Background Black patients with heart failure have a poorer prognosisthan white patients, a difference that has not been adequatelyexplained. Whether racial differences in the response to drugtreatment contribute to differences in outcome is unclear. Toaddress this issue, we pooled and analyzed data from the Studiesof Left Ventricular Dysfunction (SOLVD) prevention and treatmenttrials, two large, randomized trials comparing enalapril withplacebo in patients with left ventricular dysfunction.
Methods We used a matched-cohort design in which up to fourwhite patients were matched with each black patient accordingto trial, treatment assignment, sex, left ventricular ejectionfraction, and age. A total of 1196 white patients (580 fromthe prevention trial and 616 from the treatment trial) werematched with 800 black patients (404 from the prevention trialand 396 from the treatment trial). The average duration of follow-upwas 35 months in the prevention trial and 33 months in the treatmenttrial.
Results The black patients and the matched white patients hadsimilar demographic and clinical characteristics, but the blackpatients had higher rates of death from any cause (12.2 vs.9.7 per 100 person-years) and of hospitalization for heart failure(13.2 vs. 7.7 per 100 person-years). Despite similar doses ofdrug in the two groups, enalapril therapy, as compared withplacebo, was associated with a 44 percent reduction (95 percentconfidence interval, 27 to 57 percent) in the risk of hospitalizationfor heart failure among the white patients (P<0.001) butwith no significant reduction among black patients (P=0.74).At one year, enalapril therapy was associated with significantreductions from base line in systolic blood pressure (by a mean[±SD] of 5.0±17.1 mm Hg) and diastolic blood pressure(3.6±10.6 mm Hg) among the white patients, but not amongthe black patients. No significant change in the risk of deathwas observed in association with enalapril therapy in eithergroup.
Conclusions Enalapril therapy is associated with a significantreduction in the risk of hospitalization for heart failure amongwhite patients with left ventricular dysfunction, but not amongsimilar black patients. This finding underscores the need foradditional research on the efficacy of therapies for heart failurein black patients.
Large-scale trials of therapy for heart failure over the pastdecade have shown improvements in outcome with angiotensin-converting–enzyme(ACE) inhibitors and beta-blockers.1,2,3,4,5,6,7 In the Studiesof Left Ventricular Dysfunction (SOLVD), two concurrent trialsevaluating the efficacy of enalapril in patients with left ventricularsystolic dysfunction, enalapril was associated with a 16 percentreduction in the risk of death from any cause among patientswith symptoms6 and a 20 percent reduction in the risk of deathfrom any cause or hospitalization for heart failure among patientswithout symptoms.7 These results and the results of other studies1,2,3,4,5led to the recommendation that all patients who have heart failureaccompanied by a low ejection fraction and who can tolerateACE inhibitors and beta-blockers should be treated with bothagents.8,9
However, data from the second Vasodilator–Heart FailureTrial (V-HeFT II) indicated that although enalapril therapy,as compared with treatment with a combination of hydralazineand isosorbide dinitrate, was associated with a significantreduction in the risk of death from any cause among white patients,no such benefit was observed among black patients.10 Furthermore,in the Beta-Blocker Evaluation of Survival Trial it was foundthat white, but not black, patients with heart failure appearto benefit from the beta-blocker bucindolol,11 suggesting thatthere may be racial differences in therapeutic response. A criticalimpediment to the analysis of racial differences in therapeuticresponse is the underrepresentation of black patients in trialsof therapy for heart failure. In V-HeFT I and II,2,12 27 percentof the patients were black, and in SOLVD,6,7 12 percent wereblack. In other trials, the proportion of black patients wasconsiderably smaller,1,2,3,4,5 in part because of the inclusionof patients from large numbers of European centers.
A previous analysis of data from SOLVD identified a poorer outcomein black patients than in white patients.13 Black patients were28 percent more likely to die from any cause and 37 percentmore likely to die from any cause or to be hospitalized forheart failure than white patients, a finding that was independentof important prognostic and socioeconomic factors. However,the relatively small number of black patients and the prominentdifferences between their base-line characteristics and thoseof the white patients prevented reliable evaluation of differencesin the response to enalapril in terms of mortality. Nonetheless,a possible difference in the response to enalapril in termsof the risk of death from any cause or hospitalization for heartfailure was observed after adjustment for important prognosticvariables (P=0.08). This observation formed the rationale forthe present analysis of participants in SOLVD. In this analysis,procedures for matching14 were used to identify a populationof similar white patients in whom the response to enalaprilcould be more reliably compared with that in the black patients.
Methods
Patients
Patients 21 to 80 years of age who had a left ventricular ejectionfraction of 0.35 or less, as measured by echocardiography, radionuclideangiography, or contrast angiography, were eligible for enrollmentin SOLVD.6,7 Enrollment began in June 1986, and enrollment wascompleted in March 1989 in the case of the treatment trial andMay 1990 in the case of the prevention trial. Patients witha recent history of myocardial infarction (within the preceding30 days), clinically significant valvular heart disease, ora serious coexisting illness were excluded.6,7 All 6797 participantsunderwent a detailed base-line evaluation at the time of enrollment.Patients were enrolled in the prevention trial if they had nosymptoms of heart failure requiring treatment and were enrolledin the treatment trial if they had symptomatic disease. Therewere 4228 patients in the prevention trial and 2569 patientsin the treatment trial; most of the patients in the treatmenttrial had New York Heart Association (NYHA) functional classII or III symptoms. Patients were randomly assigned to receiveup to 20 mg of enalapril or placebo daily and then were followedfor a mean (±SD) of 35±14 months in the preventiontrial and 33±15 months in the treatment trial.6,7 Theprotocol was approved by the institutional review boards ofthe participating centers, and written informed consent to participatein the trials was obtained from all patients.
Classification of Race
Data on race and ethnic background were obtained from the SOLVDeligibility form, on which participants identified themselvesas American Indian, Asian, black, white, Hispanic, or "other."Participants who identified themselves as black or white constitutedthe comparison groups for this analysis. A total of 800 participants(404 [50.5 percent] in the prevention trial and 396 [49.5 percent]in the treatment trial) categorized themselves as black. Another5719 participants categorized themselves as white and thus wereeligible to be matched with one of the 800 black participants.
Matching
Because of the difficulty in ascertaining whether racial differencesin outcomes are attributable to race or to other factors,10,13patients were matched according to important prognostic variablesso as to allow a precise evaluation of the response to enalaprilin black patients as compared with white patients. A maximumof four white patients were matched with each black patientto increase statistical power.14 Patients were matched accordingto the trial (participation in the prevention trial or in thetreatment trial), exact value of the left ventricular ejectionfraction, randomly assigned therapy (enalapril or placebo),sex, and age (<60, 60 to 67, or >67 years). Matching wasperformed in an automated fashion, independently of outcome,with Stata software (release 6.0, Stata, College Station, Tex.).
Variables
Age, blood pressure, and left ventricular ejection fractionwere assessed as continuous variables. The randomly assignedtherapy (enalapril or placebo) as well as sex, the presenceor absence of financial distress during the 12 months beforeenrollment in SOLVD, and the cause of left ventricular dysfunction(ischemic or other) were assessed as dichotomous variables,as were other base-line characteristics, including the use ofmedications at base line. Indicator variables were used in theevaluation of NYHA functional class (class II vs. class I, andclass III or IV vs. class I) and the highest level of education(high school vs. elementary, and college or higher vs. elementary).
End Points
Deaths from any cause and hospitalizations for heart failurewere prospectively recorded for all the participants. The causesof death were evaluated in a blinded fashion and categorizedby the investigators at each center as worsening heart failure(with or without arrhythmia), arrhythmia without preceding heartfailure, another cardiovascular cause, or a noncardiovascularcause. For the present analysis, deaths due to pump failureincluded those classified as due to worsening heart failure(with or without arrhythmia), and deaths due to arrhythmia includedthose attributed to an arrhythmia without worsening heart failure.Since the composite end point of death from any cause or hospitalizationfor heart failure is considered a valid and robust indicatorof therapeutic efficacy in patients with heart failure,7,15it and its components were used as the primary end points inthis analysis.
Statistical Analysis
Characteristics assessed as continuous variables are presentedas means ±SD. Pairwise comparisons were made with useof the chi-square test or t-test. Overall incidence rates werecompared by means of the log-rank test. Estimates of the associationof enalapril with outcome were assessed with the use of Coxproportional-hazards analysis.16 Additional Cox models, whichincluded age, educational level, presence or absence of financialdistress, NYHA functional class, cause of left ventricular dysfunction,presence or absence of a history of hypertension, presence orabsence of a history of diabetes, and use or nonuse of beta-blockersat base line, were used to assess the independent associationof enalapril therapy with outcome. The presence of a statisticalinteraction was assessed in a Cox model that included the racialcategory, randomly assigned treatment, and a multiplicativeinteraction term (for the interaction between treatment andrace). Estimates of relative risks and 95 percent confidenceintervals were obtained from the Cox models. Two-sided P valuesof less than 0.05 were considered to indicate statistical significance.
Results
Matching
A total of 1196 white patients, 580 (48.5 percent) of whom wereenrolled in the SOLVD prevention trial and 616 (51.5 percent)of whom were enrolled in the SOLVD treatment trial, were matchedwith the 800 black patients (404 [50.5 percent] and 396 [49.5percent], respectively). The proportion of black patients andmatched white patients was similar in the two trials (P=0.38).There were 1, 2, 3, or 4 matched white patients for each of579, 72, 67, and 68 black patients, respectively; the remaining14 black patients could not be matched.
Characteristics
In line with previously described differences between the overallpopulations of black and white patients in SOLVD,13 the blackpatients in the analysis were slightly younger, on average,than the matched white patients and had higher mean diastolicblood pressures. Black patients were also more likely to reporthaving had financial distress in the 12 months before enrollmentand were less likely to have attended college than the matchedwhite patients. There were also differences between the blackand matched white patients with respect to medical history andmedication use at base line (Table 1). The matched white patientshad base-line characteristics and degrees of illness that weremore similar to those of the black patients than did the overallgroup of white patients. Specifically, the proportion of women,the proportion in each NYHA functional class, and the mean leftventricular ejection fraction were similar in the black patientsand the matched white patients but not in the black patientsand the overall group of white patients (Table 1).
Table 1. Base-Line Characteristics of the Patients.
The mean final dose of study drug was similar in the black patientsand the matched white patients (14.5±6.8 and 15.0±6.9mg per day, respectively; P=0.25). In 389 of the 800 black patients(48.6 percent) and 750 of the 1196 matched white patients (62.7percent), blood-pressure measurements were available at baseline and one year after the initiation of therapy. At one year,black patients randomly assigned to receive enalapril did nothave significant reductions from base line in either systolicblood pressure (a decline of 1.7±20.3 mm Hg, P=0.25)or diastolic blood pressure (a decline of 0.5±17.8 mmHg, P=0.58). In contrast, the matched white patients randomlyassigned to enalapril had significant reductions in both systolicblood pressure (a decline of 5.0±17.1 mm Hg, P<0.001)and diastolic blood pressure (a decline of 3.6±10.6 mmHg, P<0.001) during this period. Among those randomly assignedto placebo, both black patients and matched white patients hadsignificant increases in systolic blood pressure (3.0±19.8mm Hg [P=0.04] and 2.4±15.7 mm Hg [P=0.002], respectively)but no significant changes in diastolic blood pressure (increasesof 0.6±11.9 mm Hg [P=0.48] and 0.1±10.7 mm Hg[P=0.92], respectively) at one year as compared with base line.
Outcomes
Overall, most deaths were categorized as having a cardiac cause(Table 2). The rate of death was higher among the black patientsthan among the matched white patients; this difference was largelyattributable to the difference between the groups in the rateof death due to progressive pump failure. Rates of hospitalizationfor heart failure were also higher among the black patientsthan among the matched white patients. Rates of death due toarrhythmia, other cardiac causes, and noncardiac causes weresimilar in the two groups.
Table 2. Outcomes among Black Patients as Compared with Matched White Patients.
Among the patients randomly assigned to enalapril, black patientshad 7.9 more hospitalizations per 100 person-years of follow-up(95 percent confidence interval, 5.3 to 10.6) than matched whitepatients (P<0.001 by Fisher's exact test) (Figure 1). Incontrast, black patients and matched white patients randomlyassigned to placebo had similar rates of hospitalization forheart failure (2.8 more hospitalizations per 100 patient-years[95 percent confidence interval, 0.1 fewer to 10.6 more] amongblack patients; P=0.06 by Fisher's exact test). Mortality wassimilar among the black patients and the matched white patientsregardless of treatment assignment (Figure 1).
Figure 1. Rates of Death from Any Cause (Top Panel) and of Hospitalization for Heart Failure (Bottom Panel) among Black Patients and Matched White Patients Randomly Assigned to Enalapril or Placebo.
The rate of hospitalization for heart failure among black patients assigned to enalapril was significantly higher than that among matched white patients assigned to enalapril (P<0.001 by Fisher's exact test). Mortality was similar among black patients and matched white patients, regardless of treatment.
Association of Enalapril with Outcome
The risk of hospitalization for heart failure differed significantlybetween the black patients and the matched white patients assignedto therapy with enalapril (P=0.005). A 44 percent reduction(95 percent confidence interval, 27 to 57 percent) in the riskof hospitalization for heart failure was observed with enalaprilas compared with placebo among the matched white patients butnot among the black patients (Table 3). The reduction associatedwith enalapril in the risk of hospitalization for heart failurewas similar in the matched white patients enrolled in the preventiontrial (47 percent; 95 percent confidence interval, 10 to 69percent) and those enrolled in the treatment trial (45 percent;95 percent confidence interval, 26 to 60 percent). Differencesbetween the black patients and the matched white patients inthe effect of enalapril on the risk of hospitalization for heartfailure were not significantly different when patients werestratified according to the presence or absence of a historyof hypertension or a history of diabetes or according to thecause of left ventricular dysfunction. Similar results wereobserved after adjustment for these and other potentially confoundingvariables, including educational level and the presence or absenceof financial distress (Table 3). No significant alteration inmortality was observed in association with enalapril therapyin either group. Although quantitative differences in the riskof the combined end point (death from any cause or hospitalizationfor heart failure) were observed between the black patientsand the matched white patients according to treatment assignment,there was no significant interaction between treatment and race.
Table 3. Outcomes among Black and Matched White Patients Assigned to Enalapril Therapy as Compared with Placebo.
Overall Population of White Patients
Enalapril was associated with a 40 percent reduction (95 percentconfidence interval, 32 to 47 percent) in the risk of hospitalizationfor heart failure in the overall population of 5719 white patientsbefore statistical adjustment and a 46 percent reduction (95percent confidence interval, 37 to 53 percent) after adjustmentfor age, sex, educational level, presence or absence of financialdistress, left ventricular ejection fraction, NYHA functionalclass, cause of left ventricular dysfunction, presence or absenceof a history of hypertension, presence or absence of a historyof diabetes, and use or nonuse of beta-blockers at base line.Enalapril was also associated with a significant reduction of11 percent (95 percent confidence interval, 1 to 20 percent)in the risk of death from any cause before adjustment and witha 14 percent reduction (95 percent confidence interval, 3 to24 percent) in the risk of death from any cause after multivariateadjustment in the overall group of white patients.
Discussion
Enalapril therapy is associated with a significant reductionin the risk of hospitalization for heart failure in white patientswith left ventricular dysfunction, but with no significant alterationin this outcome among similar black patients. Despite similardoses of the study drug, black patients randomly assigned toenalapril had no significant reduction in systolic or diastolicblood pressure, whereas white patients had significant reductionsin both systolic and diastolic blood pressure. No significantchange in the risk of death was observed in association withenalapril among either the black or the matched white patients.
The results of V-HeFT II raised the possibility of a racialdifference in the response to ACE inhibitors because enalapril,as compared with a combination of hydralazine and isosorbidedinitrate, was associated with a reduction in mortality amongwhite patients but not among black patients.10 Interpretationof this observation is complicated by the fact that in V-HeFTI, the combination of hydralazine and isosorbide dinitrate hada benefit predominantly in black patients.10 Thus, the differencein response between black and white patients in V-HeFT II maybe attributable to a better response to enalapril among thewhite patients, a better response to hydralazine and isosorbidedinitrate among the black patients, or a combination of thesefactors.
In V-HeFT II, enalapril produced a sustained reduction in bloodpressure in the white patients but not in the black patients,10providing evidence that some of the difference in benefit maybe due to a difference in the response to ACE-inhibitor therapy.The present analysis of data from SOLVD supports this hypothesis.In addition, in the recently completed Beta-Blocker Evaluationof Survival Trial, it was found that patients with heart failurewho were white, but not those who were black, had evidence ofbenefit from beta-blocker therapy.11 These trials have raisedthe troubling possibility that black patients with heart failuremay not benefit from commonly used doses of currently recommendedtherapies to the same extent as white patients.
A lesser response to ACE inhibitors in black patients as comparedwith white patients is not surprising, given previous clinicaland experimental evidence. Black patients with hypertensionhave been shown to have smaller reductions in blood pressure,on average, than white patients given similar doses of ACE inhibitors17and beta-blockers.18 This difference in response has previouslybeen attributed to lower plasma renin activity in black patients.19,20Although the renin mechanism may contribute to responsivenessto ACE inhibitors, renin activity has not served as a usefulmarker of the long-term effects of ACE-inhibitor therapy ineither patients with hypertension21,22,23 or those with heartfailure.24 Recent evidence suggests that the long-term benefitsof ACE inhibition may be related to factors other than a reductionin circulating angiotensin.25 ACE inhibition results in increasedkinin activity, which may exert favorable long-term effectson the heart through endogenous nitric oxide release.26 Thebioactivity of endogenous nitric oxide is known to be lowerin blacks than in whites, perhaps because of higher oxidativestress in blacks.27,28 Thus, a difference in the response toACE inhibitors between black and white patients may be relatedto mechanisms other than differences in plasma renin activity.
In the present analysis, we matched white patients with blackpatients according to important prognostic factors. However,the groups differed in other respects. The black patients wereslightly younger, were more likely to report financial distress,were less educated, were more likely to have left ventriculardysfunction that was not related to ischemia, and were morelikely to have a history of hypertension or diabetes than thematched white patients. Although multivariate statistical modelingwas used, the groups may have differed in other respects aswell, and no degree of statistical adjustment can ensure completecomparability. It is also possible that the findings may haveresulted from differences between the groups in compliance,diet, medical follow-up, or access to care. However, rates ofhospitalization for heart failure were similar among the blackand matched white patients who were randomly assigned to receiveplacebo, suggesting that a diminished response to enalaprilcontributed to the poorer outcome in the black patients. Itis also possible that the dose of enalapril studied (maximum,20 mg daily) was insufficient to alter the outcome in blackparticipants. Finally, it must be recognized that racial categorizationis only a surrogate marker for genetic or other factors responsiblefor individual responses to therapy. Indeed, racial intermixingmakes genetic distinctions problematic, and any identified differenceswill certainly not apply to all the members of each stratifiedgroup.
This analysis, combined with other recent data from clinicaltrials, suggests that the overall population of black patientswith heart failure may be underserved by current therapeuticrecommendations. The fact that large-scale trials of therapyfor heart failure have been performed in preponderantly whitepopulations has limited the ability of the medical communityto assess the efficacy of current therapies in black patients.Thus, clinical trials in black patients that are designed prospectivelyto evaluate therapeutic responses appear to be warranted. Nonetheless,on the basis of available physiological, pharmacologic, andclinical data, it seems appropriate to consider current therapeuticrecommendations as applying to white patients but not necessarilyto black patients. The observation in V-HeFT I that the combinationof isosorbide dinitrate and hydralazine, a nitric oxide donor,exerted a greater benefit in black patients than in white patients12further emphasizes the idea that therapeutic recommendationsmay need to be tailored according to racial background.
Supported by a clinician scientist award from the Canadian Institutesof Health Research (to Dr. Exner) and by a clinical investigatoraward from the Alberta Heritage Foundation for Medical Research(to Dr. Exner).
Source Information
From the Cardiovascular Research Group, University of Calgary, Calgary, Alta., Canada (D.V.E.); the Cardiovascular Research Group, University of Texas Southwestern Medical School, Dallas (D.L.D.); the Clinical Trials Research Group, National Heart, Lung, and Blood Institute, Bethesda, Md. (D.V.E., D.L.D., M.J.D.); and the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis (J.N.C.).
Address reprint requests to Dr. Exner at the University of Calgary, 3330 Hospital Dr. NW, Rm. G208, Calgary, AB T2N 4N1, Canada, or at exner{at}ucalgary.ca.
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