The ultimate test of therapy for hypertension, myocardial ischemia, and congestive heart failure (CHF) is its ability to reduce morbidity and mortality from cardiovascular causes. Five major morbidity/mortality trials with amlodipine are ongoing or completed. Two other trials in progress are evaluating the effects of amlodipine on the progression of renal disease in hypertensive African-Americans with renal insufficiency and on the development and progression of atherosclerotic lesions in the coronary and carotid arteries of patients with coronary artery disease (CAD). The latter are not appropriately powered morbidity/mortality trials but will provide valuable information about the effects of amlodipine on target organ damage. Salient characteristics of the seven trials are summarized in Table 1.
The reduction in CAD morbidity and mortality resulting from antihypertensive treatment has been disappointing and far less than had been predicted on the basis of epidemiologic data (1,2). One explanation for these results is that the adverse effects of traditional antihypertensive regimens, which include diuretics and β-blockers, may have offset the beneficial effects of blood pressure reduction in early clinical trials. Hypokalemia, hypomagnesemia, hyperuricemia, hyperlipidemia, hyperglycemia, increased insulin resistance, and sudden death have been documented in patients treated for hypertension with high doses of diuretics (3-5). Although the lower doses of diuretics that are now recommended seldom produce these adverse effects, these agents have fallen from favor in clinical practice (6). The newer classes of antihypertensive drugs, particularly the calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors, are the most commonly prescribed drugs for hypertension because of their perceived improved tolerability, which favors increased compliance, and their lack of undesirable metabolic effects. The disadvantages of these agents include their high cost and the unavailability of outcome studies powered to show that they prevent cardiovascular events and cardiovascular and all-cause mortality.
Two long-term randomized trials have compared the effects of representatives of all of the major classes of antihypertensive drugs on blood pressure control in large numbers of patients with essential hypertension (7,8). These included patients with uncomplicated stage 1 and 2 disease. The Treatment of Mild Hypertension Study (TOMHS) was a randomized, double-blind, placebo-controlled clinical trial that compared the effects of five antihypertensive agents from different therapeutic classes (diuretic, β-blocker, calcium channel blocker, ACE inhibitor and α-adrenergic blocker) in combination with lifestyle modification in men and women with stage 1 essential hypertension for an average of 4.4 years of follow-up (7). Outcome measures included blood pressure, quality of life, adverse effects of antihypertensive drugs, blood lipid levels, echocardiographic and electrocardiographic (ECG) changes, and incidence of cardiovascular events. Blood pressure reductions were sizable in all six groups (five drug treatment groups and a group with lifestyle modification alone) and were significantly greater in all drug treatment groups than in the group receiving lifestyle modification alone. Fewer participants in the drug treatment groups died or experienced a nonfatal cardiovascular event than in the lifestyle modification group. Differences among the five drug treatments did not consistently favor one group in terms of any outcome measure. However, amlodipine was better tolerated than the other drug treatments. After 4 years, 82.5% of patients originally randomized to amlodipine were still taking the drug compared to 67.5-77.8% for the other drug treatments. Adverse experiences did not differ significantly among drug treatment groups, except that the diuretic was associated with a significantly higher incidence of erectile dysfunction in men. These results suggest that in selected, well-motivated patients who have uncomplicated stage 1 hypertension, antihypertensive treatment with a drug from any of the five major classes is equally effective in lowering blood pressure. Importantly, the study lacked the statistical power to discriminate among the relatively small individual drug treatment groups with respect to outcome.
THE ANTIHYPERTENSIVE AND LIPID-LOWERING TREATMENT TO PREVENT HEART ATTACK TRIAL (ALLHAT)
Long-term controlled clinical trials are needed to clarify the relative benefits and risks of blood pressure reduction with different classes of antihypertensive agents with respect to mortality and cardiovascular end points. To shorten the period of observation needed before sufficient numbers of morbidity and mortality end points are observed, these trials select for hypertensive individuals who are at high risk for cardiovascular events because of age and/or coexistence of other cardiovascular risk factors. In general, 3-5 years of follow-up are required to reach significant differences in cardiovascular disease (CVD) outcomes between the treatment arms of these costly and complex clinical trials. These critical data are needed to provide us with a fully informed basis for the choice of optimal antihypertensive therapy. The largest and most ambitious of these trials now in progress is the ALLHAT trial.
The ALLHAT trial is a practice-based, double-blind, prospective, randomized clinical trial that will enroll 40,000 high-risk hypertensive patients 55 years of age and older, of whom a substantial majority will be black (9). The ALLHAT trial is being carried out in the United States and Canada, and has two components. The anti-hypertensive component is a randomized, double-blind trial designed to determine whether the combined incidence of fatal CAD and nonfatal myocardial infarction (MI) differs between diuretic treatment (chlorthalidone) and three alternative antihypertensive drug treatments: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an α-adrenergic blocker (doxazosin). The lipid-lowering component is a randomized, open-label trial that will determine whether lowering serum cholesterol in 10,000 moderately hypercholesterolemic men and women 55 years of age and older (a subset of the 40,000 subjects in the antihypertensive trial) with an HMG CoA reductase inhibitor will reduce all-cause mortality compared to a control group receiving "usual care."
The primary hypothesis of the antihypertensive trial component is that the combined incidence of fatal CAD and nonfatal MI (first or recurrent) will be lower in hypertensive patients randomized to a calcium channel blocker, an ACE inhibitor, or an α-adrenergic blocker than in those randomized to a thiazide-like diuretic as first-line therapy. Secondary hypotheses are that the following end points will be reduced in patients randomized to a calcium channel blocker, ACE inhibitor, or α-adrenergic blocker compared to those randomized to a thiazide-like diuretic: (a) all-cause mortality; (b) combined CAD, revascularization procedures, or hospitalized angina; (c) stroke; (d) combined cardiovascular disease (CAD, stroke, coronary revascularization procedures, angina, CHF, or peripheral arterial disease); (e) left ventricular hypertrophy (LVH) by ECG; (f) renal disease (slope and reciprocal of serum creatinine, or end-stage renal disease); (g) health-related quality of life; and (h) major costs of medical care. To maximize statistical power for the antihypertensive trial, 1.7 times as many patients will be assigned to the diuretic arm as to each of the three other treatment arms (10).
The primary hypothesis of the lipid-lowering component is that mortality from all causes will be lower in the subset of hypertensive patients with low-density lipoprotein (LDL) cholesterol levels of 120-189 mg/dl (100-129 mg/dl for those with known CAD) who are randomized to receive the HMG CoA reductase inhibitor pravastatin plus a cholesterol-lowering diet [National Cholesterol Education Program (NCEP) Step I diet, USA] than in those randomized to receive diet plus usual care (11).
To qualify for ALLHAT, a patient must have hypertension and at least one other cardiovascular risk factor ([LVH, noninsulin-dependent diabetes mellitus, smoking, high-density lipoprotein (HDL) cholesterol <35 mg/dl, ST-T-wave changes indicative of ischemia on ECG, or one or more manifestations of atherosclerotic cardiovascular disease]. This can include previous MI or stroke, a history of revascularization procedure, or otherwise documented features of atherosclerotic cardiovascular disease). Untreated patients must have stage 1 or 2 hypertension (blood pressure 140-180/90-110 mm Hg) and treated patients, blood pressure ≤160/110 mm Hg when first seen and ≤180/110 mm Hg at the second visit (when medication may have been partially withdrawn), to qualify for the trial. Patients with more severe hypertension are excluded because of the small probability that they can be controlled with monotherapy alone.
Patients are randomized to receive treatment with a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), or an α-adrenergic receptor antagonist (doxazosin) as first-line therapy in the doses indicated in Table 2. The blood pressure goal in all four treatment arms is <90 mm Hg diastolic and <140 mm Hg systolic. For patients in whom satisfactory blood pressure control cannot be achieved at the maximal tolerable dose of their first-line drug, a number of second- and third-line drugs are available in open-label form (Table 2). The choice of second- and third-line drugs is at the discretion of the investigator. These are to be used in addition to, not in place of, the first-line drug, unless the first-line drug is not tolerated.
The mean duration of treatment and follow-up for ALLHAT patients is planned to be 6 years. Procedures are in place for early discontinuation of the trial or a portion of the trial if any of the first-line drugs is associated with unfavorable outcomes.
THE ANGLO-SCANDINAVIAN CARDIAC OUTCOMES TRIAL (ASCOT)
The concept is similar to that of the ALLHAT trial. A total of 18,000 high-risk hypertensive patients will be randomized to receive amlodipine or atenolol as baseline therapy, using a PROBE (Prospective Randomized Open Blinded Endpoints) design. If additional therapy is needed, perindopril will be added to the amlodipine arm and bendrofluazide to the atenolol arm to compare a "contemporary" regimen with the standard recommended β-blocker plus diuretic. A doxazosin gastrointestinal therapeutic system (GITS) may be used as third-line therapy if needed.
A lipid-lowering arm is also included. Patients with a total cholesterol ≤6.5 mmol/l and total cholesterol:HDL ratio ≤4.5, i.e., levels that would usually not be treated medically, will be randomized to atorvastatin vs. placebo.
The primary end point is fatal CAD and nonfatal MI. A number of secondary and tertiary end points will also be studied.
THE PROSPECTIVE RANDOMIZED AMLODIPINE SURVIVAL EVALUATION TRIAL (PRAISE)
Treatment with short-acting calcium channel blockers has been shown to worsen CHF and to increase the risk for death in patients with severe LV dysfunction (12-15). Physicians have therefore been advised to avoid these drugs in patients with CHF, even though they may be indicated for treatment of coexistent angina or hypertension (16). Whether adverse effects on CHF are common to all calcium channel blockers was unknown at the time the PRAISE trial was initiated. Two short-term (8-12-week) controlled trials had shown that amlodipine improved symptoms and exercise tolerance without adversely affecting the clinical status of patients with CHF (17,18). Because of their brief duration and the small number of patients enrolled (<300), these studies lacked the statistical power to assess the effects of amlodipine on cardiovascular disease outcomes and mortality. The PRAISE trial was therefore designed to address the safety issue in patients with advanced CHF.
The PRAISE trial has examined the long-term effects on morbidity and mortality of adding amlodipine to conventional therapy (diuretic + digitalis + ACE inhibitor) in patients with severe CHF. A total of 1,153 patients with class III (80%) or class IV (20%) CHF secondary to CAD (n = 732) or nonischemic dilated cardiomyopathy (n = 421) were randomized to amlodipine plus usual care or placebo plus usual care, and were followed for a median of 13.8 months (19). The average ejection fraction of all enrollees was 21%. Randomization was stratified by etiology of the CHF, because the a priori hypothesis of the study was that amlodipine might affect patients differently depending on the cause of their heart disease.
The diagnosis of CAD in PRAISE was made by the clinical judgment of the investigators, rather than by coronary angiography, so that the findings could be generalized to usual practice. The primary end point of the study was the combined risk for all-cause mortality and cardiovascular morbidity, defined as hospitalization for ≥24 h for acute pulmonary edema, severe hypoperfusion, acute MI, or sustained or hemodynamically destabilizing ventricular tachycardia or fibrillation. The major secondary end point of the study was all-cause mortality.
Overall, there were 222 primary events (39%) (fatal and nonfatal) in the amlodipine-treated patients and 246 events (42%) in the placebo group. Amlodipine therapy was associated with a 9% (NS) reduction in risk for a primary event. There were 190 deaths (33%) in the amlodipine group and 223 deaths (38%) in the placebo group, giving a 16% reduction in risk for death in the amlodipine group (p = 0.07). For both all-cause mortality (p = 0.004) and the combined primary end point (p = 0.04), there was a significant interaction between treatment and etiology of the CHF. The effects of amlodipine were therefore analyzed separately in the two strata.
In patients with nonischemic dilated cardiomyopathy, amlodipine treatment reduced the risk for combined fatal and nonfatal events and for all-cause mortality (Fig. 1). Combined fatal and nonfatal events totaled 78 in the placebo group and 58 in the amlodipine group, a 31% reduction (p = 0.04). Furthermore, there were 74 deaths in the placebo group vs. 45 in the amlodipine group, a 46% reduction in all-cause mortality (p < 0.001).
Amlodipine had no effect no risk for either combined fatal and nonfatal events or all-cause mortality in patients with ischemic heart disease as the cause of their CHF (Fig. 2). In the ischemic stratum, there were 168 combined fatal and nonfatal events in the placebo group and 164 in the amlodipine group, 45% of both treatment groups. There were 126 deaths in the placebo group and 123 in the amlodipine group, 34% of both groups.
Peripheral edema and pulmonary edema were more common with amlodipine than with placebo. The peripheral edema associated with amlodipine treatment was not accompanied by weight gain, which probably reflected dihydropyridine calcium channel blocker-induced peripheral vasodilatation rather than worsening of CHF. Furthermore, the pulmonary edema associated with amlodipine was not correlated with other measures of disease progression and occurred in only a small percentage of patients. Accordingly, the authors postulated that it was related to amlodipine-induced dilatation of pulmonary arteries rather than an effect on the heart. There were 10 neoplasms (2%) in the placebo group and nine (2%) in the amlodipine group.
The PRAISE trial demonstrated that amlodipine has no adverse effect on the natural history of CHF, even in class IV patients. Specifically, amlodipine treatment was not associated with increased mortality or worsening signs or symptoms of CHF or with increased frequency of MI, life-threatening arrhythmias, or hospitalization for serious cardiovascular events. In addition, worsening angina and uncontrolled hypertension were reported less frequently in amlodipine-treated patients than in controls. These findings suggest that amlodipine can be used safely in patients with CHF, even with class IV disease. In contrast, earlier reports of the use of shorter-acting calcium channel blockers in chronic CHF had demonstrated increased risk for worsening heart failure, MI, and death (13-15,20). Although the pathophysiologic mechanisms of these adverse effects are not clearly understood, they have generally been attributed to the negative inotropic effects of these agents, with secondary activation of the sympathadrenal and renin-angiotensin systems (21). Whether the safety of amlodipine in CHF is related to its vasoselectivity, to its slow onset, its sustained action, and/or to other mechanisms is unclear, as discussed by Packer et al. (19). It should be noted that there are conflicting results for the sustained-release formulation of the dihydropyridine calcium channel blocker felodipine from studies not powered to show a difference in morbidity/mortality. This agent has recently been shown to be safe in patients with CHF (22), supporting the hypothesis that long-acting dihydropyridine calcium channel blockers are well tolerated in CHF. However, another study suggested that it resulted in worsening CHF (23).
The finding of a selective beneficial effect of amlodipine in patients with nonischemic dilated cardiomyopathy was unexpected and unexplained by the parameters measured in the PRAISE trial. Benefit was seen for both primary and secondary end points. Although previous trials of antiarrhythmic therapy (24) and β-adrenergic blocker therapy (25) in patients with CHF have reported a positive treatment effect in patients with nonischemic cardiomyopathy only, the mechanism of this preferential effect remains unknown. The PRAISE-2 trial has been undertaken, in part, to clarify these issues. PRAISE-2 will use a design similar to that of PRAISE to study larger numbers (n = 1,800) of patients with nonischemic dilated cardiomyopathy, and will include subgroup analyses of the effects of age, gender, and baseline LV function on outcome. The primary end point is total mortality.
CLINICAL TRIALS OF THE EFFECTS OF AMLODIPINE ON TARGET ORGAN DAMAGE
The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), is a double-blind, placebo-controlled angiographic trial of over 800 patients followed for 3 years. This trial will compare the effects of amlodipine vs. placebo on the development and progression of atherosclerotic lesions in the coronary and carotid arteries.
The African-American Study of Kidney Disease (AASK) trial is evaluating the effects of amlodipine on the progression of renal disease in hypertensive African-Americans with renal insufficiency. Comparator drugs in this double-blind trial are ramipril and metoprolol. The sample size for AASK is 1,151 participants, the end point is development of renal dysfunction, and the follow-up period is approximately 7 years.
The PRAISE trial has already provided important information about the role of amlodipine in CVD patients. All of the clinical trials reviewed here, involving over 60,000 individuals, will give further insight into the safety and efficacy of amlodipine in preventing death and disability caused by CVD.
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Official Satellite Symposium for the XVIIth Congress of the European Society of Cardiology, The National Exhibition Centre, Birmingham, United Kingdom August 28, 1996