More Late-Breaking Clinical Trials Presented at the American College of Cardiology Meeting

Conference Coverage

DINAMIT

Drs. Stuart Connolly and Stefan Hohnloser presented results from the Defibrillator In Acute Myocardial Infarction Trial (DINAMIT). Prior studies had shown that patients with recent myocardial infarction and left ventricular dysfunction are at high risk for death in the period after myocardial infarction. It has also been shown that impaired cardiac autonomic modulation is associated with both arrhythmic events and sudden death. Therefore, the DINAMIT investigators began a study on primary prevention of death with implantable cardioverter defibrillators including patients with recent (within 6-40 days) myocardial infarction, a left ventricular ejection fraction of £ 35%, and depressed heart rate variability.

Patients with New York Heart Association class IV heart failure were excluded. Importantly, patients who underwent either coronary artery bypass grafting or 3-vessel percutaneous angioplasty after the myocardial infarction were also excluded.

Patients were enrolled at 73 centers in 10 countries. Most of the centers were either in Canada or Europe. There were only 2 US centers. Enrollment began in April 1998 and was concluded in September 2002. The mean follow-up was 2.5 years, and 674 patients were randomized. The primary outcome was mortality from all causes. Baseline demographics were as follows: male gender, 76%; mean age, 61.5 years; histories of prior infarct, 35%; diabetes, 30%; hypertension, 46%; and anterior myocardial infarction location, 72%. Slightly more than half of the patients had overt congestive heart failure during the index myocardial infarction. Mechanical ventilation was required for stabilization in 10% of the patients and intra-aortic balloon counterpulsation in 6%. During the index myocardial infarction, 65% of the patients received acute reperfusion therapy. Among those who did receive reperfusion therapy, 52% of those in the ICD group and 35% of those in the control group received only intravenous thrombolytics. Data about coronary anatomy either at the time of the initial infarct or at a follow-up catheterization were not reported, but the left ventricular ejection fraction was 28% in both groups. At enrollment, 87% of the patients were receiving a beta adrenergic blocker, 95% were on an ACE inhibitor, 79% were on lipid-lowering drugs, and 92% were on antiplatelet agents.

Multivariate analysis of survival showed no improvement in mortality with ICD therapy. The annual mortality rate was 7.5% in the ICD group vs 6.9% in the control group. The hazard ratio for ICD therapy was 1.08 (95% confidence interval, 0.76-1.55; P = .66). There was a marked decrease in the number of deaths classified as arrhythmic in the ICD group, but it did not result in improvement of overall mortality. In conclusion, the authors felt that ICD therapy did not reduce mortality in high-risk patients early after myocardial infarction.

Comment by John DiMarco, MD, PhD

DINAMIT is another important study that deals with the use of ICD therapy for primary prevention of death. Most studies of either secondary or primary prevention of death in patients with established heart disease have shown a mortality reduction of between 20% and 30%. In DINAMIT, reduction in arrhythmic mortality was seen, but no decrease in overall mortality was observed. The reason for this is uncertain based on the data released so far. However, one might speculate that recurrent ischemic events were very important in this group. From the data presented so far, it appears that many patients were incompletely revascularized at the time of the index myocardial infarction. Patients with incomplete revascularization would have formed a high-risk subgroup unlikely to derive optimal benefit from an ICD. It is possible that ischemic events or changes in ventricular remodeling leading to end-stage heart failure were more important than arrhythmias arising from scar in determining mortality in these patients. A recent paper from the MADIT II Trial by Wilbur et al1 showed that there was no benefit in a subgroup of patients who received their defibrillator within the first 18 months after myocardial infarction. Again, this probably represents our poor ability to risk-stratify patients for deaths due to primary arrhythmia as opposed to progressive myocardial disease in patients with recent major events.

The DINAMIT data will leave clinicians with a continuing clinical problem. The data would suggest that ICD implant is not beneficial in patients with recent myocardial infarction. However, clinicians must still deal with patients with recent myocardial infarctions who by all clinical criteria are at high risk. At present, data from randomized trials indicate that an aggressive revascularization strategy and optimal medical therapy are the only interventions of proven clinical benefit. It is likely that Medicare and other insurers will restrict the use of ICDs in these subgroups unless some more effective risk stratification for arrhythmias as the primary mechanism for death can be identified.

Reference

1. Wilbur DJ, et al. Circulation. 2004;109:1082-1084.

SCD-HeFT

Dr. Gust Bardy presented the results from the Sudden Cardiac Death and Heart Failure Trial (SCD-HeFT). The primary hypothesis for SCD-HeFT was to determine if either amiodarone or a shock-only implantable cardioverter defibrillator (ICD) reduced all-cause mortality compared to placebo in patients with either ischemic or nonischemic New York Heart Association class II or III congestive heart failure with systolic dysfunction. Patients were enrolled in 148 sites in the United States, Canada, and New Zealand. The total enrollment was 2521 patients. Enrollment began in September 1997 and ended in July 2001 when the target enrollment number had been reached. Follow-up was continued until the end of October 2003. Patients were randomized to either drug therapy or ICD therapy. The drug therapy group then was again randomized to either amiodarone or placebo, and drugs were prescribed in a double-blind fashion. Patients who received amiodarone received a 4-week period of intermediate dose loading and then were treated with between 200 mg and 400 mg per day depending upon their body weight. Patients who received an ICD received a single-chamber ICD that was programmed to deliver VF therapy only with a fibrillation detection interval of 320 msec. Back-up ventricular pacing was provided, if required, at a rate of 50 bpm with hysteresis from 34 bpm.

The mean age of the patients enrolled was 60 years. Females compromised 23% of the group; 23% were non-Caucasian. Heart failure had been present for a mean duration of 24.5 months. The mean left ventricular ejection fraction was 25%. Seventy percent of the group had New York Heart Association class II congestive heart failure, with the remainder having class III. Ischemic heart disease was the primary diagnosis in 52%, and the remaining 48% had a nonischemic cardiomyopathy. Coronary artery bypass grafting or revascularization had been performed before trial entry in 37% of the patients. The mean QRS duration was 112 msec, with 41% of the patients having a QRS duration of ³ 120 msec. Medications for heart failure were carefully followed in the study. At baseline, 96% of the patients were receiving either an ACE inhibitor or an angiotensin receptor blocker, 69% were receiving a beta-blocker, 19% were receiving spironolactone, and 82% were receiving loop diuretics. Appropriate pharmacologic therapy was well maintained throughout the study.

Mortality was analyzed by intention to treat. In the placebo group, the mortality rate was close to linear throughout the study, with an actuarial rate of 7.2% per year. Amiodarone therapy produced no improvement in mortality. The hazard ratio for amiodarone vs placebo was 1.06 (P = .529). A subgroup analysis suggested a slightly higher mortality in patients with class III congestive heart failure who received amiodarone, but all other subgroups had no significant differences in mortality. In contrast, ICD therapy showed significant benefit. Over the 5 years of the study, there was a 23% reduction in mortality with ICD therapy vs placebo. The hazard ratio was 0.73 (97.5% confidence interval, 0.62-0.96; P = .007). Subgroup analysis suggested significantly increased benefit in patients with class II congestive heart failure and in patients who were enrolled outside the United States. Importantly, there was no difference between patients who had ischemic heart disease or nonischemic heart disease as the etiology for their heart failure.

Comment by John DiMarco, MD, PhD

SCD-HeFT is a very important trial. It clarifies some of the major issues confronting physicians who are attempting to use either drug therapy or ICD therapy for the primary prevention of sudden cardiac death. Numerous prior studies have looked at the use of amiodarone for primary prevention of death after myocardial infarction and in patients with congestive heart failure. Among patients with recent myocardial infarction, a slight benefit had been suggested but was not present in all trials. In patients with congestive heart failure, one study (GESICA) suggested decreased mortality, whereas another study (CHF-STAT) showed no benefit. The current data confirm that amiodarone produces no benefit in patients with congestive heart failure in overall mortality. Therefore, the use of amiodarone should be only for control of symptoms.

In SCD-HeFT, the investigators observed a 23% reduction in overall mortality with the use of ICD therapy. This is consistent with the mortality reduction seen in other primary prevention trials. It clearly establishes that there is benefit in patients with nonischemic heart disease as well as in patients with ischemic heart disease. It also confirms that benefit is seen in patients with both normal QRS durations and wide QRS durations.

The final important observation from SCD-HeFT is the marked improvement in total mortality produced with recent innovations in pharmacologic therapy. The overall mortality seen in SCD-HeFT was only 7.2% per year. This is a 28% reduction from what was initially estimated when the study was planned. It is important to note, however, that ICD therapy is an additive to the improvement produced by pharmacologic therapy. However, as mortality in patients with heart failure declines, the absolute benefit seen with a 23% mortality reduction drops to under 2% per year. This relatively low absolute benefit may make Medicare and other insurers reluctant to approve ICD implants in all patients who have heart failure and left ventricular dysfunction.

Although SCD-HeFT did not show benefit in a subgroup of patients with class III congestive heart failure, it should be remembered that another trial in patients with nonischemic cardiomyopathy (DEFINITE) showed increased benefit in patients with class III congestive heart failure. Congestive heart failure class may be difficult to estimate since it depends on the patient’s current status and where he is in terms of his pharmacologic management. Therefore, I don’t think too much weight should be placed on the observation at this time.

In conclusion, SCD-HeFT is a critical trial, which confirms the benefits of ICD therapy in patients with heart failure. It also clarifies the role of amiodarone in these patients. We can now expect major discussions with the Centers for Medicare & Medicaid Services and other insurers about the cost-effectiveness of the mortality reduction in these patients. It will be important for payers to accept the importance of these data before ICD therapy can be widely used in patients with heart failure.

PROVE IT

Source: Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

Prove it is a long-awaited late-breaking clinical trial presented at the American College of Cardiology Annual Meeting in March. This was a comparison of 2 different statins and doses in patients with an acute coronary syndrome (ACS). The complete study was published in the April 8, 2004, New England Journal of Medicine and was released on its web site before publication.

PROVE IT was funded by Bristol-Myers Squibb and Sanyko and was designed as a noninferiority trial to assess whether there would be a difference in clinical outcomes in ACS patients given either pravastatin (P) or atorvastatin (A) in different doses. This study was carried out in 8 countries and 250 hospitals; the final cohort was 4152 patients, average age of 58, 78% male, who were hospitalized with either unstable angina or myocardial infarction (MI). The majority of subjects underwent revascularization (70% percutaneous coronary intervention [PCI]). After stabilization, and within 10 days of presentation, patients were randomized to 40 mg of P or 80 mg of A. Of note, this study used a 2-by-2 factorial design, with a separate investigation of a 10-day course of the antibiotic gatifloxacin or placebo; the results of this component are not yet available. There were a number of exclusions, most significantly including acute MI within 6 months, bypass surgery within 2 months, or use of inhibitors of the cytochrome P-450 3A4 system. Patients could be randomized if they had been on lipid-modifying therapy prior to admission if total cholesterol was < 200 mg/dL at the time of initial screening. The cholesterol entry cutpoint for statin non-users was < 240 mg/dL measured within 24 hours of admission. Of note, prior statin therapy was reported in 25% of the entire cohort, which included 37% smokers, 50% hypertensives, 18% diabetics, 18% prior MI, and 15% prior PCI. Baseline lipids were cholesterol 180 mg/dL; LDL 106; HDL 39; and triglycerides 155. Patients all had dietary counseling and frequent visits/blood work. The trial ended in late 2003, with an average follow-up of 24 months (range, 18-36), at which time 925 prespecified 925 events were reported. Primary end points were all-cause death, MI, revascularization for unstable angina, any revascularization 30 days after enrollment, and stroke. There were a variety of secondary end points, most consisting of individual primary end points. A definition on noninferiority was established after consideration of 2-year event rates. This was not demonstrated; atorvastatin was superior to pravastatin.

Specific Results

The Kaplan-Meier event rates of the primary end point demonstrated a 16% reduction in favor of A (26.3% P and 22.4% A; P = .005). Secondary end points of coronary death, MI, or revascularization were reduced by 14% with A (P = .03). MI or urgent revascularization were reduced by 25% with A (P < .001). Individual end points included a 14% reduction in need for revascularization and 29% decrease in recurrent unstable angina but no significant decrease in death, MI, or stroke. Of note, the benefit of A was greater among patients with a baseline LDL of > 125 mg/dL (RR, 34%), compared to a 7% event differential for those with a baseline LDL of < 125 mg/dL (P for interaction = .02). Discontinuation rates were approximately 22% at 1 year and 30% at 2 years, with no differences between the drugs. There were slightly more liver enzyme abnormalities with high-dose A, whereas myalgias were comparable between the 2 statins. The authors conclude that "more intensive lipid lowering significantly decreased" major clinical events. They believe that the specific benefit with A was predicted by the degree of lipid lowering. LDL levels achieved at the end of the study were 95 mg/dL for P and 62 mg/dL for A (P < .001). In the approximately 1000 patients who had previously been on statin therapy, LDL levels were unchanged by P but fell by an additional 32% with A (P = .001). CRP declined from 12 mg/L to 2.1 with P and 1.3 with A (P < .001). While the P values for mortality were not significant, there was a 28% reduction of this end point; the investigators suggest that high-dose A may "decrease the risk of fatal events." Event benefits were noted as early as 30 days after trial entry and became significant at 6 months. Contrary to the MIRA-CL trial, there was no reduction in stroke rates. Patients who had been on statin therapy at the onset of hospitalization showed no benefit, nor did those with a baseline LDL cholesterol of < 125 mg/dL. The authors conclude that the continued benefit throughout the study period of 2 and a half years probably results from a "slower rate of progression of atherosclerosis," but they recognize that the positive early outcomes suggest a benefit from rapid stabilization of plaque as well as decreased atherosclerotic progression. They conclude that the LDL cholesterol goal for patients with established CAD may be lower than the < 100 mg/dL recommended in current guidelines for patients with acute coronary syndromes.

Comment by Jonathan Abrams, MD

This is an important study that adds considerable fuel to the argument that "lower is better" with regard to total, and particularly LDL, cholesterol in the management of patients with overt coronary artery disease. Some are bewildered why Bristol-Myers Squibb would have funded a study with this outcome. In fact, at the time of the study design, there was considerable debate as to how low LDL cholesterol needs to be. The CARE (post-MI) investigators, many involved in the PROVE IT study, had stressed that an LDL goal of 125 mg/dL might be sufficient based on the analysis of the CARE data. Thus, CARE subjects who started at < 125 mg/dL did not appear to benefit from P, and lowering LDL beyond 125 mg/dL did not produce a greater efficacy. This controversial viewpoint was greatly debated, but the argument has disappeared with the advent of more statin data. The 125 mg/dL debate may have been a major factor in the design of PROVE IT, which was initiated to document that P was noninferior to high-dose A. There is no placebo arm in PROVE IT; therefore, one cannot conclude that P produced no benefit. Whether high-dose A had effects beyond aggressive LDL cholesterol lowering (ie, pleiotropic actions of statins) cannot be determined. In the recently published REVERSAL Trial,1 Nissen has suggested that the benefits of high-dose A in stabilizing coronary artery atheroma burden, as well as decreasing progression of disease as assessed by intravascular ultrasound, was derived from vascular effects beyond cholesterol lowering (ie, pleotropism). However, until there are more convincing data, it is reasonable to conclude that the benefits of lipid modification with statins is related solely to the degree of LDL cholesterol lowering; there has not been a single outlier in all the statin trials. If other agents were available that had the efficacy and potency of the statins, there is no reason to believe that they would not achieve comparable reductions in major CV end points. I agree with the authors that in regard to current guidelines, we must consider a further reduction in the target LDL, based on PROVE IT and REVERSAL. Nevertheless, the major problem in lipid therapy in CAD or in patients at high risk for vascular disease is the inadequate proportion of individuals on any lipid-modifying therapy, as well as the failure to reach the LDL target of < 100 mg/dL. The latter goal is widely accepted; PROVE IT and REVERSAL strongly support that lower indeed is better in patients with established disease (and perhaps high-risk healthy individuals). However, individuals who were on a statin at trial entry received no benefit, in spite of the fact that those randomized to A had an additional 32 mg/dL lowering of baseline LDL cholesterol. This suggests that the benefits from statins are considerably reduced as ambient LDL approaches 100 mg/dL, an argument also suggested by the CARE trial results, but not concordant with the HOPE trial. Another explanation is that pre-study use of statins had already induced considerable vascular stabilization (although not enough to eliminate all events). On the other hand, in the three-quarters of the PROVE IT cohort who were not previously on a statin, there is no question that the differential between the median LDL in the A and P cohorts was responsible for decreasing hard events. Atorvastatin lowered LDL to a median of 62 mg/dL, the lowest of any lipid trial to date, and a new benchmark for lipid studies.

Reference

1. Nissen SE, et al. JAMA. 2004;291:1071-1080.