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to the design and possible successful outcome to the study. As the clinical community becomes more sophisticated and more agents appear, more definitive outcomes are required. Thus in the field of cardiovascular drug development, mortality endpoints are often required to prove efficacy and safety. For an antiarrhythmic or a heart failure treatment agent, mortality has become critical. This is not at the exclusion of other concerns for mechanism and antiarrhythmic or anti-CHF effects, but still mortality is a powerful regulatory persuader. For an antiarrhythmic, the effect in the PES laboratory, the reduction in symptoms like syncope, and the reduction in death are to be hoped for and all correlate together to tell the story that the drug is antiarrhythmic. But still the effect on mortality outcome, and especially the effect on sudden death, is expected to be evaluated and to be associated with mortality reduction. When one moves along into the field of atrial fibrillation, the prevention of the arrhythmia is not felt to be sufficient, but rather remaining in sinus rhythm without adverse side effects, such as embolization or stroke, appears to be requisite. But are we testing an anticoagulant or an antiarrhythmic? Both could possibly prevent embolization and stroke, but by entirely different mechanisms. Thus, the antiarrhythmic effect must be demonstrated as well as a favorable outcome and each might require a different study to be demonstrated. The field of CHF drug development is a complex one. The ACE inhibitors demonstrate significant hemodynamic action and this is expected to correlate with a favorable mortality effect. However, establishing a dose on the hemodynamic actions may not be appropriate. Concomitant therapy with digitalis and diuretics may be beneficial or adverse. The beta blockers may have a significant role to play and maybe they have to be given concomitantly with the ACE inhibitor. Finally, when several studies have shown benefit, can approval for CHF therapy be based on hemodynamic surrogates and a class effect be granted in terms of mortality and ACE inhibition? Clearly further ACE-inhibition mortality studies are not possible and a positive control study would not prove comparability in terms of mortality since the number of patients to prove that would be prohibitive.1 |
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I believe that novel endpoints such as hemodynamic effects of a drug and the correlation with converting-enzyme inhibition can and will be employed. Valid animal models that show correlative results with the pivotal mortality studies in man with other agents of the class will lend credence to a class-effect claim. If, for an ACE inhibitor, one had an hemodynamic effect, one showed short-term improvement in exercise capacity in heart failure patients, one had similar effects on converting enzyme inhibition, and one also had data in an animal mortality study that showed there was benefit, all this would lead to the possibility of a mortality claim. However, potentially significant differencesand I emphasize the word potentiallymay make one ACE inhibitor different enough from the others to question the class effect in terms of mortality. In |
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