CALCIUM CHANNEL BLOCKERS













Diltiazem vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with diltiazem was similar to placebo

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.

Average hourly BP reduction (CCB minus Placebo)
SBP 9.5 - 13.2 mmHg
DBP 5.9 - 8.5 mmHg




ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD Prevention, JAMA (2002) [PubMed abstract]
  • The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
  • Age > 55 years
  • SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
  • One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
  • History of hospitalized or treated symptomatic heart failure
  • EF < 35%
Baseline characteristics
  • Average age 67 years
  • Race: White - 47% | Black - 32% | Hispanic - 16%
  • Women - 47%
  • Average BP - 146/84
  • Receiving treatment for hypertension - 90%
  • Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
  • Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
  • Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
  • Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
  • Treatment was titrated to a BP goal of < 140/90
  • If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
  • There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results

Duration: Average of 4.9 years
Outcome Chlorthalidone Amlodipine Lisinopril Comparisons
Primary outcome (6-year rate) 11.5% 11.3% 11.4% 1 vs 2 p=0.65 | 1 vs 3 p=0.81
Overall mortality (6-year rate) 17.3% 16.8% 17.2% 1 vs 2 p=0.20 | 1 vs 3 p=0.90
Stroke (6-year rate) 5.6% 5.4% 6.3% 1 vs 2 p=0.28 | 1 vs 3 p=0.02
Heart failure (6-year rate) 7.7% 10% 8.7% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Achieved BP goal (< 140/90) at 1 year 57.8% 55.2% 50.6% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Potassium < 3.5 mEq/L at 2 years 12.7% 2.6% 1.5% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
New-onset diabetes at 4 years 11.6% 9.8% 8.1% 1 vs 2 p=0.04 | 1 vs 3 p<0.001

Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
















PRAISE study - Amlodipine vs Placebo in Severe Heart Failure, NEJM (1996) [PubMed abstract]
  • The PRAISE study enrolled 1153 patients with severe heart failure
Main inclusion criteria
  • NYHA class III or IV heart failure
  • EF < 30%
Main exclusion criteria
  • SBP < 85 or > 159
  • DBP > 89
  • Serum creatinine > 3 mg/dl
  • Treatment with beta blockers
  • Treatment with CCB
Baseline characteristics
  • Average age 64 years
  • NYHA class: III - 81% | IV - 19%
  • Average BP - 117/72
  • Average EF - 21%
Randomized treatment groups
  • Group 1 (571 patients) Amlodipine once daily with a target dose of 10 mg (average dose achieved was 8.8 mg)
  • Group 2 (582 patients) Placebo once daily
  • Almost all patients in the study were taking digoxin, an ACE inhibitor, and diuretics
  • Randomization was stratified by type of heart failure - ischemic or nonischemic dilated cardiomyopathy
Primary outcome: Composite of death from any cause or hospitalization for major cardiovascular event defined as acute pulmonary edema, severe hypoperfusion, acute myocardial infarction, or sustained or hemodynamically destabilizing ventricular tachycardia or fibrillation
Results

Duration: Median of 13.8 months
Outcome Amlodipine Placebo Comparisons
Primary outcome 39% 42% p=0.31
Overall mortality 33% 38% p=0.07
Peripheral edema 27% 18% p<0.05
Pulmonary edema 15% 10% p<0.05
Drug discontinuation 14.4% 16% N/A
  • In the subgroup of patients with nonischemic dilated cardiomyopathy, amlodipine improved both the primary outcome (p=0.04) and overall survival (p<0.001) when compared to placebo
  • The amlodipine group achieved a significantly lower BP than the placebo group at 3 months (SBP and DBP lower by 2 mmHg)

Findings: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.