Endothelial Dysfunction and Nitric Oxide Enhancing Therapy
Endothelial Dysfunction and Nitric Oxide Enhancing Therapy
Despite ethnic differences in heart failure prevalence, risk profiles, and outcomes, no clinical trials have been designed to prospectively examine the mechanisms responsible for these differences. The African-American Heart Failure Trial is the first prospective trial designed to test a novel therapy that enhances endothelial function and nitric oxide bioavailability in African-American patients with advanced heart failure.
Congestive heart failure (CHF) is the leading cause of hospitalization in the elderly and the most rapidly growing cardiovascular diagnosis related group). While prevalence, morbidity, and mortality vary with age, there are also significant differences in prevalence and outcome by ethnicity. African Americans have a higher prevalence, mortality, and different risk profile for CHF than those of European descent. Clinical trials over the last 20 years have defined the mechanistic role of the renin-angiotensin aldosterone system, the sympathetic nervous system, and other regulators of vascular tone as important contributors to the syndrome of CHF and as therapeutic targets. Based on clinical trial data from international cohorts, blockades of the renin-angiotensin-aldosterone system and sympathetic nervous system have resulted in major improvements in morbidity and mortality for patients with CHF while manipulation of other mediators of vascular tone has been less successful. Despite ethnic differences in prevalence, disease severity, and heart failure (HF) risk profiles, there have been no clinical trials to date designed to prospectively examine the mechanisms responsible for the observed interethnic differences, nor have there been prospective trials to examine whether significant ethnic and gender differences exist in response to therapeutic agents.
Two of the most important clinical trials providing the basis for contemporary HF treatment were the Vasodilator-Heart Failure Trial(s) (V-HeFT I and II). V-HeFT I compared the effects on mortality of vasodilator therapy consisting of either combined hydralazine/isosorbide dinatrate or prazosin vs. placebo. While hemodynamic variables were similar in the two vasodilator arms, mortality was favorably impacted only by treatment with combined hydralazine/isosorbide dinitrate. This outcome suggested that mechanisms beyond hemodynamic improvement were addressed by the hydralazine/isosorbide dinitrate combination. V-HeFT II compared two treatments, the angiotensin-converting enzyme enalapril vs. combined hydralazine/isosorbide dinitrate without a placebo arm. In this study, mortality trended lower in the enalapril treatment arm. These two trials had nearly 30% African-American subjects, unique amongst HF trials, thus providing a database that could be retrospectively analyzed for the effects of ethnicity on treatment response.
Recent retrospective analyses of these two seminal HF trials comparing African Americans to whites in the trial cohorts revealed significant ethnic differences in response to treatment, supporting the hypothesis that ethnic differences in the balance of regulators of vascular function might exist. Thus, analysis by ethnicity of both V-HeFT trials revealed the following: In V-HeFT I, a combination of hydralazine/isosorbide dinitrate was compared with prazosin or placebo. A significant mortality benefit was observed in African-American, but not white, patients treated with hydralazine/isosorbide dinitrate. There was no difference between placebo and prazosin. In V-HeFT II comparing treatment with enalapril to hydralazine/isosorbide dinitrate, a significant survival advantage of enalapril was observed only in white patients. In African-American patients, there was no survival advantage of enalapril over hydralazine/isosorbide dinitrate. Similarly, when the Studies of Left Ventricular Dysfunction (SOLVD) database was reanalyzed by ethnicity, significant reductions in hospitalizations and in the combined end point of death or hospitalization for CHF were observed in white patients in the enalapril treatment arm but not in African-American patients. Data from trials examining the antihypertensive effects of angiotensin-converting enzyme inhibitors in blacks and whites are consistent with these findings in confirming a lesser blood pressure lowering effect in blacks where the prevalence of low-renin hypertension is greater. Beta-blocker studies have shown mixed results when ethnic differences were sought. Retrospective analysis of the effects of carvedilol comparing African Americans to whites found no differences in response between ethnic groups. By contrast, the Beta-blocker Evaluation Survival Trial (BEST) examining the effect of bucindolol treatment on HF showed benefits in whites, but no survival advantage in African-American patients. While such retrospective analyses are of value in attempting to fill a knowledge gap, they are fraught with difficulties, including differences in baseline characteristics between African-American and white subjects within trial cohorts, as well as an inadequate sample size to determine the significance of the findings. There are, however, hypotheses generating, and the consistency of findings of ethnic differences in these retrospective analyses suggest that pathophysiological mechanisms responsible for the syndrome of CHF might vary by ethnicity.
Data from prospective clinical trials with adequate numbers of ethnic and gender subgroups coupled with genetic and mechanistic data are essential to advance physicians' understanding of disease pathophysiology, as well as to develop optimally-targeted therapy. The African-American Heart Failure Trial (A-HeFT) is a groundbreaking trial that addresses this need. The A-HeFT is based on the hypothesis that therapy directed toward restoring endothelial function via treatment with a combined nitric oxide (NO) donor and antioxidant may provide a new pharmacologic approach to the treatment of CHF. It is the first cardiovascular trial done in a single ethnic cohort where disease morbidity and mortality are higher and where data suggest that commonly used treatments may have lesser effects consistent with a different balance of disease mechanisms.
Despite ethnic differences in heart failure prevalence, risk profiles, and outcomes, no clinical trials have been designed to prospectively examine the mechanisms responsible for these differences. The African-American Heart Failure Trial is the first prospective trial designed to test a novel therapy that enhances endothelial function and nitric oxide bioavailability in African-American patients with advanced heart failure.
Congestive heart failure (CHF) is the leading cause of hospitalization in the elderly and the most rapidly growing cardiovascular diagnosis related group). While prevalence, morbidity, and mortality vary with age, there are also significant differences in prevalence and outcome by ethnicity. African Americans have a higher prevalence, mortality, and different risk profile for CHF than those of European descent. Clinical trials over the last 20 years have defined the mechanistic role of the renin-angiotensin aldosterone system, the sympathetic nervous system, and other regulators of vascular tone as important contributors to the syndrome of CHF and as therapeutic targets. Based on clinical trial data from international cohorts, blockades of the renin-angiotensin-aldosterone system and sympathetic nervous system have resulted in major improvements in morbidity and mortality for patients with CHF while manipulation of other mediators of vascular tone has been less successful. Despite ethnic differences in prevalence, disease severity, and heart failure (HF) risk profiles, there have been no clinical trials to date designed to prospectively examine the mechanisms responsible for the observed interethnic differences, nor have there been prospective trials to examine whether significant ethnic and gender differences exist in response to therapeutic agents.
Two of the most important clinical trials providing the basis for contemporary HF treatment were the Vasodilator-Heart Failure Trial(s) (V-HeFT I and II). V-HeFT I compared the effects on mortality of vasodilator therapy consisting of either combined hydralazine/isosorbide dinatrate or prazosin vs. placebo. While hemodynamic variables were similar in the two vasodilator arms, mortality was favorably impacted only by treatment with combined hydralazine/isosorbide dinitrate. This outcome suggested that mechanisms beyond hemodynamic improvement were addressed by the hydralazine/isosorbide dinitrate combination. V-HeFT II compared two treatments, the angiotensin-converting enzyme enalapril vs. combined hydralazine/isosorbide dinitrate without a placebo arm. In this study, mortality trended lower in the enalapril treatment arm. These two trials had nearly 30% African-American subjects, unique amongst HF trials, thus providing a database that could be retrospectively analyzed for the effects of ethnicity on treatment response.
Recent retrospective analyses of these two seminal HF trials comparing African Americans to whites in the trial cohorts revealed significant ethnic differences in response to treatment, supporting the hypothesis that ethnic differences in the balance of regulators of vascular function might exist. Thus, analysis by ethnicity of both V-HeFT trials revealed the following: In V-HeFT I, a combination of hydralazine/isosorbide dinitrate was compared with prazosin or placebo. A significant mortality benefit was observed in African-American, but not white, patients treated with hydralazine/isosorbide dinitrate. There was no difference between placebo and prazosin. In V-HeFT II comparing treatment with enalapril to hydralazine/isosorbide dinitrate, a significant survival advantage of enalapril was observed only in white patients. In African-American patients, there was no survival advantage of enalapril over hydralazine/isosorbide dinitrate. Similarly, when the Studies of Left Ventricular Dysfunction (SOLVD) database was reanalyzed by ethnicity, significant reductions in hospitalizations and in the combined end point of death or hospitalization for CHF were observed in white patients in the enalapril treatment arm but not in African-American patients. Data from trials examining the antihypertensive effects of angiotensin-converting enzyme inhibitors in blacks and whites are consistent with these findings in confirming a lesser blood pressure lowering effect in blacks where the prevalence of low-renin hypertension is greater. Beta-blocker studies have shown mixed results when ethnic differences were sought. Retrospective analysis of the effects of carvedilol comparing African Americans to whites found no differences in response between ethnic groups. By contrast, the Beta-blocker Evaluation Survival Trial (BEST) examining the effect of bucindolol treatment on HF showed benefits in whites, but no survival advantage in African-American patients. While such retrospective analyses are of value in attempting to fill a knowledge gap, they are fraught with difficulties, including differences in baseline characteristics between African-American and white subjects within trial cohorts, as well as an inadequate sample size to determine the significance of the findings. There are, however, hypotheses generating, and the consistency of findings of ethnic differences in these retrospective analyses suggest that pathophysiological mechanisms responsible for the syndrome of CHF might vary by ethnicity.
Data from prospective clinical trials with adequate numbers of ethnic and gender subgroups coupled with genetic and mechanistic data are essential to advance physicians' understanding of disease pathophysiology, as well as to develop optimally-targeted therapy. The African-American Heart Failure Trial (A-HeFT) is a groundbreaking trial that addresses this need. The A-HeFT is based on the hypothesis that therapy directed toward restoring endothelial function via treatment with a combined nitric oxide (NO) donor and antioxidant may provide a new pharmacologic approach to the treatment of CHF. It is the first cardiovascular trial done in a single ethnic cohort where disease morbidity and mortality are higher and where data suggest that commonly used treatments may have lesser effects consistent with a different balance of disease mechanisms.
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