Indications:Patients with heart failure and left ventricular dysfunction.
TypeofStudy:Letters to the editor
ComparativeDrug:Captopril was given at unspecified doses. Duration not stated.
AdverseEffects:An unspecified number of patients had hypotension, renal dysfunction, hyperkalemia, and cough.
FreeText:Comments on Diovan and reply. The study reported the treatment of Diovan, captopril, or both in patients with myocardial infarction (MI) complicated by heart failure or left ventricular dysfunction. The comment states that this was not a placebo-controlled trial as conveyed by the study, as the authors used an "imputed placebo" to calculate the patients hazard ratio and was included in a figure with hazard ratios from from other trials that were placebo-controlled. This does not reveal a clear difference between patients in an "imputed placebo" group and historical controls. This would seem unethical to submit patients to the risks of participating in future placebo-controlled clinical trials when a large number of historical controls are available for analysis. Another comment states that the authors reported that Diovan was as effective as captopril in reducing the rate of death and other cardiovascular outcomes in high-risk patients after MI, although the overall rate of complications were similar for Diovan and captopril, the rate of serious complications, including hypotension, renal dysfunction; and hyperkalemia, was significantly higher in the Diovan group than in the captopril group (21.3% vs. 15.8%). Thus, given the similar efficacy, captopril is the safer drug and should be used for these patients. Also, another comment states that the authors reported that patients receiving Diovan were less likely to discontinue therapy because of a drug-related adverse event, suggesting a favorable safety and tolerability profile for the angiotensin-receptor blocker. But the absence of a late separation of the curves in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) strongly suggests that "escape" from the effect of angiotensin-converting-enzyme (ACE) inhibition may indeed not exist or may at best have negligible clinical consequences. Hypotension leading to discontinuation of the study drug, arguably a more serious adverse event than cough, occurred almost twice as often in patients receiving Diovan as in those receiving captopril (1.4% vs. 0.8%; cardiovcardiovascular event; P<0.05). This suggest that Diovan is a clinically effective alternative to captopril in patients who are at high risk for cardiovascular events after myocardial infarction, however, serious adverse events were less frequent with angiotensin converting enzyme (ACE) inhibitors. Thus, VALIANT removes two major rationales for favoring angiotensin-receptor blockers over ACE inhibitors, which clearly remain first-line therapy. In reply the authors of the study state that given the established mortality-related and other cardiovascular benefits of ACE inhibitors in patients with myocardial infarction who are at higher risk, random assignment to placebo was not an option. The "imputed placebo" analysis was conducted to support the noninferiority analysis. And they are not implying that an imputed placebo (or historical controls) could replace a direct and robust comparison between treatments in concurrently randomized patients, as in VALIANT. The similar mortality and morbidity rates in the Diovan and captopril groups do, however, provide the best available evidence that Diovan is as effective as a proven ACE inhibitor (and better than placebo). The predominantly early occurrence of cardiovascular events after acute myocardial infarction may make the analysis of time to a first event an insensitive tool with which to evaluate the clinical importance of "escape" from the long-term effects of ACE inhibition. However, the post hoc analysis, which showed fewer cumulative hospitalizations for myocardial infarction and heart failure with combination Diovan-and-captopril treatment, supports the possibility of "ACE escape". The most important adverse clinical outcomes were the efficacy measures - death and major cardiovascular events (death from cardiovascular causes, myocardial infarction, hospitalization for heart failure, resuscitation after cardiac arrest, or stroke) --the rates of which did not differ between the captopril group (.33.4 percent) and the Diovan group (32.8 percent). The study drug-related reasons for down-titration and discontinuation, though not necessarily serious, underscore the importance of clinical monitoring when patients are receiving clinically effective (mortality-reducing doses) of either an ACE inhibitor or an angiotensin-receptor blocker. Though, as reported, renal problems and hyperkalemia were more common in the Diovan group, there was no excess in terms of hospitalizations for renal dysfunction or hyperkalemia. Hypotension serious enough to warrant discontinuation of study medication occurred more often in the Diovan group than in the captopril group (1.4% vs. 0.8 %; excess, 6 per 1000; P<0.05). However, discontinuation because of any adverse event was more frequent in the captopril group (7.7 percent, vs. 5.8 percent in the Diovan group; excess, 19 per 1000; P<0.05). The different side-effect profiles of these two effective alternative approaches should assist clinicians in individualizing therapy to extend the appropriate use of these lifesaving interventions to more survivors of myocardial infarction.
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