Hypertension: New Trials – Best Treatments

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HypertensionNew Trials Best Treatments

• Karen Moncher, MD
• Assistant Professor
• University of Wisconsin School of Medicine and
  Public Health

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Overview

• Epidemiology
• Clinical Trials and Trends
• All things old become new again
• Management Guidelines
• Compelling reasons for treatment
• Management based on patient problems and
  pharmacology
• Patient Adherence

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Top 10 HTN RX Problems

• 10. Lack of Public Awareness 68
• 9. Lack of Provider Awareness - Systolic BP
• 8. Lack of Treatment 54
• 7. Lack of Provider Awareness Lifestyle RX
• 6. Providers / Patients - office BP is higher
• 5. Thought that BP rise with age is not a risk

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Top 10 HTN RX Problems

• 4. Lack of use of combination therapy, especially
  with inexpensive thiazide diuretic (concept that
  thiazide is synergistic with all)
• 3. Inappropriate choice of antihypertensive agent
  based on patient
• 2. Providers and patients underestimate the
  benefits of RX, assume less Quality of Life
• 1. Adherence - Adherence - Adherence

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Percent Decline in Age-Adjusted Mortality Rates
for Stroke by Sex and Race United States, 1972-94
The decline in age-adjusted mortality for stroke
in the total population is 59.0. Age-adjusted
to the 1940 U.S. census population.
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Percent Decline in Age-Adjusted Mortality Rates
for CHD by Sex and Race United States, 1972-94
The decline in age-adjusted mortality for CHD in
the total population is 53.2. Age-adjusted to
the 1940 U.S. census population.
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Incidence of Reported End-Stage Renal Disease
Therapy, 1982-1995
253
Provisional data. Adjusted for age, race, and
sex.
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Demographic Trends
Elderly US population will double baby boomer
generation
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Risk Factors, Including Hypertension and
Dyslipidemia, Promote CVD by Contributingto
Endothelial Dysfunction
Smoking
Hypertension
Dyslipidemia
Diabetes
Endothelial dysfunction
Atherosclerosis
CVD
Liao. Clin Chem. 1998441799-1808 Spieker et
al. J Hum Hypertens. 200014617-630 Belton et
al. Circulation. 2000102840-845 Ross. N Engl J
Med. 1999340115-126.
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Overview

• Epidemiology
• Clinical Trials and Trends
• All things old become new again
• Management Guidelines
• Compelling reasons for treatment
• Management based on patient problems and
  pharmacology
• Patient Adherence

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Major Outcomes in High Risk Hypertensive Patients
Randomized to Angiotensin-Converting Enzyme
Inhibitor or Calcium Channel Blocker vs Diuretic

• The Antihypertensive and Lipid-Lowering Treatment
  to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT Collaborative Research Group Sponsored
by the National Heart, Lung, and Blood Institute
(NHLBI)
JAMA. 20022882981-2997 Dec. 18, 2002
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ALLHAT Trial Design

• Randomized, double-blind, multi-center clinical
  trial
• Determine whether occurrence of fatal CHD or
  nonfatal MI is lower for high-risk hypertensive
  patients treated with newer agents (CCB, ACE-I,
  alpha-blocker) compared with a diuretic
• Known ASCVD, DM, smoker, LVH, low HDL
• 42,418 high-risk hypertensive patients 55 years

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ALLHATJAMA 2002 Dec. 18

• 33357 men and women - diverse races
• HTN and at least one other CHD risk factor
• Compared Thiazide, Lisinopril, Amlodipine, and
  previously stopped doxazosin arm
• Primary outcome Fatal CHD or non-fatal MI
• Secondary outcomes
• Total Mortality - CVA
• Combined CHD - CHF

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ALLHAT Step 1Treatment Protocol
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BP Results by Treatment Group
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Cumulative Event Rates for All-Cause Mortality by
ALLHAT Treatment Group
Chlorthalidone Amlodipine Lisinopril
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Cumulative Event Rates for Combined CVD by ALLHAT
Treatment Group
Chlorthalidone Amlodipine Lisinopril
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Cumulative Event Rates for Heart Failure by
ALLHAT Treatment Group
.15
.12
Chlorthalidone Amlodipine Lisinopril
.09
Cumulative CHF Rate
.06
.03
0
0
1
2
3
4
5
6
7
Years to HF
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Biochemical Results
plt.05 compared to chlorthalidone Ann Intern
Med. 1999130461-470
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ALLHAT Conclusions

• Amlodipine (representing CCB), lisinopril
  (representing ACE-I) and chlorthalidone
  (representing thiazide-type diuretics) were
  comparable in preventing major coronary events
  or increasing overall survival.
• Although chlorthalidone did not differ from
  amlodipine in overall CVD event prevention, it
  was superior to amlodipine in preventing heart
  failure.

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ALLHAT Conclusions

• Chlorthalidone was superior to lisinopril in
  preventing aggregate CV events, principally
  stroke, HF, angina, and coronary
  revascularization
• Chlorthalidone was superior to doxazosin
  (representing alpha-blockers) in preventing CV
  events, including both HF and other CVD.

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Overall Conclusions
Because of the effectiveness of thiazide-type
diuretics in preventing one or more major forms
of CVD and their lower cost, they should be the
drugs of choice for first-step antihypertensive
drug therapy, unless there are other compelling
indications.
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Isolated Systolic Hypertension

• Systolic Pressure ??140 mmHg
• Diastolic lt 90 mmHg

JNC VI Report, NIH, NHLBI
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SHEP Study

• Treatment of elderly patients with ISH
• Thiazide diuretic plus atenolol if needed
• Stroke, total mortality, CVD events
• 63 patients had BP controlled with diuretic
  alone
• CVA reduced 36 (3/100) and CVD events reduced 6
  per 100 in 4.5 years
• JAMA 19912653255-3264

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HTN in the Elderly Trial

• ACE (enalapril) vs. HCTZ
• 6083 adults with HTN aged 65 - 84 years
• Australia Family Practice clinics
• Open-label study in multiple practices
• BP reduction was the same 26/12 mm Hg
• All CVD events or death reduced for men (17 or
  approximately 4 / 100)
• No difference in events for women
• NEJM 2003348583-592

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BP-Lowering Treatment Trialists
Meta-analysisComparisons of Active Treatments
and Control
BP Difference From Placebo(SBP/DBP mm Hg)
Relative Risk
RR (95 CI)
Stroke
0.72 (0.64, 0.81)
ACEI vs placebo
-5/-2
Coronary heart disease
0.80 (0.73, 0.88)
-5/-2
ACEI vs placebo
Heart failure
-5/-2
0.82 (0.69, 0.98)
ACEI vs placebo
Major CV events
-5/-2
ACEI vs placebo
0.78 (0.73, 0.83)
CV mortality
-5/-2
ACEI vs placebo
0.80 (0.71, 0.89)
Total mortality
-5/-2
ACEI vs placebo
0.88 (0.81, 0.96)
0.5
1.0
2.0
FavorsActive
FavorsControl
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
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BP-Lowering Treatment Trialists Meta-analysis
Comparisons of Different Active Treatments
BP Difference Between Rx(SBP/DBP mm Hg)
Relative Risk
RR (95 CI)
Major CV events
1.02 (0.98, 1.07)
2/0
ACEI vs D/BB
1.04 (1.00, 1.09)
1/0
CA vs D/BB
0.97 (0.92, 1.03)
1/1
ACEI vs CA
CV mortality
1.03 (0.95, 1.11)
ACEI vs D/BB
2/0
1.05 (0.97, 1.13)
CA vs D/BB
1/0
1.03 (0.94, 1.13)
ACEI vs CA
1/1
Total mortality
1.00 (0.95, 1.05)
2/0
ACEI vs D/BB
0.99 (0.95, 1.04)
1/0
CA vs D/BB
1.04 (0.98, 1.10)
1/1
ACEI vs CA
FavorsFirst Listed
FavorsSecond Listed
0.5
1.0
2.0
Ddiuretic BB?-blocker. Blood Pressure Lowering
Treatment Trialists Collaboration. Lancet.
20033621527-1535.
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BP-Lowering Treatment Trialists Meta-analysis
Comparisons of Different Active Treatments
BP Difference Between Rx(SBP/DBP mm Hg)
Relative Risk
RR (95 CI)
Stroke
1.09 (1.00, 1.18)
ACEI vs D/BB
2/0
0.93 (0.86, 1.00)
CA vs D/BB
1/0
1.12 (1.01, 1.25)
ACEI vs CA
1/1
Coronary heart disease
0.98 (0.91, 1.05)
ACEI vs D/BB
2/0
1.01 (0.94, 1.08)
CA vs D/BB
1/0
0.96 (0.88, 1.04)
ACEI vs CA
1/1
Heart failure
1.07 (0.96, 1.19)
ACEI vs D/BB
2/0
CA vs D/BB
1.33 (1.21, 1.47)
1/0
ACEI vs CA
0.82 (0.73, 0.92)
1/1
FavorsFirst Listed
FavorsSecond Listed
0.5
1.0
2.0
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
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Overview

• Epidemiology
• Clinical Trials and Trends
• All things old become new again
• Management Guidelines
• Compelling reasons for treatment
• Management based on patient problems and
  pharmacology
• Patient Adherence

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National Guidelines Recognize the Relationship
Between Hypertension and Dyslipidemia

• JNC 7 recommends assessing a patients lipid
  profiles when setting appropriate BP treatment
  goals
• NCEP ATP III recognizes hypertension as a major
  risk factor that modifies lipid goals

When hypertension or dyslipidemia is
diagnosed,test for the other condition.
Chobanian et al. JAMA. 20032892560-2572. Expert
Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA.
20012852486-2497.
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JNC 7 Classification and Management of BP for
Adults
Treatment determined by highest BP
category. Treat patients with chronic kidney
disease or diabetes to BP goal of lt130/80 mm Hg.
Initial combined therapy should be used
cautiously in those at risk for orthostatic
hypotension. ARBangiotensin-II receptor blocker
CCBcalcium-channel blocker. Chobanian et al.
JAMA. 20032892560-2572.
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JNC 7 Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (lt140/90 mm Hg)
(lt130/80 mm Hg for those with diabetes or
chronic kidney disease)
Initial Drug Choices
Chobanian et al. JAMA. 20032892560-2572.
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Algorithm for Treatment of Hypertension
Not at Goal Blood Pressure
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Laboratory Tests Recommended Before Initiating
Therapy

• Urinalysis
• Complete blood count
• Blood chemistry (potassium, sodium, creatinine,
  and fasting glucose)
• Lipid profile
• 12-lead electrocardiogram

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Physical Examination

• Blood pressure readings (2 or more)
• Height, weight, and waist circumference
• Funduscopic examination
• Examination of the neck, heart, lungs, abdomen,
  and extremities
• S4 IMPORTANT!
• Neurological assessment

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Examples of IdentifiableCauses of Hypertension

• Renovascular disease
• Renal parenchymal disease
• Polycystic kidneys
• Aortic coarctation

• Pheochromocytoma
• Primary aldosteronism
• Cushing syndrome
• Hyperparathyroidism
• Exogenous causes

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Blood Pressure Lifestyle

• Blood Pressure is highly sensitive to weight
  loss
• 5 - 10 weight loss will often control BP
• Dietary Approaches DASH (SBP 11 DBP 8)
• 6 servings of fruits / vegetables
• low sodium (no added salt)
• low to no alcohol
• high calcium, low fat
• NEJM 20013443-9
• www.nhlbi.nih.gov/health/public/heart/hbp/dash

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Sodium Recommendations

• No Added Salt (2400 mg/day)
• Hypertension, impaired liver function,
  cardiovascular disease, cardiac failure, and
  acute and chronic renal failure.
• 1000 mg (45 mEq)
• Cirrhosis of the liver, pulmonary edema,
  moderate to severe cardiac failure, acute and
  chronic liver failure.
• For short term use only due to decreased
  palatability and adherence.

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Pharmacologic Treatment

• Decreases cardiovascular morbidity and mortality
  based on randomized controlled trials.
• Protects against stroke, coronary events, heart
  failure, progression of renal disease,
  progression to more severe hypertension, and
  all-cause mortality.

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Algorithm for Treatment ofHypertension
Initial Drug Choices

• Uncomplicated
• Diuretics
• b-blockers
• When other compelling reasons (or others are
  contraindicated)
• ACE or Calcium Blocker

Based on randomized controlled trials.
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Algorithm for Treatment of Hypertension
(continued)
Initial Drug Choices

• Compelling Indications
• Heart failure
• ACE inhibitors
• Diuretics
• Myocardial infarction
• b-blockers (non-ISA)
• ACE inhibitors (with systolic dysfunction)
• Diabetes mellitus (type 1) with proteinuria
• ACE inhibitors
• Isolated systolic hypertension (older persons)
• Diuretics preferred
• Long-acting dihydropyridine calcium antagonists

Based on randomized controlled trials.
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Algorithm for Treatment ofHypertension
(continued)
Initial Drug Choices
Specific indications for the following drugs

• ACE inhibitors
• Angiotensin II receptor
• blockers
• a-blockers

• a-b-blockers
• b-blockers
• Calcium antagonists
• Diuretics

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Specific Drug Indications
Some antihypertensive drugs may have favorable
effects on co-morbid conditions

• Angina
• b-blockers
• Calcium blockers
• Atrial tachycardia and fibrillation
• b-blockers
• Non-dihydropyridine
• calcium antagonists

• Heart failure
• Carvedilol
• Losartan
• Myocardial infarction
• Diltiazem
• Verapamil

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Specific Indications (continued)
Some antihypertensive drugs may have favorable
effects on comorbid conditions

• Cyclosporine-induced hypertension
• Calcium blockers
• Diabetes mellitus (1 and 2) with proteinuria
• ACE inhibitors (preferred)
• Calcium blockers
• Diabetes mellitus (type 2)
• Low-dose diuretics

• Dyslipidemia
• a-blockers
• Prostatism (benign prostatic hyperplasia)
• a-blockers
• Renal insufficiency (caution in renovascular
  hypertension and creatinine lt 3 mg/dL
• - ACE inhibitors

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Patients Undergoing Surgery

• Those not on prior drug therapy may be best
  treated with cardio-selective b-blockers before
  and after surgery.
• Those with controlled blood pressure should
  continue medication until surgery and begin as
  soon after surgery as possible.

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Using Thiazide Diuretics

• Can use either HCTZ or chlorthalidone
• Use only 12.5 - 25 mg. Daily
• Higher doses no more effective, and have more
  side effects and electrolyte problems
• Do not affect lipids or glucose significantly
• Do result in LVH regression
• Synergistic with all other classes of medications
  reduce plasma volume

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Gout

• Diuretics can increase serum uric acid levels.
• Diuretics should be avoided in patients with
  gout.
• Diuretic-induced hyperuricemia does not require
  treatment in the absence of gout or urate stones.

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Using ACE Inhibitors

• Patients with
• Diabetes Mellitus
• Nephropathy / Albuminuria
• Post- MI
• Congestive Heart Failure
• Once daily (except captopril)
• Use ARB if cough develops
• Use with care if hyperkalemia / CRF

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Angiotensin Receptor Blocker and Hypertension

• LIFE Trial
• Losartan vs. Atenolol (w / HCTZ if needed) for
  9193 patients Hypertension aged 55-80 years
• BP decrease 28/9 mmHg both groups
• CVD mortality 8.7 vs 16.9 (46 reduction)
• Stroke 10.6 vs 18.9 (40 reduction)
• New DM 12.6 vs 20.1 (38 reduction)
• Total Mortality 21.2 vs 30.2 (54 reduction)
• per 1000 patient-yrs JAMA 20022881491

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Uses of Calcium Blockers

• Isolated Systolic HTN / Elderly
• African Americans w/better response
• CHD Angina
• HTN resistant especially with a diuretic
• Exercise induced HTN
• Peripheral arterial disease
• Migraine HTN

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Calcium Blockers

• A calcium blocker is not a calcium blocker
• AV node inhibitors / modest vasodilators
• Verapamil
• Diltiazem
• Vasodilators Dihydropyridines
• Amlodipine (Norvasc)
• Felodipine (Plendil)
• Nifedipine also negative iontrope / adrenergic

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Algorithm for Treatment ofHypertension
Initial Drug Choices
Not at Goal Blood Pressure (lt 140/90 mm Hg)
No response or troublesome side effects
Inadequate response but well tolerated
Substitute another drug from different class
Add second agent from different class (diuretic
if not already used)
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Causes for InadequateResponse to Drug Therapy

• Nonadherence to therapy / lifestyle
• Alcohol use
• Volume overload
• Failure to add a diuretic
• Drug-related causes
• Non-steroidal anti-inflammatories
• Identifiable causes of hypertension

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Overview

• Epidemiology
• Clinical Trials and Trends
• All things old become new again
• Management Guidelines
• Compelling reasons for treatment
• Management based on patient problems and
  pharmacology
• Patient Adherence

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Guidelines for ImprovingAdherence to Therapy

• Close follow-up 4 6 weeks
• Prescribe long-acting / once daily medications
• Adjust therapy to minimize adverse affects
• Use synergistic medications
• Utilize other health professionals
• Consider using nurse case management
• Involve the patient in self-care

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Advantages of Self-Measurement

• Identifies white-coat hypertension
• Assesses response to medication
• Improves adherence to treatment
• Potentially reduces costs
• May confirm HTN to patient and may provide lower
  readings than those recorded in clinic

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Thank you!Questions?
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Additional Slides
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A population-wide strategy to reduce overall
blood pressure by only a few mm Hg could affect
overall cardiovascular morbidity and mortality as
much as or more than treatment alone.
A Population-Wide Strategy
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Lifestyle Modifications

• For Prevention and Management
• Lose weight if overweight.
• Limit alcohol intake.
• Increase aerobic physical activity.
• Reduce sodium intake.
• DASH diet

• For Overall and Cardiovascular Health
• Maintain adequate intake of calcium and
  magnesium.
• Stop smoking.
• Reduce dietary saturated fat and cholesterol.
• Increase fruits/vegetables/fiber and healthy oils

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Children and Adolescents

• Blood pressure at 95th or higher percentile is
  considered elevated.
• Lifestyle modifications should be recommended.
• Drug therapy should be prescribed for higher
  levels of blood pressure.
• Attempts should be made to determine other causes
  of high blood pressure and other cardiovascular
  risk factors.

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95th Percentile of Blood Pressure by Selected
Ages and Height in Girls
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95th Percentile of Blood Pressure by Selected
Ages and Height in Boys
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Classification of Blood Pressure for Adults
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