typical American diet is
4,100 mg per day for
men and 2,750 for
women (JNC-7)
Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary
Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10
EBM of DASH Diet & Sodium
Restriction
• Controlling for
sodium content, the
DASH diet provides
significant BP
reductions
• Add sodium
restrictions and
further reductions in
BP are obtained
Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary
Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10
Exercise 30 minutes most days
• A 2002 systematic Meta-analysis of
Randomized Control Trials (RCTs) showed the
following results
– BP reductions appear to be independent of weight
loss
– Method of aerobic activity (biking, walking, etc)
did not show a statistically significant link to BP
reductions
– Neither frequency nor intensity of exercise
showed statistically significant reductions in BP
Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: A metaanalysis of randomized, controlled trials. Ann Intern Med 2002;136:493-503. M
Smoking
• Smoking
– In the first year
after quitting,
excess risk of a
cardiovascular
event is cut in
half, and after 515 years, the
rate approaches
that of a never
smoker
Annual Smoking Related Deaths 1995-1999
from Center for Disease Control and Prevention
Caffeine
• Acute vs. Chronic Effects
• Surrogate endpoints vs. Primary Endpoints
Caffeine increases BP
– Acute elevations in Systolic and Diastolic BP
– But what about Morbidity and Mortality ?
Hartley, et al Hypertension Risk Status and Effect of Caffeine on Blood Pressure.
Hypertension 2000;36:137-141
Caffeine’s effects on morbidity and
mortality
– No controlled trials have demonstrated an increased
risk of cardiovascular endpoints
– Several studies have demonstrated no linear
relationship between caffeine consumption and
hypertension rates
• MacDonald, TM, et al. Caffeine Restriction: effect on mild
hypertension BMJ 1991(303)1235-8
• Winkelmayer, WC, et al. Habitual Caffeine Intake and the
Risk of Hypertension in Women. JAMA 2005:(294)18:23302335
– JNC-7 only mentions caffeine in the context of
abstention 30 minutes before taking a BP reading
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
Loop Diuretics – Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Loop Diuretics – Mechanism of Action
• Act mainly in
ascending loop of
Henle to decrease
sodium
reabsorption
• Action is shorter
but more intense
than other
diuretics
• Preferred for
edema vs. BP
management
Na↑ Ca↑
Mg↑ K↑
Thiazide Diuretics – Mechanism of
Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Thiazide Diuretics– Mechanism of
Action
• Increase urinary
excretion
• Works at the distal
convoluted renal
tubules
• Increase urinary
excretion of
potassium
• Additional MOA
– May cause
peripheral
vasodilation, but
this is unclear
Na Cl↑
+ K↑
Potassium Sparing Diuretics –
Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Potassium Sparing Diuretics–
Mechanism of Action
• Mild Diuretic
Effects
• Usually used for
synergistics
effects
Na↑
K↓
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
ACE Inhibitors – Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
ACE
Renin
Angiotensin Receptor Blockers–
Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Renin Inhibitors – Mechanism of
Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
Beta Blockers – Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Non-DHP CCB– Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
Alpha Blockers – Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
DHP CCB– Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
Renin
Antihypertensive Therapies
• Volume Management
– Loop Diuretics
– Thiazide Diuretics
– Potassium Sparing Diuretics
• Including Aldosterone Antagonists (Aldo Ant)
• RAAS Agents
– Angiotensin Converting Enzyme Inhibitors (ACEI)
– Angiotensin II Receptor Blockers (ARB)
– Renin Inhibitors
• Direct Cardiac Agents
– Beta Blockers (BB)
– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
• Vasodilators
– Dihydropyridine Calcium Channel Blockers (DHP CCB)
– Alpha 1 Antagonists
Initial Evaluation
Goals
• Identify target organ damage
• Identify secondary causes
• Identify other CVD risk factors and assess overall
CVD risk
• Identify lifestyle contributory factors
• Identify factors or conditions that influence
therapy decisions (contraindications, indications,
etc.)
Ideal Antihypertensive Drugs
• Prevents all complications of hypertension (all
cause mortality, CVD mortality, CVD events,
renal failure, etc.)
• Effective as monotherapy
• Favorable quality of life profile
• Does not worsen other conditions, safe
• Once a day dosing
• Inexpensive
Examples Surrogate end
•
•
•
•
•
Blood pressure
Glucose, lipids
Carotid artery thickening
Fasting insulin levels
Hemodynamic effects
Benefits of Drug Therapy
• Pharmacotherapy has been associated with the
following benefits:
• 35-40% reduced risk of stroke
• 20-25% decrease in MI
• > 50% decrease in CHF
• Several drug classes are proven to prevent
complications, and a majority of patients will require
combination therapy.
• However, there are important advantages and
disadvantages of the various drugs and drug classes
used to treat hypertension.
Thiazide diuretics
• Place in therapy :“gold standard”.
• More recent studies using low doses of
thiazide diuretics have found reductions in all
CVD events and they are “virtually
unsurpassed” in preventing complications
(JNC-7). Overall, they have the strongest body
of evidence to support their use as a first line
agent.
Antihypertensive and lipid lowering
treatment to prevent heart attack trial
ALLHAT
• Most robust prospective randomized
controlled clinical trial
• Primary end point: Incidence of fatal CHD or
fatal MI
• Secondary outcomes were all-cause mortality
, stroke , combined CHD ( fatal CHD, non-fatal
MI, Coronary revasularization , or angina with
hospitalizations)
ALLHAT: Primary end point
Drug
6-year
rate of
events
(%)
Relative
risk
(95%
CI)
p vs
chlorthalidone
Chlorthalidone
11.5
--
--
Lisinopril
11.4
0.99
(0.911.08)
0.81
Amlodipine
11.3
0.98
(0.901.07)
0.65
ALLHAT Cooperative Research Group. JAMA
2002; 288:2981-2997
Secondary outcomes: Amlodipine vs chlorthalidone
End
point
Amlodipine
(%)
6-year 10.2
rate of
heart
failure
Chlorthalidone
(%)
Relative
p
risk (95%
CI)
7.7
1.38
(1.251.52)
ALLHAT Cooperative Research Group. JAMA
2002; 288:2981-2997
<0.001
Secondary outcomes: Lisinopril vs chlorthalidone
End point Lisinopril
(%)
Chlorthalidone
(%)
Relative
risk
(95%
CI)
p
6-year
33.3
rate of
combined
CVD
30.9
1.10
(1.051.16)
<0.001
6-year
rate of
stroke
6.3
5.6
1.15
(1.021.30)
0.02
6-year
rate of
heart
failure
8.7
7.7
1.19
(1.071.31)
<0.001
ALLHAT Cooperative Research Group. JAMA
2002; 288:2981-2997
ALLHAT subgroup analysis: Relative risk of heart failure
with amlodipine vs chlorthalidone by race
Comparison
Relative 95% CI
risk
p
Overall
1.37
1.24-1.51
<0.001
Blacks
1.46
1.24-1.73
<0.001
Nonblacks
1.32
1.17-1.49
<0.001
Wright JT Jr et al. JAMA 2005; 293:1595-1608.
ALLHAT subgroup analysis: Relative risk of stroke, combined
CVD outcomes, and heart failure by race with lisinopril vs
chlorthalidone
Comparison
Relative 95% CI
risk
Stroke
•Black
participants
•Nonblack
participants
Combined CVD
1.40
1.17-1.68
1.00
0.85-1.17
•Black
1.19
1.09-1.30
•Nonblack
Heart failure
1.06
1.00-1.13
•Black
1.30
1.10-1.54
•Nonblack
1.13
1.00-1.28
Wright JT Jr et al. JAMA 2005; 293:1595-1608.
ALLHAT
• -The ALLHAT study found no advantage of
amlodipine or lisinopril over chlorthalidone in
preventing HTN complications in type 2
diabetics or impaired fasting glucose, and
chlorthalidone was better at preventing CHF,
despite an increased risk of new cases of DM.
(Arch Intern Med 2005;165:1401-9.
•
SHEP STUDY
• - The SHEP study found that diabetics received the
same benefit as non diabetics from low dose
thiazide therapy (JAMA 1996; 276: 1886-92)
•
DM
Non-DM
• CV Events
0.66
0.66
• Stroke
0.78(ns)
0.62
• CHD Events
0.44
0.81(ns)
• Death
0.74(ns)
0.85(ns)
Other Benefits of thiazides include:
•
•
•
•
Effective as monotherapy – no tolerance
Once a day
Inexpensive
Adds to the effectiveness of other classes of
antihypertensives
• Two epidemiologic studies suggest long-term
thiazide use may reduce the risk of hip fractures
• They may be among the best tolerated classes of
antihypertensives
Adverse Effects:
•
•
•
•
Increases in lipids and glucose with high dose.
Decreases in K+, Mg++, and Na+.
Increases in uric acid and calcium.
Drug interactions: NSAIDs, corticosteroids, and
lithium.
• Contraindicated in GFR<30ml/min
Management of Diuretic
Induced Hypokalemia
Prevention
• Low doses of diuretic with or without potassium sparing agent.
Treatment options:
• Discontinue diuretic
• High dose potassium chloride if continue diuretic
• Add potassium-sparing diuretic if continue diuretic
–
–
–
–
–
Most effective regimen
Spares Mg++ as well
Convenient and inexpensive
Positive outcome data
Triamterene and amiloride have minimal BP lowering effect
_ Spironolactone
Potassium Sparing diuretics
• Is it Okay to empirically start all patients with
HTN on fixed doses of combination products
to avoid hypokalemia?
KEY counseling points
• Increased urination when starting the
medication
• Taking the dose in morning to minimize
nocturia
• Signs and Symptoms of hypokalemia
• Consumption of K rich foods
• Salt substitutes
Loop diuretics
• More potent diuretics
• Smaller decrease in PVR , and less vasodilation
• Less effective as antihypertensives as
compared to Thiazide diuretics
• Diuretics of choice in severe CKD
(GFR<30ml/min)
Summary Slide
ACE inhibitors
• Recommended for all compelling indications
• Clearly demonstrated reduction in HTN
related complications
• Patients who cannot take or tolerate first line
agents
ACE inhibitors
• CHF , Diabetes and CKD have a compelling
indication for ARBS
• The overall efficacy appears comparable to
thiazides and CCBs.
• They have a higher rate of stroke and lower rate
of CHF and new cases of DM than CCBs.
• They also have a higher rate of stroke and lower
rate of DM than diuretics.
• Lack metabolic side effects such as lipid or
glucose alterations. Some data suggests ACEI may
reduce the onset of DM.
ACE Inhibitors – Dose Conversions
Generic (Brand)
Typical Daily
Dose (Oral) ‡
Maximum Daily Dose (Oral) ‡ Frequency
Lisinopril
(Prinivil,Zestril)
5-40mg
80mg
‡ Typical oral dose for use in Hypertension. Other indications may have differing doses.
All doses are once daily except where noted
QD
ACE Inhibitors – Mechanism of Action
Sympathetic
Activation
Cardiac
Output
Blood
Pressure
Peripheral
Resistance
Aldosterone
HR
Stroke
Volume
Plasma
Volume
AT II
ACE
Renin
ACE Inhibitors – Side Effects
• Hypotension
• Cough: 5-20% of patients develop a dry nonproductive
• Angioedema
– 1% in general population
– 4% in African Americans
– Also less effective in African American as
monotherapy
• Hyperkalemia
ACE Inhibitors – Monitoring
• Efficacy
– Blood Pressure
• Safety
– Chem 7
• K+
• SCr/BUN
– Angioedema
– Cough
Summary slide
Angiotensin Receptor Blockers(ARB)
• Reserve for patients who cannot tolerate an
ACEI.
• Evidence to support with Type 2 Diabetes
who have diabetic nephropathy with
albuminuria
ANGIOTENSIN RECEPTOR BLOCKERS
MECHANISM OF ACTION
RENIN
Angiotensin I
Angiotensinogen
ACE
Other paths
ANGIOTENSIN II
AT1
RECEPTOR
BLOCKERS
AT1
Vasoconstriction
RECEPTORS
Proliferative
Action
AT2
Vasodilatation
Antiproliferative
Action
ARB Costs
GENERIC
BRAND
DOSE
Telmisarten
MICARDIS
40mg qd
COST/Y
R$
676
Losartan
COZAAR
50mg QD
588
Valsartan
DIOVAN
160mg qd
647
Irbesartan
AVAPRO
150mg qd
542
Olmisartan
BENICAR
20mg qd
538
Adverse effects
• Similar to ACEI’s
• Angiedema
• Both ACE and ARBs contraindicated in
pregnancy and bilateral renal artery stenosis
Summary slide
Calcium channel Blockers(CCB)
• Elderly and Black patients have greater BP
reductions
• Used in Combination with diuretics
• Do not alter Lipids , glucose or electrolyte
Types of CCB
• Dihyropyridines
• Non-dihydropyridines
Calcium Antagonists
Nifedipine
Nicardipine
+++
Verapamil
Diltiazem
Isradipine
Felodipine
Amlodipine
++
+
+++
+++
+++
Coronary
vasodilation
+++
++
+++
+++
+++
+++
Myocardial
contractility
Heart rate
↓/0
↓↓
↓
↓/0
0
0
↑
↓
↓
↑/0
↑
0
AV node
conduction
0
↓↓
↓
0
0
0
Systemic
vasodilation
Calcium Antagonists Costs
GENERIC
diltiazem ER
BRAND
DOSE
COST/YR
$
DILTIA XT
240mg qd
DILACOR XR
257
verapamil SR
CALAN SR
240mg qd
142
verapamil ER
COVERA HS
240mg qd
268
Nifedipine ER
ADALAT CC
60mg qd
563
felodipine ER
PLENDIL
5mg qd
312
amlodipine
NORVASC
5mg qd
110
diltiazem ER
CARDIZEM
CD
PROCARDIA
XL
240mg qd
432
60mg qd
545
nifedipine ER
CCB
• Recommended to treat HTN in patients with
diabetes
• Nondihyropyridines CCB slow the progression
of CKD
• Add on therapy after an ACEI or ARB and
thaizide diuretic
• Additional anti -ischemic effects with BB or
when alternatives to BB are needed
Adverse effects
• Dihydopyridines (nifedipine, nicardipine,
isradipine, amlodipine and felodipine):
headache, dizziness, flushing, peripheral edema,
and reflex tachycardia.
• Verapamil – constipation, dizziness, fatigue,
peripheral edema, heart failure and depressed
A-V conduction.
• Diltiazem—similar to verapamil but less likely to
cause constipation
Beta Blockers
• All the approved beta blockers for hypertension
appear to have similar effectiveness in lowering BP.
• Long-term studies have shown that beta blockers can
reduce the morbidity and mortality from
hypertension, notably stroke and CHF.
• Beta-blockers are effective for treating other
conditions including certain tachyarrhythmia’s and
migraine prophylaxis
Beta blockers
• Several studies suggest beta blocker based
regimens increase the risk of new onset
diabetes (especially when combined with
thiazides) as compared to other drug classes
(Lancet 2005;366:895-906).
Beta –Blockers
• However, meta-analyses suggest that beta-blockers
may be less effective as compared to other
antihypertensive drugs in older patients when used as
initial therapy for primary prevention (Lancet
2005;366:1545-53, CMAJ 2006;174:1737-42).
• Based on the above, beta-blockers are not
recommended as a first-line agents in older patients
without another indication for beta-blocker use. They
also are not the best control treatment in hypertension
primary prevention clinical trials.
Beta blockers
• Use post-myocardial infarction has
demonstrated clear benefit in reducing fatal
and non-fatal recurrent MIs (for non-ISA beta
blockers and acebutolol). Strong clinical
benefit has also been demonstrated for
patients with CHF and angina
Beta Blockers
Alpha- Water Lipid
T½
Cardiosele
Block Solubi Solubi Bioavail (Hour
Drug
ctivity
ISA
ers
lity
lity
ability
s)
Atenolol
+
+
50
6-9
Nadolol
+
40
17-22
Acebutol
+
+
+
+
40
3-6
ol
Pindolol
+++
+
+
90
2-5
Metoprol
+
+
+
40
3-4
ol
Timolol
+
+
75
2-5
Labetolol
+
+
40
3-4
Propranol
+
30
2-5
ol
ISA = intrinsic sympathomimetic activity: T ½ = elimination half-life.
Beta-Blockers
• Reduce morbidity and mortality in patient
with compelling indication s
• (LVD, CAD and diabetes)
• Elderly and black patients may have less BP
control with BB
Beta Blocker Costs
GENERIC
BRAND
DOSE
COST/YR
$
46
atenolol
TENORMIN
50mg qd
propranolol
INDERAL
80mg bid
76
metoprolol
pindolol
LOPRESSOR
50mg bid
VISKIN
10mg bid
59
111
acebutolol
SECTRAL
400mg qd
200
labetalol
NORMODYNE
200mg bid
201
nadolol
CORGARD
80mg qd
190
metoprolol ext. rel.
TOPROL XL
100mg qd
410
carvedilol
Coreg
12.5mg bid
1249
Which BB should be used?
•
•
•
•
Selective vs non –selective
Intrinsic sympathomatic activity
Lipid solubility
Comorbidities
Side effects
•
•
•
•
fatigue
Depression
Metabolic side effects
Hypogycemia
Beta-Blockers
• These agents can cause problems for patients
with asthma, COPD, heart block, brittle
diabetes, and peripheral vascular disease
(nonCS) and may worsen the lipid profile
short-term (decrease HDL, increase TG-non
ISA beta blockers
Monitoring
•
•
•
•
HR ( no less than 60beats/min )
Glucose /lipids
Discontinuation
Exercise intolerance, fatigue, insomnia, cold
extremities can occur. Postural hypotension
with labetalol due to alpha-blocking effects.
Suggestions for selecting
pharmacotherapy factoring in Cost
Condition/Status
Hypertension without
compelling indication
First Choice
Low dose chlorthalidone or
HCTZ or
Alternate
Amlodipine or ACEI
Comments
British guidelines recommend
ACEI if age < 55 and diuretic
or CCB age 55+
African American
Low dose chlorthalidone or
HCTZ
Amlodipine if at risk for diabetes
Isolated systolic hypertension
Low dose chlorthalidone or
HCTZ or amlodipine
ARB
CHF
ACEI + beta-blockers +/spironolactone (severe CHF)
ARB if ACEI cough or
angioedema
ACEI not recommended for
initial therapy but can be used
as add on therapy
Beta-blockers are not
recommended for initial
therapy
Diuretics usually needed as
additive therapy
Prior MI
Angina
Beta-blockers + ACEI
Beta Blockers or CCB
Nephropathy (diabetic and
nondiabetic)
ACEI
ARB if ACEI cough or
angioedema
Diabetes without nephropathy
ACEI or thiazide or
amlodipine
ARB if ACEI cough or
angioedema. Beta-blocker can be
used if first line agents can’t be
used.
Post-stroke
Thiazide + ACEI
Stage 2 hypertension
Thiazide + ACEI or
ACEI + CCB
ARB can replace ACEI if
intolerance to cough or
angioedema.
Consider adding ACEI to
decrease CVD risk
Diuretics often needed as
additive therapy. Goal BP <
130/80
Combination therapy often
required. Goal BP < 130/80.
Some guidelines recommend
ACEI
Not much data to guide
selection of alternative
regimens
Combination therapy is
usually required.
Relative risk of all-cause mortality for beta blockers vs
placebo or other treatments
Comparative
drug
RR of all-cause mortality
for beta blockers
95% CI
Placebo
0.99
0.88–1.11
Diuretics
1.04
0.91–1.19
ACE
inhibitors/
ARBs
1.10
0.98–1.24
Calcium
blockers
1.07
1.00–1.14
Wiysonge CS et al. Cochrane Database Syst Rev
2007;1:CD002003.
Relative risk of total cardiovascular disease for beta
blockers vs placebo or other treatments
Comparative
drug
RR of total CV disease for
beta blockers
95% CI
Placebo
0.88
0.79–0.97
Diuretics
1.13
0.99–1.13
ACE
inhibitors/
ARBs
1.00
0.72–1.38
Calcium
blockers
1.18
1.08–1.29
Wiysonge CS et al. Cochrane Database Syst Rev
2007;1:CD002003.
Relative risk of stroke for beta blockers vs placebo or other
treatments
Comparative
drug
RR of stroke for beta
blockers
95% CI
Placebo
0.80
0.66–0.96
Diuretics
1.17
0.65–2.09
ACE
inhibitors/
ARBs
1.30
1.11–1.53
Calcium
blockers
1.24
1.11–1.40
Wiysonge CS et al. Cochrane Database Syst Rev
2007;1:CD002003.
Relative risk of discontinuing treatment for beta blockers vs
placebo or other treatments
Comparative
drug
RR of stopping treatment
for beta blockers
95% CI
Placebo
2.34
0.84–6.52
Diuretics
1.86
1.39–2.50
ACE
inhibitors/
ARBs
1.41
1.29–1.54
Calcium
blockers
1.20
0.71–2.04
Wiysonge CS et al. Cochrane Database Syst Rev
2007;1:CD002003.