Current and novel pharmacologic approaches in advanced heart failure
Since the late 1980s, when the first two randomized trials of vasodilator therapy demonstrated improved survival in advanced heart failure, there have been few (if any) significant pharmacologic or mechanical advances in the treatment of patients with severe heart failure. Although β-blockers, new calcium blockers, and angiotensin II receptor blockers appear promising, they cannot be endorsed for this group of patients until several multicenter randomized controlled clinical trials are completed (Tables IV and V). The reasons for our limited success in this subgroup of patients with heart failure are numerous. If we are to foster therapeutic advances in this field, we must be able to carefully define heart failure etiology and stratify when necessary, or focus on one etiology in drug development strategies. An uncoupling of therapeutic effect by etiology with several agents has recently been observed. Even in the advanced heart failure group a distinction between volume overloaded and volume depleted heart failure has been proposed. We must be able to better characterize this heterogeneous group of patients. Second, we must advance our basic understanding of the disease process, particularly the disease progression from hypertrophy to dilatation, and the roles of apoptosis, oxidative stress, cytokine activation, and neurohormonal activation. Finally, a new approach is required for the investigation of patients with advanced heart failure. This approach initially will require a dedicated international group of investigators committed to the study of the patient with advanced heart failure. Heart failure trials have traditionally focused on highly selective patient populations. Novel global approaches are required to facilitate the study of large patient populations, with multiple doses or intensities of therapies, using mortality as an end point, and underpinned with mechanistic substudies.
O'Connor, CM; Gattis, WA; Swedberg, K
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