Published online before print March 19, 2007, doi: 10.1161/CIRCULATIONAHA.106.644013
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(Circulation. 2007;115:1747-1753.)
© 2007 American Heart Association, Inc.
Heart Failure |
Early and Sustained Benefit on Event-Free Survival and Heart Failure Hospitalization From Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine
Consistency Across Subgroups in the African-American Heart Failure Trial
From the Department of Medicine (A.L.T., J.N.C.), University of Minnesota, Minneapolis, Minn; Minneapolis Veterans Affairs Medical Center (S.Z.), Minneapolis, Minn; Baylor University Medical Center at Dallas (C.W.Y.), Dallas, Tex; Veterans Affairs Medical Center (P.C.), Washington, DC; Xavier University of Louisiana (K.F.), New Orleans; Association of Black Cardiologists (M.T.), Jackson, Miss; University of North Carolina (K.A.), Chapel Hill; Clinical and Regulatory Strategies, LLC (A.Y.O.), Princeton, NJ; Moorehouse School of Medicine (E.O.), Atlanta, Ga; and NitroMed, Inc (S.W.T., M.L.S., M.W.), Lexington, Mass.
Correspondence to Anne L. Taylor, MD, University of Minnesota Medical School, C694 Mayo Memorial Bldg, Mayo Mail Code 293, 420 Delaware St SE, Minneapolis, MN 55455. E-mail taylo135{at}umn.edu
Received June 8, 2006; accepted November 20, 2006.
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Abstract |
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Background— We previously reported that the fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride (FDC I/H) significantly decreased the risk of all-cause death and first hospitalization for heart failure (HF) and improved quality of life in patients with New York Heart Association class III or IV heart failure in the African-American Heart Failure Trial (A-HeFT). The current analyses further define the effect of FDC I/H on the timing of event-free survival (mortality or first hospitalization for HF) and time to first hospitalization for HF, as well as effects by subgroups and effects on cause-specific mortality.
Methods and Results— Kaplan-Meier analyses of the 1050 A-HeFT patients on standard neurohormonal blockade demonstrated that FDC I/H produced a 37% improvement in event-free survival (P<0.001) and a 39% reduction in the risk for first hospitalization for HF (P<0.001). These benefits appeared to emerge early (at 
50 days of treatment) and were sustained through the duration of the trial. Subgroup analyses of treatment effect by age, sex, baseline blood pressure, history of chronic renal insufficiency, presence of diabetes mellitus, cause of HF, and baseline medication usage demonstrated consistent beneficial effect of FDC I/H on the primary composite score and event-free survival across all subgroups. Mortality from pump failure was reduced by 75% (P=0.012).
Conclusions— FDC I/H treatment of black patients with moderate to severe HF who were taking neurohormonal blockers produced early and sustained significant improvement in event-free survival and hospitalization for HF in the A-HeFT cohort, with significant reduction in mortality from cardiovascular and pump failure deaths. The treatment effects on the primary composite end point and event-free survival were consistent across subgroups.
Key Words: heart failure • cardiovascular diseases • nitric oxide • African Americans • trials
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Introduction |
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The African-American Heart Failure Trial (A-HeFT) demonstrated a striking reduction in mortality and improvement in the primary morbidity/mortality outcome in response to therapy with a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in black patients with severe heart failure.1 This therapy was superimposed on guideline-recommended intensive background neurohormonal blockade and was associated with a mortality reduction that quantitatively was nearly identical to that observed in the self-identified black cohort in the first Vasodilator Heart Failure Trial (V-HeFT) performed in patients treated only with digoxin and diuretic.2,3 Because efficacy therefore appeared to be independent of the effects of renin-angiotensin system inhibitors and ß-blockers, the data suggest that this drug combination, which includes a nitric oxide (NO) donor (isosorbide dinitrate) and an antioxidant (hydralazine) to protect generated NO from degradation, may exert its effect through an independent NO pathway.
Clinical Perspective p 1753
The primary A-HeFT outcome report did not examine mechanism of death or demographic and phenotypic subgroups of patients to identify individuals who might display greater or lesser response to the FDC I/H. Furthermore, the mortality data suggested that the benefit of the fixed-dose combination became apparent only after 6 months of therapy. This delay of survival benefit might be anticipated if the efficacy of the drug were related to inhibition of left ventricular (LV) structural remodeling, as demonstrated in V-HeFT.2 However, FDC I/H is also a potent vasodilator regimen that should improve LV function and possibly impact morbidity by producing reductions in preload and afterload before its effect on mortality becomes apparent. In the present report, we examine these issues with adjudicated data on mechanism of death, detailed subgroup analysis, and assessment of the time course of morbidity end points.
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Methods |
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Study Design
The A-HeFT study design, patient characteristics, end-point definitions, and complete methodology have been published previously in detail.1,4,5 In brief, A-HeFT was a randomized, placebo-controlled, double-blind trial with self-identified black patients recruited at 169 centers in the United States. The study protocol was reviewed and approved by appropriate institutional review boards. All patients gave written informed consent. Independent committees adjudicated all primary and secondary end points, reviewed data for safety, and oversaw the 2 prespecified interim analyses done to assess adequacy of sample size only.
Inclusion and Exclusion Criteria
Patients 18 years and older, self-identified as African American and with New York Heart Association class III or IV heart failure for at least 3 months, were eligible for screening. Patients were required to be undergoing standard background heart failure therapy, as determined by their physician, which included ACE inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), ß-blockers for at least 3 months before randomization, digoxin, spironolactone, and diuretics. Evidence of LV dysfunction within the 6 months preceding randomization was required and consisted of either a resting LV ejection fraction 
35% or a resting LV ejection fraction 45% with an LV internal diastolic diameter >2.9 cm/m2 of body surface area or >6.5 cm by echocardiography.1 Exclusion criteria included the following: (1) females who were pregnant, nursing, or of childbearing age who were not practicing effective contraception; (2) acute myocardial infarction, acute coronary syndrome, or stroke within the previous 3 months; (3) cardiac surgery or percutaneous coronary intervention within 3 months or the likelihood of a requirement for such procedures during the study; (4) significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension; (5) cardiac arrest or life-threatening arrhythmias within the previous 3 months (unless they had been treated with an implantable defibrillator); (6) treatment with parenteral inotropes within 1 month before randomization; (7) likely need to undergo cardiac transplantation during the trial period; (8) symptomatic hypotension; (9) the presence of an illness other than heart failure that was likely to result in mortality within the study period; (10) an inability to comprehend or complete the quality-of-life (QoL) assessment instrument; and (11) contraindications to nitrate or hydralazine therapy.1,4,5
Study Procedure
Patients were stratified according to inclusion of a ß-blocker in background therapy and were randomized to receive either FDC I/H or a placebo, added to background therapy. Therapy was initiated at 1 tablet that contained either placebo or the fixed-dose combination of 37.5 mg of hydralazine HCl and 20 mg of isosorbide dinitrate 3 times daily. Dosing was uptitrated to 2 tablets 3 times daily, equivalent to a total dose of 225 mg of hydralazine HCl and 120 mg of isosorbide dinitrate per day in 3 divided doses. Uptitration was dependent on the absence of drug-induced side effects as judged by the investigator. Patients were followed up for up to 18 months, with assessments of LV ejection fraction, LV internal diastolic diameter, LV wall thickness, and brain natriuretic peptide levels at 6 months and QoL assessment performed every 3 months. Patients were telephoned monthly, and they returned for follow-up visits at 3-month intervals.1
The primary efficacy end point for the trial was a novel composite score that weighted all-cause mortality, first hospitalization for heart failure throughout the 18-month follow-up period, and change in QoL at 6 months.1,4,5 The QoL was assessed with the Minnesota Living with Heart Failure Questionnaire, a 21-question self-administered instrument in which higher scores indicate worse QoL.6 Secondary end points included the following: (1)individual components of the primary composite score; (2) cause-specific mortality; (3) total number of heart failure hospitalizations; (4) total number of all hospitalizations; (5) total days in-hospital; (6) overall QoL throughout the trial; (7) number of unscheduled emergency room and office/clinical visits; (8) changes in LV ejection fraction, LV internal diastolic diameter, and LV wall thickness at 6 months; (9) change in brain natriuretic peptide level at 6 months; and (10) the newly recognized need for cardiac transplantation. Patients undergoing cardiac transplantation during the trial were censored at the time of transplantation.1 History of chronic renal insufficiency was based on patients’ medical history at randomization.
Statistical Analysis
Time to either death or first hospitalization for heart failure (event-free survival) and time to first hospitalization for heart failure were compared by Kaplan-Meier survival analysis methods with the log-rank test. Analyses were based on an intention-to-treat principle. The Cox proportional hazards models were used to calculate hazard ratios and CI intervals. For the main analysis that compared treatments, the association of treatment and log time was used to test lack of fit. This was not significant for any of the main models. Post hoc hazard ratios with 95%CIs were calculated for analysis of the treatment effect on the primary composite end point, all-cause mortality and first hospitalization for heart failure, by subgroups, including age, sex, cause of heart failure, comorbidities such as diabetes mellitus and history of chronic renal insufficiency, and baseline heart failure medications. Additional descriptive statistics calculated for patient characteristics were displayed as counts (and percentages). Cause-specific mortality was compared between groups with the Fisher exact test. Interactions for the primary composite score were performed with 2-way ANOVAs with interaction terms. Interactions for event-free survival were performed with Cox proportional hazards models with interaction terms.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Baseline characteristics of the cohort are shown in Table 1. With the exception of slightly more women, diabetic patients, and patients with hyperlipidemia and a slightly higher diastolic blood pressure in the FDC I/H group, no baseline differences existed between the 2 treatment arms.
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Cause-Specific Mortality
The primary composite score was previously reported to be significantly better in the FDC I/H group than in the placebo group, and death due to any cause was significantly reduced in the FDC I/H group.1 Examination of the adjudicated causes of death (Table 2) revealed that cardiovascular deaths were significantly reduced in the FDC I/H group. Pump failure death was most prominently reduced (by 75%) compared with the placebo group (P=0.012). No significant effect existed on sudden cardiac death or noncardiovascular deaths.
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Time-to-Event Analyses
Event-free survival, defined as death or first hospitalization for heart failure, was significantly improved in the FDC I/H group compared with placebo (hazard ratio 0.63, 95% confidence interval 0.49 to 0.81, P<0.001; Figure 1). Time to first hospitalization for heart failure was also significantly reduced (hazard ratio 0.61, 95% confidence interval 0.46 to 0.80, P<0.001), as shown in Figure 2. The treatment effect on both event-free survival and first hospitalization for heart failure appeared to emerge at 50 days and diverged significantly from the placebo group for the duration of the follow-up period.
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Subgroup Analyses
To better understand the treatment effect on the basis of patient demographics, baseline characteristics, and baseline medications, subgroup analyses were performed on the primary composite score, which consisted of a weighted score of death due to any cause, first hospitalization for heart failure, and change in QoL at 6 months.1 As shown in Figure 3, the beneficial treatment effect was consistent across the subgroups with the exception of the groups not receiving loop diuretics at baseline, not having a history of hypertension, and receiving calcium channel blockers, groups that had small numbers of patients (83, 110, and 213, respectively, when the FDC I/H and placebo arms were combined) and wide confidence intervals. No significant interaction existed in any subgroups as defined by treatment for the primary composite score analysis. The subgroup-by-treatment interaction probability values for the primary composite score were as follows: age 0.073, sex 0.806, ischemic cause of heart failure 0.995, history of hypertension 0.151, atrial fibrillation 0.440, diabetes mellitus 0.305, history of chronic renal insufficiency 0.642, ACEI use 0.782, ARB use 0.987, ACEI or ARB use 0.764, ß-blocker use 0.674, aldosterone antagonist use 0.472, digitalis glycoside use 0.932, use of loop diuretics 0.314, use of calcium channel blocker 0.154, and systolic blood pressure >126 mm Hg 0.749. Subgroup analyses were also performed on the composite of mortality or first hospitalization for heart failure (event-free survival). As shown in Figure 4, the beneficial effects on event-free survival were also consistent across subgroups, regardless of age (<65 or 
65 years), sex, heart failure cause, systolic blood pressure (> or 125 mm Hg), presence of diabetes mellitus, history of chronic renal insufficiency, or background medication use. The only exception occurred in the small group (n=83, 11 events) not receiving loop diuretics at baseline, in which the 95% confidence interval was very large. Consistent with the point estimates favoring FDC I/H therapy in the event-free survival subgroup analysis, no significant interactions existed in any subgroups by treatment. The subgroup-by-treatment interaction probability values for event-free survival were as follows: age 0.683, sex 0.611, ischemic cause 0.436, history of hypertension 0.575, atrial fibrillation 0.130, diabetes mellitus 0.508, history of chronic renal insufficiency 0.278, ACEI use 0.178, ARB use 0.865, use of ACEI or ARB 0.672, ß-blocker use 0.823, use of aldosterone antagonist 0.103, use of digitalis glycoside 0.431, nonaldosterone antagonist diuretic use 0.184, use of calcium channel blocker 0.294, and systolic blood pressure >126 mm Hg 0.972.
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Adverse Effects
Adverse effects of dizziness and hypotension, which occurred more frequently in the FDC I/H arm, have been reported previously.1 An additional concern during the trial was the potential adverse effect of lupus-like syndrome, which has been noted to occur with hydralazine therapy, although generally at higher doses than those used in the A-HeFT trial.7 We therefore examined the frequencies of adverse events consistent with a lupus-like syndrome in the A-HeFT cohort. Table 3 shows the frequencies of adverse events including terms that might indicate the presence of arthritis consistent with lupus-like syndrome. With the exception of arthralgia, the incidences of these adverse events were similar between the treatment groups. Only 1 patient in the FDC I/H group was identified as having lupus-like symptoms, and the symptoms resolved without any change in study medication.
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Discussion |
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The results of these analyses further delineate the treatment effects of FDC I/H in the A-HeFT cohort. Treatment with FDC I/H improved both the primary composite end-point score and event-free survival in nearly all post hoc selected subgroups of the study cohort, irrespective of clinical characteristics or background therapy. Significant therapeutic benefit occurred early and was sustained over the course of treatment, with a significant early effect on hospitalization for heart failure and event-free survival and a later significant mortality benefit, previously published as analysis of overall outcomes of the trial.1 Mortality from pump failure was significantly reduced by FDC I/H consistent with a beneficial effect on structural remodeling. These results suggest that at least 2 therapeutic targets were responsible for the overall favorable effect.
The syndrome of heart failure is characterized by 2 largely independent mechanisms. Reduced cardiac output and elevated LV filling pressure result in symptoms that may be relieved in the short term by a more normal LV hemodynamic profile. Shortened survival, however, is related in large part to progression of the disease, characterized by structural remodeling of the LV. It is well recognized that heart failure therapy may have divergent effects on these 2 mechanisms. Over a short period of time, ß-blockers may not improve LV function and may transiently worsen symptoms, but they have been associated with a longer-term survival advantage.8–11 Inotropic agents may produce short-term symptomatic benefit but are associated with poor long-term survival.12–14 The data from A-HeFT suggest that FDC I/H exerts both a short-term hemodynamic benefit and a long-term survival benefit. This dual effect, similar to that observed with ACEIs15–17 and ARBs,18,19 is consistent with an early vasodilator-induced hemodynamic improvement in LV function and a later inhibition of LV remodeling.20,21 The fact that this dual benefit was observed in patients already treated with ACEIs or ARBs and ß-blockers lends credence to the suggestion that the drug combination is exerting its effects via a mechanism not responsive to neurohormonal inhibiting therapy.
The initial therapeutic effect sought in the V-HeFT I trial that first utilized combined isosorbide dinitrate and hydralazine was based on the combined hemodynamic effects of the 2 agents.2 In V-HeFT I, 2 vasodilator preparations, prazosin and combined isosorbide dinitrate and hydralazine, were compared with placebo in patients treated only with background therapy of digoxin and diuretics.2 Despite significant blood pressure lowering in the prazosin arm, only combined isosorbide dinitrate and hydralazine (which had no effect on blood pressure in V-HeFT I)2 reduced mortality and improved ejection fraction. Subsequently, the V-HeFT III trial assessed heart failure mortality reduction by the calcium channel blocker vasodilator felodipine, which lowered blood pressure but again had no mortality benefit.22 A detailed analysis of outcomes related to baseline blood pressure and blood pressure changes in A-HeFT was reported by Anand et al.23 Although systolic blood pressure was reduced by FDC I/H in the overall cohort, FDC I/H decreased blood pressure in patients with baseline systolic blood pressure above the median of 126 mm Hg but produced no significant blood pressure reduction in patients with systolic blood pressure below the median systolic blood pressure. However, FDC I/H was associated with a similar reduction in mortality and improvement in event-free survival whether baseline systolic blood pressure was above or below the median. Thus, although vasodilators may reduce congestion via hemodynamic improvement, a mortality benefit occurs only with vasodilating drugs with additional properties, such as ACEIs or ARBs.15–21 Survival benefit is also observed with nonvasodilator drugs, including some but not all ß-blockers, for which the mortality benefit occurs after several months of treatment without a major effect on LV hemodynamics.8–11
Data strongly suggest that FDC I/H has effects in addition to vasodilation, and we hypothesize that these effects may result from enhancement of NO bioavailability. Organic nitrates function as NO donors or congeners,24 whereas hydralazine is a potent antioxidant that diminishes consumption of NO by reactive oxygen species.25–27 NO vasodilates via cGMP signaling pathways24 but also has important direct effects on myocardial metabolism,28 energy regulation,29 hypertrophy,30 and remodeling.30–32 Thus, a purely hemodynamic effect of the combination might explain the early reduction in hospitalizations by reduced pulmonary congestion. This is consistent with clinical26 and laboratory studies33 that have demonstrated that addition of hydralazine to nitrates dramatically prolongs the reductions in pulmonary artery and pulmonary capillary wedge pressures produced by nitrates.
The later emerging mortality benefit at 6 months,1 primarily from reductions in pump failure, may reflect a favorable effect on myocardial structural remodeling. FDC I/H had only a modest and not statistically significant effect on sudden cardiac death, but it significantly impacted mortality by virtue of a reduction of cardiovascular deaths and pump failure beginning at 180 days of therapy.1 Preliminary analysis of echocardiographic data at 6 months showed a significant increase in ejection fraction and a decrease in the LV internal diastolic diameter in the FDC I/H group34 that was consistent with an effect on remodeling.
Although post hoc subgroup analyses may be vulnerable to problems of inadequate sample size, classification of patients into incorrect subgroups, and low power to test for potential interactions,35,36 the subgroup analyses of the A-HeFT cohort are directionally very consistent with treatment effects in the entire cohort. This was true whether the primary composite score, mortality, or hospitalizations were considered. The uniformity of benefit across subgroups coupled with the strength of effect in the entire cohort suggest that this therapy should be considered indicated in all black heart failure patients with LV systolic dysfunction and advanced (New York Heart Association class III or IV) symptoms.
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Acknowledgments |
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Source of Funding
The study sponsor was NitroMed, Inc (Lexington, Mass).
Disclosures
Dr Cohn was the inventor of 2 patents (6,784,177 and 6,465,463) for the use of combinations of hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate in heart failure. In return for equity and potential future royalties, NitroMed licensed from him the patent for mortality reduction of the drug combination in heart failure. NitroMed subsequently applied for a patent for use in black patients. Dr Anne Taylor, S. Ziesche, and Dr Adams have received research support from NitroMed and served on advisory boards. Drs Ferdinand and Yancy have received consulting and lecture fees from NitroMed. Drs Carson and Ofilli report having received consulting fees and having served on paid advisory boards for NitroMed. Dr Olukotun has received consulting fees from NitroMed. Drs Sabolinski, Tam, and Worcel are employees and stockholders of NitroMed, Inc. Dr Cohn has received consulting fees and serves on the scientific advisory board of NitroMed.
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References |
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Footnotes |
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Guest Editor for this article was James E. Udelson, MD.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047775.
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Circulation 2007 115: 1697.
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