Physiologic determinants of survival in congestive heart failure. The survival hypothesis: how small uncontrolled studies should influence the design of large-scale clinical trials.

A number of small and largely uncontrolled trials have studied the use of vasodilators and inotropic agents in patients with chronic heart failure over the last 15 years. These trials have been of short duration and primarily designed to answer questions about dosages, mechanisms, and toxicity, and therefore they have not been particularly useful in addressing the issue of survival. Despite this drawback, these small clinical trials have been important in providing data about drugs that might be used in large-scale controlled clinical trials designed to test the survival hypothesis--that specific therapy may prolong life in patients with congestive heart failure. Nitrates, hydralazine, and the converting-enzyme inhibitors have emerged as the vasodilators that are most promising in our quest to prolong survival in patients with chronic heart failure. Milrinone has been perhaps the most extensively studied inotropic-vasodilator drug, but there are no data so far to suggest that it may prolong survival. The principal questions that need to be addressed are: Do vasodilators that improve symptoms also improve survival? Which vasodilator drug regimen is most effective in prolonging survival? Should inotropic agents be considered for survival trials? What dose of vasodilator should be used? When in the natural course of the disease should therapy be initiated? Answers are now available to some of these questions, but large-scale clinical trials will be necessary to clarify all of the answers.