Late-Breaking Clinical Trials
December 1, 1998 8 minutes read
Late-Breaking Clinical Trials
conference coverage
Synopsis: Several studies were recently reported that should influence cardiology practice.
Source: American Heart Association Annual Scientific Sessions, November 8-11, 1998, Dallas, TX.
PREVENT
Prevent (prospective randomized evaluation of vascular events of Norvasc Trial) study is a 17-center randomized trial assessing the effects of amlodipine or placebo on the atherosclerotic process as well as clinical coronary artery disease (CAD) end points in individuals with documented coronary disease. The rationale for the trial relates to previous data suggesting that calcium antagonists may slow the progression of coronary atherosclerosis, particularly early or minor lesions. The trial took place between 1992 and 1997. Eight hundred twenty-five patients were randomized to amlodipine or a placebo, with a minimum three-year follow-up. Subjects were treated with amlodipine or a placebo of 10 mg/d for three years. Serial quantitative coronary arteriography was carried out at baseline and at the end of the study; at seven centers, serial carotid ultrasound measurements were made every six months. The primary end point was a decrease in progression of coronary atherosclerosis in specific arterial segments that had a baseline of less than 30% stenosis. Secondary end points included arteriographic status of other coronary lesions, serial B-mode carotid ultrasound, standard clinical events, and safety. The patient population was predominantly male, with a mean age of 57. Approximately one-quarter were smokers, more than 40% had a prior myocardial infarction, and almost 70% had angina pectoris. The majority of patients had single-vessel disease, 24% had two-vessel disease, and 20% had three-vessel disease. The coronary segment in each patient that was the site of arterographic analysis was not anticipated to need percutaneous intervention or bypass within three years.
The primary end point showed no benefit, with failure to demonstrate a difference between amlodipine and the placebo for coronary lesions of less than 30%, as well as 30-50%, and greater than 50%, over the course of the study. However, the secondary end point of carotid intimal-medial thickness (IMT) was a positive effect for amlodipine, with a reduced IMT in an analysis of four of 12 walls of the internal and external carotid arteries. Regarding clinical events, there was a 31% decrease in total CAD events and procedures, although there was no reduction in mortality or nonfatal myocardial infarction. There was no significant reduction in any major vascular event. However, hospitalization for angina pectoris was reduced by 33% (P = 0.02), and need for revascularization was reduced by 33% (P = 0.001). Revascularization was decreased by 46%; there was 48% less angioplasty in the amlodipine cohort and 42% less CABG. With respect to adverse events, there was no difference between the placebo and amlodipine regarding serious side effects, discontinuation rates, cancer, or bleeding. In summary, amlodipine did not decrease early coronary lesions in the coronary bed but appeared to slow carotid atherosclerosis. While there was no decreased risk for major vascular events, there was a decrease in the number of hospitalizations for angina as well as coronary revascularization procedures. Patients on and off beta-blockers appeared to respond equally.
Comment by Jonathan Abrams, MD
Amlodipine is the most widely used cardiovascular drug in the world. Many studies in patients with angina as well as hypertension have been positive. The drug is well tolerated and is the standard dihydropyridine calcium antagonist. Prior studies with nifedipine (Intact) and nicardipine (Montreal Heart) have suggested a decrease in angiographic progression of CAD, particularly in early, nonobstructive lesions. In PREVENT, coronary artery segments that were minimally diseased at baseline were selected as the target site for serial angiography. In the placebo group, there was more progression of the disease than had been anticipated, but the active drug therapy did not slow progression. More important, angina-driven events (hospitalization, revascularization) were decreased in the amlodipine patients.
This is one of few trials that have demonstrated that an anti-anginal agent reduces the need for coronary angiography. In ACIP, a beta-blocker was shown to decrease ambulatory ischemia. A variety of ambulatory ECG studies have demonstrated decreases in daily life ischemia with beta-blockers and calcium antagonists. In ASSIST, atenolol was beneficial with respect to myocardial ischemia. However, no anti-anginal drug has been shown to diminish the need for revascularization or hospitalization for unstable angina. The discrepancy between the coronary and carotid data cannot be readily explained. A decreased progression of carotid IMT is consistent with an anti-atherosclerotic effect of amlodipine. It may be that the effects on the coronary circulation were too modest to be readily detectable using QCA techniques. The PREVENT data do not provide a mechanistic explanation for the reduction in angina and revascularization; the angiographic data suggest that this was not due to a change in atherosclerotic plaque burden. However, endothelial function, microvascular reserve, and plaque stabilization may have improved with amlodipine. Alternatively, it may be that the calcium blocker is simply a highly effective anti-anginal agent that, when added to a population of patients with documented CAD, provided sufficient anti-ischemic benefit to alter the clinical status of this patient cohort, diminishing angina rates and, thus, the need for angiography. In any case, PREVENT confirms that amlodipine is a highly effective agent for the treatment of angina but does not provide conclusive evidence that the primary hypothesis of this study is valid (i.e., that calcium blockers inhibit the progression of coronary atherosclosis).
AVERT: Atorvastatin vs. Revascularization
This multicenter, nine-country study was designed to investigate the potential of aggressive, lipid-lowering strategy with atorvastatin vs. angioplasty in stable patients with CAD with few symptoms and single- or double-vessel disease with preserved left ventricular function. Mean LDL cholesterol was 140; patients had to be able to complete a four-minute exercise test without ischemia. Three hundred forty-one subjects were randomized to receive 80 mg of atorvastatin daily or the scheduled angioplasty that triggered the enrollment process. Follow-up was approximately 18 months. The primary input was any major ischemic event, including death, nonfatal infarction, stroke, revascularization, or hospitalization for unstable angina. Secondary end points included the time to the first ischemic event as well as safety parameters. Because of the concern that the patient cohort treated with atorvastatin alone might have threatening episodes of ischemia, two interim analyses were scheduled. The patients were evenly matched; approximately 90% were male, with a mean age of 58; more than 50% had single-vessel disease, and 44% had two-vessel disease. The LAD was involved in more than one-third. More than 40% of these subjects had a prior infarction. Patients had angina class 1 or 2. Baseline LDL cholesterol was 140 mg/dL. The angioplasty group received the usual medical care, and at the end of the study, their LDL cholesterol had fallen by 18% to 119 mg/dL. The high dose of atorvastatin resulted in a 46% drop in LDL cholesterol, to a mean of 77 mg/dL. Atorvastatin subjects had less angina and experienced a 36% reduction in the combination of cardiovascular events (nonfatal myocardial infarction, revascularization, hospitalization for angina), compared with individuals treated with angioplasty and usual care. The actual overall event was 13% in the atorvastatin cohort and 21% in the angioplasty cohort (P = 0.048). The time to the first ischemic event was shorter in the angioplasty cohort than in the statin group, with major curve separation beginning at approximately 6-7 months (P = 0.027); the overall combined end point was relatively low overall—approximately 2% per year. Both angioplasty and coronary bypass surgery were decreased by lipid lowering, as was hospitalization for unstable angina; 87% of these individuals did not suffer an event by 18 months. Safety monitoring revealed a 2.4% incidence of increased liver enzymes. No patient had other adverse reactions and there were no elevations of creatine kinase.
Comment by Jonathan Abrams, MD
This long-awaited study, although modest in patient size, strongly suggests that aggressive lipid lowering in patients with stable CAD is beneficial and may avert or delay revascularization procedures. This is consistent with plaque stabilization and improvement in coronary endothelial function, as well as slowing of progression of coronary atherosclerosis. None of these putative mechanisms can be assessed in this trial. The LDL target achieved is the lowest in any reported statin trial to date; the potency of atorvastatin allows this to occur, and the final mean LDL cholesterol of 77 mg/dL appears to put downward pressure on what is the optimal target LDL for patients with vascular disease. The recently post-CABG trial also achieved an LDL cholesterol level of substantially below 100, and demonstrated a significant reduction in saphenous vein graph disease. Thus, it appears that a statin should be part of the therapy of most or perhaps all patients with CAD, with a target LDL cholesterol of less than 100 mg/dL. Whether the trial would have been less positive if the achieved LDL-C was 10 or 20 mg/dL higher can only be resolved by subsequent studies. At this time, it does appear reasonable to include as state-of-the-art medical therapy a statin, along with aspirin and anti-anginal drugs. AVERT results support an extremely aggressive approach to cholesterol lowering in patients with established coronary disease, and raise the possibility that such therapy may truly alter the natural history of coronary disease, and potentially decrease the need for revascularization while stabilizing coronary atherosclerosis to prevent acute ischemic events.
VA-HIT Trial
HIT is a VA cooperative trial conducted at 20 centers that asked the question if individuals with low HDL and normal LDL cholesterol would benefit from raising HDL with a fibrate. This ambitious trial enrolled 2531 patients between 1991-1993 who had an HDL of less than 40 mg/dL and an LDL of less than 140, with triglycerides less than 300. Subjects were randomized to gemfibrozil 1200 mg daily in long-acting formulation or placebo. The primary end point was CAD death or nonfatal myocardial infarction. Mean follow-up was seven years. Secondary end points included all-cause of mortality, stroke, revascularization procedures, and nonfatal MI. The male patient cohort was 90% white, with a mean age of 64. Patients were overweight with an increased waist-hip ratio. Twenty percent were smokers, more than 50% had hypertension, and 25% had diabetes. Baseline lipids were: TC 175; LDL-C 111; HDL-C 32; and TG 161. The primary end point of CAD death or nonfatal MI was 21.6% in placebo subjects vs. 17.3% in gemfibrizil patients (RR = 22%, P = 0.006), with similar results on CAD death and nonfatal MI. Strokes and TIA were decreased. Unstable angina and revascularization were unaffected by therapy. Event curves began to separate by 18-24 months. Treatment lowered TC 28%; HDL increased 7.5%, LDL-C increased 4%, and TG decreased by 25%.
Comment by Jonathan Abrams, MD
Only the Helsinki Heart Study has demonstrated a benefit for HDL-C elevation in patients that had elevated TG, low HDL, and modest elevation of LDL-C. In the HIT population, baseline LDL levels were excellent, yet individuals taking gemfibrozil clearly benefited with respect to cardiac events. Thus, it appears that efforts to increase HDL cholesterol, even in individuals who have no other lipoprotein abnormality, are justified in secondary prevention CAD subjects. The HIT trial confirms the value of gemfibrozil. However, greater HDL elevations can be achieved with niacin, and this is a reasonable alternative for many individuals. Whether other fibrate drugs will have a greater or equivalent effect than gemfibrozil remains to be determined. At the present time, all patients with vascular disease who meet the lipid criteria in VA-HIT should be considered for gemfibrozil treatment.
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