To the Editor: Taylor et al. (Nov. 11 issue)1 show that isosorbidedinitrate plus hydralazine increased survival in a group ofblack patients with heart failure. The authors state that aretrospective analysis of the Vasodilator Heart Failure Trial(VHeFT) studies2 identified black patients with heart failureas the group benefiting from this therapy.
Black patients in the V-HeFT cohorts had a lower prevalenceof a history of coronary artery disease and a higher prevalenceof a history of hypertension than did white patients (Table 1).These differences indicate proportional differences in thecauses of heart failure in the subgroups of black patients andwhite patients — findings that are consistent with thoseof other trials.3,4 According to the report by Taylor et al.on the African-American Heart Failure Trial (A-HeFT),1 nonischemiccauses of heart failure also predominated in their cohort ofall black patients.
Table 1. Prevalence of a History of Hypertension or Coronary Artery Disease (CAD) in Black Patients and White Patients in the Vasodilator Heart Failure Trials (V-HeFT I and II).
Differences in the causes of heart failure might have betterguided the design of a trial evaluating treatment with isosorbidedinitrate plus hydralazine. These characteristics are more biologicallyrelevant than race. It is clinically more practical for physiciansto identify a history of hypertension or coronary artery diseaseinstead of asking if the patient is black. There is a largepopulation of nonblack patients with heart failure from hypertensionor other causes who may not benefit if this therapy is approvedby the Food and Drug Administration for black patients only.
Andrew E. Moran, M.D., M.P.H. Columbia University New York, NY 10032
Richard S. Cooper, M.D. Loyola University Maywood, IL 60153
References
Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-2057. [Free Full Text]
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:178-187. [CrossRef][Medline]
Yancy CW, Fowler MB, Colucci WS, et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001;344:1358-1365. [Free Full Text]
Dries DL, Exner DV, Gersh BJ, et al. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999;340:609-616. [Erratum, N Engl J Med 1999;341:298.] [Free Full Text]
To the Editor: There is evidence that hypertensive cardiomyopathyis associated with certain clinical characteristics, includingan increased body-mass index, black race, and female sex.1 Accordingly,approximately 40 percent of patients in A-HeFT were thoughtto have a cardiomyopathy resulting solely from hypertension.Despite the moderate size of the cohort, it would be interestingto contrast the primary outcome in patients who were predominantlyhypertensive with that in patients with ischemic heart failure.Could the increased prevalence of hypertensive cardiomyopathyin the black population explain the results of A-HeFT? If so,this might be just the transcendent phenotype the authors arelooking for.
Timothy P. Fitzgibbons, M.D. Boston University Medical Center Boston, MA 02118 timothy.fitzgibbons{at}bmc.org
References
Dunlap SH, Sueta CA, Tomasko L, Adams KF Jr. Association of body mass, gender and race with heart failure primarily due to hypertension. J Am Coll Cardiol 1999;34:1602-1608. [Free Full Text]
To the Editor: In the A-HeFT trial, isosorbide dinitrate andhydralazine were added to "standard therapy," as determinedby the patients' own physicians. The mean baseline blood pressureof 127/78 mm Hg, however, suggests that the study populationhad inadequate afterload reduction and suboptimal blood-pressurecontrol. Although it is apparently normal, this blood pressureis relatively high in patients with class III or IV heart failureand an average ejection fraction of 24 percent. In addition,Taylor et al. do not report on the baseline use of calcium-channelblockers, such as amlodipine, which has been used safely inpatients with chronic severe heart failure1 and may be particularlybeneficial in treating hypertension in black patients. Thus,the benefits of isosorbide dinitrate and hydralazine in theA-HeFT trial may primarily reflect improved blood-pressure controlin an undertreated population.
Arthur Y. Chow, M.D. New York Presbyterian Hospital–Weill Cornell Medical Center New York, NY 10021
References
Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-1114. [Free Full Text]
To the Editor: Taylor et al. chose as their primary end point a composite score, referencing Packer.1 Unfortunately, Packerexplicitly rejects their composite score, stating "The clinicalcomposite score does not attempt to combine efficacy of unequalweight, that is, it does not try to combine death (a major weight)and a change in symptoms (minor weight) into a single score."1Taylor et al. use a composite score but do not explain how theydeveloped their scoring system and its components, which includedeath (a score of –3), the first hospitalization for heartfailure (–1), and a worsening of the quality of life by10 or more units, as measured by the Minnesota Living with HeartFailure questionnaire (–2). They were fortunate that eachcomponent of the composite score by itself was statisticallysignificant. The comment by Taylor et al. that this study providessupport for the use of such an end point in future trials isan overreach. The authors do not explain how they developedpower expectations for their study other than to say that oncethey did, they used interim analyses to correct their originalexpectations, citing Cui et al.2 to justify the interim adjustment.
Eran Y. Bellin, M.D. Montefiore Medical Center Bronx, NY 10467 ebellin{at}montefiore.org
References
Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001;7:176-182. [CrossRef][ISI][Medline]
Cui L, Hung HMJ, Wang SJ. Modification of sample size in group sequential clinical trials. Biometrics 1999;55:853-857. [CrossRef][ISI][Medline]
To the Editor: In their study of isosorbide dinitrate and hydralazinein black patients with heart failure, Taylor et al. do not recordlupus-like syndrome as a reported adverse event. Drug-inducedlupus is a relatively common side effect of hydralazine use,with a reported incidence of up to 20 percent.1,2 There is alsoevidence that lupus-like syndrome occurs more frequently atdoses of 200 mg or more daily1,2; Taylor et al. used a totaldaily dose of 225 mg. Recent experience with spironolactoneshowed that the initial enthusiasm for using a new therapy inheart failure can have potentially fatal, and avoidable, sideeffects in patients.3 Clinicians should counsel patients appropriatelyabout the potential side effect of hydralazine-induced lupusand monitor them for this disorder, especially until its incidencein patients who are treated with the regimen suggested by Tayloret al. is better characterized.
Andrew B. Eisenberger, M.D. Montefiore Medical Center Bronx, NY 10467 aeisenbe{at}montefiore.org
References
Batchelor JR, Welsh KI, Tinoco RM, et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980;1:1107-1109. [CrossRef][ISI][Medline]
Cameron HA, Ramsay LE. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br Med J (Clin Res Ed) 1984;289:410-412.
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-551. [Free Full Text]
The authors reply: Drs. Moran and Cooper and Dr. Fitzgibbonssuggest that the hypertensive phenotype might be a better distinguishingfeature than race to predict a response to isosorbide dinitrateplus hydralazine. This is a reasonable hypothesis, but preliminarysubgroup analysis of the A-HeFT data suggests that the responseto this combination drug was similar in patients with ischemicheart disease and those without. Thus, it is unlikely that thehypertensive phenotype alone will serve as an adequate identifierof a favorable response.
Dr. Chow suggests that the mechanism of the efficacy of treatmentwith isosorbide dinitrate plus hydralazine may be attributableonly to blood-pressure reduction. Although vasodilation to reduceleft-ventricular workload certainly may contribute to the beneficialeffect of isosorbide dinitrate plus hydralazine, previous trialshave shown that this is unlikely to be the only factor in improvedsurvival. Prazosin lowered blood pressure more than isosorbidedinitrate and hydralazine did in V-HeFT I, but only the nitrate–hydralazinecombination reduced mortality.1 Felodipine in V-HeFT III2 andamlodipine in the Prospective Randomized Amlodipine SurvivalEvaluation3 lowered blood pressure but did not improve survival.Therefore, it is unlikely that reduced pressure load was theonly factor in the improvement in outcome in heart failure.
Dr. Bellin expresses concern about our composite score. We believeit is appropriate and rational to mix mortality, hospitalization,and quality-of-life outcomes, since all are important variablesin the management of a chronic disease. The scoring system isarbitrary but weights variables by seriousness. Thus, deathreceived the worst score, and hospitalizations and quality oflife received lesser scores. Power calculations were facilitatedby applying this new composite score to the original V-HeFTdatabase. The statistical model allowed for an interim analysisto assess the adequacy of the power calculation. This is describedin our report.
Dr. Eisenberger expresses concern about hydralazine-inducedlupus. We performed antibody studies in all patients in thefirst V-HeFT.1 To our surprise and relief, we found no excessof lupus in the treatment group as compared with the placebogroup in any of the V-HeFT studies. We did not measure antibodiesin A-HeFT, but only one patient in the cohort of 1050 was describedby his physician as having symptoms that suggested a lupus-likesyndrome. The incidence in these two cohorts of patients withheart failure was extraordinarily low. Thus, 225 mg daily ofhydralazine apparently has not induced a measurable occurrenceof lupus in what is now more than 1000 patients. We do agreewith Dr. Eisenberger that appropriate monitoring for this potentialside effect is quite reasonable.
Anne L. Taylor, M.D. Jay Cohn, M.D. University of Minnesota Medical School Minneapolis, MN 55455 taylo135{at}umn.edu
Manuel Worcel, M.D. NitroMed Lexington, MA 02421
References
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. [Abstract]
Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Circulation 1997;96:856-863. [Free Full Text]
Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-1114. [Free Full Text]
Kahn, J.
(2008). Exploiting Race in Drug Development: BiDil's Interim Model of Pharmacogenomics. Social Studies of Science
38: 737-758
[Abstract]
Bibbins-Domingo, K., Fernandez, A.
(2007). BiDil for Heart Failure in Black Patients: Implications of the U.S. Food and Drug Administration Approval. ANN INTERN MED
146: 52-56
[Abstract][Full Text]
Barr, D. A.
(2005). The Practitioner's Dilemma: Can We Use a Patient's Race To Predict Genetics, Ancestry, and the Expected Outcomes of Treatment?. ANN INTERN MED
143: 809-815
[Abstract][Full Text]
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