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J Am Coll Cardiol, 2005; 45:2-3, doi:10.1016/j.jacc.2005.05.004 © 2005 by the American College of Cardiology Foundation |
Department of Medicine and Division of Cardiology, Cornell University Medical Center, New York, New York
* Reprint requests and correspondence: Dr. Bruce B. Lerman, Department of Medicine, Division of Cardiology, Cornell University Medical Center, 525 East 68th Street, Starr 409, New York, New York 10021. (Email: blerman{at}med.cornell.edu).
The Cardiac Resynchronization-Heart Failure (CARE-HF) trial compared the time to death or hospitalization for a cardiovascular event in patients with New York Heart Association (NYHA) functional class III or IV heart failure who were randomly assigned to either medical therapy or to medical therapy plus a resynchronization pacemaker (1). Remarkably, there was an absolute 10% mortality benefit in patients who received a resynchronization device. Similar to most previous trials, this study confirmed a device-related benefit in quality of life, symptoms, NYHA functional class, and left ventricular (LV) function. However, this is the first study to demonstrate a mortality benefit from a resynchronization pacemaker. To what was this outcome attributable? Primarily to a decrease in the incidence in death due to progressive heart failure and sudden cardiac death. Also noteworthy, these benefits were seen in both patients with ischemic and nonischemic cardiomyopathy. Therefore, decreasing the degree of dyssynchrony and improving LV performance by resynchronization therapy translates directly into a significant mortality benefit. Extrapolating from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial (2), it would be reasonable to surmise that an additional mortality benefit would be observed with a combined resynchronization-defibrillator device because of further reduction in the incidence of sudden cardiac death.
An innovative remote method (implantable pressure-sensing lead in the right ventricular outflow tract connected to an implantable monitor the size of a pacemaker) to continuously monitor intracardiac pressures and manage patients with congestive heart failure was introduced in the Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial (3). This single-blind study randomized patients to receive either therapy guided by device-based hemodynamic monitoring or to receive therapy independent of the device (control group). Although an overall 22% reduction in heart failure-related events among the study group did not achieve statistical significance, a 41% reduction (p = 0.03) in events was observed in the pre-specified NYHA functional class III subgroup of patients, which comprised 85% of enrollment. This study highlights the continuing trend toward device-based therapy in patients with congestive heart failure (resynchronization pacemakers, defibrillators, ventricular assist devices as destination therapy, and now continuous hemodynamic monitoring). If the utility of the monitor can be confirmed and the technology further developed, it would be an obvious and relatively small step to bundle this feature with the other heart failure devices presently available.
Several late-breaking clinical trials of pharmacologic therapies warrant discussion based on their potential implications for future care and research. The Women’s Health Study examined the effect of low-dose every-other-day aspirin versus placebo on the primary prevention of first cardiovascular event in nearly 40,000 healthy women (4). In contrast to the clear benefit of aspirin on reducing the risk of myocardial infarction (MI) in men (4,5), aspirin use was not associated with a decreased risk of fatal or nonfatal MI in the overall population of women (relative risk [RR] 1.02, 95% confidence interval [CI] 0.84 to 1.25, p = 0.83) and with only a nonsignificant 9% decreased risk of major cardiovascular events (95% CI 0.80 to 1.03, p = 0.13).
However, although aspirin use has not been found to significantly reduce the risk of stroke in men (1), low-dose aspirin use in women was associated with a significant 17% reduction in the risk of stroke (95% CI 0.69 to 0.99, p = 0.04), driven by a 24% reduction in the risk of the more common ischemic stroke (95% CI 0.63 to 0.93, p = 0.009) and a nonsignificant increased risk of the less common hemorrhagic stroke (RR 1.24, 95% CI 0.82 to 1.87, p = 0.31). As would be expected, aspirin use was associated with a higher risk of major gastrointestinal bleeding requiring transfusion (RR 1.40, 95% CI 1.07 to 1.83, p = 0.02). Subgroup analysis in this study (4) was of particular significance for the finding that aspirin use was shown to decrease the risk of major cardiovascular events, MI, and ischemic stroke in women 65 years or older, a subgroup with the highest event rates (4). This study (4) highlights the importance of carefully examining biologic differences between men and women in the design and interpretation of clinical trials (6) and leaves decisions on the role of aspirin for primary prevention of cardiovascular disease open to discussion between women and their physicians (4,6).
The Treating to New Targets (TNT) investigators (7) presented evidence on the efficacy and safety of reducing low-density lipoprotein (LDL) cholesterol levels to <70 mg/dl compared with the goal of <100 mg/dl based on current guidelines (8), in patients with chronic coronary heart disease. After a run-in phase of treatment with atorvastatin 10 mg daily, the 10,001 patients with LDL cholesterol levels <130 mg/dl were randomly assigned to double-blind therapy with either 10 mg or 80 mg of atorvastatin per day. Compared with patients given 10 mg of atorvastatin, the 80-mg therapy group had lower mean LDL levels during treatment (77 vs. 101 mg/dl) and significant reductions in the risk of a major coronary event, any coronary event, cerebrovascular event, hospitalization for heart failure, and any cardiovascular event. The decreases in risk seen with higher-dose atorvastatin were associated with an increased incidence of persistent liver enzyme elevations (1.2% vs. 0.2%), but no significant increases occurred in creatine kinase levels, myalgias, or rhabdomyolysis. However, there was no significant reduction in overall mortality, with the decrease in deaths from coronary disease balanced by an increase in the number of deaths not from cardiovascular causes, although the study was not powered to detect changes in the risk of death from any cause (7,9). Although these findings suggest that further lowering of LDL cholesterol below currently recommended levels may provide additional cardiovascular benefits (7), they also raise some concerns about the safety of an 80 mg dose and whether other means of achieving an LDL cholesterol level of 70 mg/dl will be equally effective in reducing the risk of cardiovascular events (9).
A recent trend in treating hypertension, emphasized in Joint National Commission-VII (10), is the common need for combination treatment regimens. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) investigators (11) presented data comparing cardiovascular outcomes between a traditional beta-blocker/diuretic regimen (atenolol ± bendroflumethiazide) and a more contemporary calcium channel blocker (CCB)/angiotensin-converting enzyme (ACE) inhibitor (amlodipine ± perindopril) antihypertensive regimen in more than 19,000 patients. All assigned medications were taken by a large majority of subjects, making the ASCOT study a trial of regimens rather than a comparison of individual classes of antihypertensives. The blood pressure lowering arm of the ASCOT study was stopped by its Data Safety Monitoring Board in October 2004 when fewer than 75% of the planned primary end points had occurred because of a significant 14% lower all-cause mortality in the CCB/ACE inhibitor arm. The rates of other events were also significantly lower on the newer treatment combination, including reductions of about 15% in all coronary end points and cardiovascular events and procedures and of nearly 25% in stroke and cardiovascular death. Less rapid blood pressure control and more deleterious metabolic changes—including almost 50% more new-onset diabetes, 4.5 mg/dl lower high-density lipoprotein cholesterol, and 25 mg/dl higher triglycerides—with the beta-blocker/diuretic regimen than with CCB/ACE inhibitor treatment, may have contributed to the worse clinical outcomes with traditional treatment.
Finally, the results of the ASCOT study suggest that the prognosis of hypertension, the most common cardiovascular condition, can be improved by newer antihypertensive treatment combinations that lower blood pressure faster and avoid metabolic side effects.
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