Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm?

Despite significant advances in the management of heart failure (HF), African Americans with HF remain a problematic patient cohort. When affected with HF, African Americans experience a more adverse natural history, greater likelihood for hospitalization, a lesser response to certain evidence-based therapies and a possible greater risk of death.1,2 This burden of heart failure in African Americans has been recently highlighted by provocative findings from the CARDIA database.3,4 The African American Heart Failure Trial (A-HeFT) established the benefit of adjunctive administration of isosorbide dinitrate/hydralazine (ISDN/HYD) in addition to standard therapy for African American patients with symptomatic heart failure. The risk of death was reduced by 43%, the need for first hospitalization was reduced by 33%, and markers of quality of life were improved.5 The use of ISDN/HYD was incorporated in the 2005 ACC/AHA Guideline Recommendations for the Treatment of Chronic Heart Failure in Adults as a Class IIA recommendation; later in the Heart Failure Society of America 2006 Comprehensive Heart Failure Practice Guideline as an “is recommended” (or top tier) strategy; and most recently in the 2009 Focused Update of the ACCAHA Heart Failure Guidelines now recognized as a Class I recommendation.6–8 These guideline statements are concordant, strongly supportive, and indicate the robust “level of evidence” that supports these statements. However, recent publications have confirmed marked underutilization of this adjunctive treatment regimen for heart failure in African Americans. At best, fewer than 10% of appropriate patients are receiving any combination of ISDN/HYD.9 The manufacturer of the proprietary combination, BiDil®, suspended its sales and marketing team with no further product development planned.10 The likelihood that a significant increase in the use of ISDN/HYD will occur is nil. What happened? Certainly, there is an often observed but unfortunate time lapse between discovery and implementation of novel treatment strategies in heart failure. In addition, polypharmacy in heart failure is a real issue; side effects, especially headaches, from ISDN/HYD can be uncomfortable for some patients; ISDN/ HYD is a thrice-daily regimen, which is clearly problematic; and the cost of proprietary ISDN/HYD is not trivial. Beyond these obvious concerns, one must give additional consideration to several other worrisome explanations for the limited application of this treatment strategy. The primary A-HeFT data have not been uniformly accepted. The data have been attributed to an antihypertensive effect; a “fluke” finding that needed confirmation, or simply as an exploitative marketing gimmick using the leverage of race to generate a business model for a patented combination of two otherwise widely available generic compounds. Perhaps the most troublesome issues, however, are the very construct of race as a marker of disease/drug responsiveness and the real but immeasurable effect of disparate healthcare. Recent analyses of the original A-HeFT database have demonstrated convincingly that positive findings persist when the data are controlled for the presence of hypertension. The blood pressure lowering effect of ISDN/HYD is directly related to the elevation of blood pressure at baseline. Patients with lower blood pressures had minimal evidence of blood pressure reductions while those with higher blood pressures had a greater antihypertensive effect. Regardless of the blood pressure change, the magnitude of benefit of ISDN/HYD was similar. For the entire A-HeFT cohort, the blood pressure lowering effect of ISDN/HYD was approximately 2 mmHg.11 A-HeFT was designed to confirm a provocative signal that was retrospectively observed in the Vasodilator in Heart Failure trials, I & II (V-HeFT I & II)12 and indeed A-HeFT confirmed the benefit of ISDN/HYD. The similarity in the magnitude of the response to ISDN/HYD in African Americans in V-HeFT I and A-HeFT is noteworthy and supports a reproducible finding in the setting of prevailing standard background medical therapy (at the time of each trial) for heart failure that confirms this treatment effect. A recent analysis of the 198 patients enrolled in the Extended Access A-HeFT trial (X-A-HeFT) further replicated the A-HeFT results by demonstrating an annual mortality rate of 6.3%, which is similar to the primary A-HeFT results.13 Moreover, when the A-HeFT data were subjected to the more rigorous clinical trial endpoint of freedom from death or hospitalization, the findings were again remarkably consistent and strikingly positive.14 A-HeFT tested a proprietary, rather than a generic, combination of ISDN/HYD. Data have since emerged that potentially important pharmacokinetic differences do exist between the proprietary formulation and the combination of generic drugs—this is important given the requirement of the FDA that generic equivalents are noted as such only if there is demonstrable pharmacokinetic similarity to the proprietary compound. Such is not the case for generic ISDN and HYD. The pharmacokinetic profile of BiDil® was not bioequivalent to the formulation used in V-HeFT I or V-HeFT II.15 The clinical importance of these pharmacokinetic differences between ISDN/HYD and BiDil® remains to be clarified. However, even if the compounds are deemed similar, the underuse of ISDN/HYD does not appear to be a function of avoidance of BiDil®, but rather apparent underutilization for any iteration of ISDN/HYD. Thus, the race issue remains. Importantly, A-HeFT did not prospectively investigate the benefit of ISDN/HYD in a non-African American population—a frequently cited critique and source of consternation. However, a statistically significant signal of efficacy for ISDN/HYD was absent in the non-African American groups in retrospective analyses of the prior trials. Though the likelihood is high that others are responsive to this regimen, it is unwise to test this possibility until descriptors of drug responsiveness beyond race are available. Given the magnitude of adjunctive benefit of ISDN/HYD when added to standard therapy, further research to expand the indication to other suitable patient cohorts is warranted. Another plausible consideration is the effect of disparate healthcare—a real but immeasurable impediment. Disparate healthcare does not merely reflect aggregate differences in treatments or outcomes for a given group, but rather it reflects those differences in treatment and outcome that persist after accounting for issues of appropriate indication, patient preference, or physiological variances.16 These differences in outcomes persist because of bias/stereotyping, cultural ignorance, and/or limited access to care/financial barriers—all of which define disparate healthcare. This is a difficult hypothesis to prove without precise socioeconomic/behavioral data but less than ideal care for African American patients with heart failure may be a contributing consideration. If heart failure in African Americans was a benign illness and the benefit of ISDN/HYD was merely cosmetic, the arguments regarding race-based therapy could persist ad infinitum. However, the sum total of all impediments limiting the uptake of ISDN/HYD has prevented full realization of the benefit of adjunctive combined vasodilator therapy for African American patients with a life-threatening illness, i.e., symptomatic heart failure. One life could be saved annually for every 15 African American patients treated with ISDN/ HYD and one hospitalization might be prevented for every 12 patients treated.17 These missed opportunities are unacceptable consequences of the hesitant uptake of adjunctive ISDN/HYD use in heart failure. There may be a better way to address this issue and other similar considerations in the future that invoke the question of race and/or ethnicity in medicine. There is a certain disquiet caused by the incorporation of race in any diagnostic or treatment algorithm. Race is a poor proxy for any scientific or physiologic grouping and is therefore not an adequate construct to predict disease or determine drug responsiveness. At best, race is a nonphysiologic, sociopolitical designation that represents a crude surrogate for several more precise makers, among which are certain genotypes that are associated with disease and drug responsiveness but may also include other biological factors, socioeconomic influences, and environmental circumstances. As such, the emerging discipline of genomic medicine may represent a reasonable alternative, with limitations, to supplant racial designations with a risk factor or prediction characteristic that is much more precise. A number of candidate genetic polymorphisms do appear to be overrepresented in some African Americans and may be associated with either disease progression or limited/ greater responsiveness to medical therapy for heart failure. The combination of a deletion in the α2c-adrenergic receptor and a polymorphism in the β1-adrenergic receptor genes may be more common in African Americans and has been associated with a marked increase in the incidence of heart failure.18 Additional data demonstrate that a single nucleotide polymorphism at position 389 in the beta-1 receptor may predict responsiveness to certain beta-blockers and this loss of gain polymorphism appears more frequently in African Americans but is observed in others as well.19 One of the early outputs from the Genetic Risk Assessment Study in A-HeFT, (GRAPH), demonstrated that a polymorphism in the aldosterone synthase promoter, which is more common in African Americans, was associated with a greater response to ISDN/HYD in A-HeFT20 Moreover, a very promising genetic marker has been observed within the GRAPH cohort that appears to predict responsiveness to ISDN/HYD and implicates functionality of the NOS3 enzyme.21 These early genomic observations in African Americans are not definitive and will require confirmation in prospective studies with larger patient populations but the potential exists for genomic medicine to facilitate a marked improvement in the care of certain patients with heart failure and to expand the population impacted to all patients with a characteristic clinical phenotype (apart from race) and a susceptible genetic profile. Clearly, appropriate caution is required before we presume that genomics will fully address this particular iteration of disparate care. As noted, many other factors are at play and the early findings that capture candidate markers must be validated and replicated before actual clinical use can proceed. Moreover, there must be clear safeguards present to avoid misuse of genetic data or even “genetic profiling” but the upside of the measured and appropriate application of genomic medicine is greater than the apparent risks yet identified. Gaining a better understanding of how pharmacogenomics and other nongenetic factors can be used to predict therapeutic effectiveness in individual patients represents an exciting future in medicine and all reasonable efforts must and should continue as we develop this important but delicate nuance in cardiovascular care.