Beta blockers are standard therapy for myocardial infarction. However, there are few data documenting the safety and efficacy of these drugs in patients who have heart failure or left ventricular dysfunction. The Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study specifically included these patients.

Investigators in this trial found a 23% reduction in all-cause mortality (p=0.03). However, there was only an 8% reduction in the combined risk of death or cardiovascular hospitalization (p=0.3). To explain this discrepancy, Dr. Sachner-Bernstein and colleagues compared the CAPRICORN trial design with the design of previously conducted studies. These studies evaluated agents such as beta blockers and ACE inhibitors in patients with heart failure and left ventricular dysfunction.

Dr. Sachner-Bernstein and colleagues noticed that CAPRICORN seemed to evaluate the same endpoint as the other trials: death or cardiovascular hospitalizations. However, the endpoint definition was actually much broader than the other trials, because it included every cardiovascular hospitalization. The other trials only included prespecified types of cardiovascular hospitalizations relevant to the treatment under investigation.

They hypothesized that this broad definition of cardiovascular hospitalization biased CAPRICORN trial results. They conducted a post-hoc analysis of the CAPRICORN data according to cardiovascular morbidity definitions from 7 other treatment trials that included patients with heart failure or left ventricular dysfunction.

In every case, these trials focused only on major cardiovascular hospitalizations, not any hospitalization regardless of clinical importance. Dr. Sachner-Bernstein noted that the CAPRICORN endpoint excluded hospitalizations for elective procedures, but included any hospitalization that was at least suspected to be cardiovascular. This means that the morbidity endpoint counted chest pain, shortness of breath, and even lower extremity pain as cardiovascular hospitalizations.

The researchers applied these other morbidity endpoints to CAPRICORN data. They found a consistent 20% to 30% reduction in combined risk of death and morbidity. For example, the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) trial evaluates the effect of an aldosterone blocker in post-myocardial infarction heart failure patients. Using the EPHESUS combined endpoint of death or hospitalization for myocardial infarction, heart failure, stroke or arrhythmia, the hazard ratio was 0.79 (0.66 - 0.94). This finding was statistically significant (p=0.006).

Based on these results, Dr. Sachner-Bernstein suggested that future trials should avoid all-inclusive definitions of cardiovascular hospitalization. The endpoints should only include those events that could be influenced by the therapy under study.

In addition, clinicians should look beyond the study design issues in CAPRICORN, he said. Instead, they should look at the results of CAPRICORN in the context of the potential benefit for post-myocardial infarction patients.