The concerns which have been previously raised and vetted by many authors include the appropriateness of race as a construct in medicine, the integrity of the supporting science, the absence of a true proprietary compound as opposed to a convenient 'repackaging' of generic drugs and the targeting of one group of patients as the sole benefactor of this therapy.
Certainly, this debate has black and white issues but also shades of gray. All can agree that little benefit emanates from further polarization of the health care community and addressing issues as a function of race is indeed awkward and problematic. Likewise, it is appropriate to exercise caution when a non-physiological descriptor such as race is used to implicate a disease process or to substantiate a certain treatment intervention. From this point however, significant digression in thought and opinion on this and related issues occurs. Several issues merit specific comment: the clinical context of this issue; the supporting science for this issue; the accepted interpretation of the foregoing clinical trials; ongoing corroborative work that supports the paradigm of vasodilators as therapy for heart failure affecting African Americans; and the compelling clinical issues that currently exist along with the missed opportunities to reduce hospitalizations and decrease the risk of death due to heart failure.
Heart failure is an increasingly common malady that affects at least 5 million Americans. Unlike other forms of heart disease, it is actually growing in prevalence. Heart failure is likely to impact more than10 million Americans in the next decade. It is already the leading cause of hospitalization in persons over the age of 65 and it is the single largest healthcare expenditure for Medicare. By description, heart failure is any disease of the heart muscle that leads to an inability of the heart to provide all of the needs for the body. This is manifest in a constellation of signs and symptoms that include weakness, fatigue, loss of energy, reduced exercise capabilities, shortness of breath and swelling. Death occurs all too frequently and many times it is abrupt or 'sudden' due to certain heart rhythm disturbances.
Fortunately recent advances in medical and device therapies have improved the outcomes for all patients with heart failure. One advance is the discovery of the unique benefit of vasodilator therapy ( i.e., the combination of isosorbide dinitrate and hydralazine generically or BiDil], but application and use of these proven effective strategies has not been optimal. This is especially the case regarding the use of vasodilator therapy for African Americans with heart failure.
Why focus on African Americans with heart failure—are African Americans with heart failure truly different?
Heart failure has now been well-described by this author and others to be a different disease process with a very different history and altered experiences when it affects African Americans. It cannot be overlooked that this disease occurs at an earlier age in African Americans, is of greater consequence with more advanced symptoms and results in both a higher need for hospitalization and, in the 45-64 yr old age range, it leads to a higher risk of death. As well, there have been worrisome signals that when viewed as a group, African Americans have not consistently responded in a similar manner to therapies that have been tested and proven to be beneficial in heart failure. These unsettling observations remain speculative as they represent post hoc analyses of datasets not intended to look specifically at African Americans. Nevertheless, the signals of inconsistent responsiveness to certain drugs cannot be overlooked and the potential contribution of these variances to the adverse natural history of African Americans remains a concern. Thus, there is a real difference in the experience that African Americans have when affected by heart failure.
Is there a scientific rationale to support potential differences seen in African Americans?
It is admittedly difficult to prospectively test variances in clinical diseases and responsiveness to medical therapies as a function of socioeconomic status. However, a number of clinical trials have controlled for known quantitative descriptors of socioeconomic status and have discovered that differences in outcomes persist between African Americans and others. Therefore, we must look beyond the more easily impugned economic differences and begin to address whether or not certain physiological differences are implicated. A series of scholarly experiments conducted in multiple major medical centers by highly credible investigators have demonstrated that a potential source of difference can be found in the integrity of the blood vessel response to disease. In general, African Americans have been found to have stiffer blood vessels with a greater inclination towards higher blood pressures and a more malignant response to high blood pressurespecifically, more kidney failure, more strokes and more heart disease. At a biological level these variations may be centered on the integrity of the nitric oxide system. Nitric oxide helps to maintain homeostasis [i.e., appropriate tone] of the blood vessels and if it is lacking in amount or effectiveness, exaggerated blood vessel disease, and in turn heart disease, is likely to occur. A number of animal models have convincingly demonstrated this paradigm. The corollary with the African American experience in heart disease is consistent with this theory but not yet confirmatory.
What is race and do any of these observations respect a genetic predisposition to disease?
The foregoing is the most provocative scientific question and is in turn the most speculative component of this discussion. Race is neither physiologic nor scientific; rather it is a social construct that reflects a group of persons with shared ancestry and similar customs/lifestyles that also intermarry. Clearly, African Americans represent a heterogeneous group and there is no reason to believe that any single genetic trait is uniformly and exclusively distributed in African Americans. Race is not a proxy for genetics and any effort to ascribe such is shallow and lacking in understanding. However, within a group, it is conceivable that certain traits may be over represented and that these traits might contribute to disease. An example of such is the incidence of hypertension, diabetes and systemic lupus [an inflammatory joint condition] all noted to have a higher incidence in African Americans but clearly are not restricted to African Americans. Meaningful research is ongoing to determine the precise genetic signals that predict disease, (in this case heart failure), and that anticipate responsiveness to therapy. Even though pharmacogenomics, [i.e., drug responsiveness based on genetic profiles], represents the future, no drug to date, including BiDil, is proven to be effective according to genetic markers nor has a drug yet been approved by the FDA based on pharmacogenomics. To suggest otherwise for this or any other compound is disingenuous.
What is the origin of BiDil as specific therapy for heart failure in African Americans?
Human medical research has evolved dramatically from the earlier days of medicine where trial and error and/or anecdotal experience established the standards of care. Today, top tier human clinical research relies on rigorous controlled and blinded clinical studies which are done to establish the benefit of therapy. The control group undergoes the prevailing treatment regimen plus a placebo for a given disease while the tested group receives the 'prevailing or control' therapy plus the new intervention. To have the strongest statistical veracity, both the patient and the treating physician/investigator are 'blinded' to whether or not the active drug or a placebo has been given. The original Vasodilator Heart Failure Trials represent landmark data as they were not only the first trials to show that treatment of heart failure with any regimen led to improved outcomes but also these were the among the first trials to take advantage of the controlled blinded environment that is now the standard for clinical investigation.
In this context the results of the early vasodilator trials are compelling. Combined vasodilator therapy was proven to be effective but only minimally so over standard therapy. It was because of this modest effect, i.e., just barely statistically significant, that the FDA denied the request for approval of this therapy in the 90s—especially in the context of other therapies already proven to be more effective. The late 1990s also ushered in a plethora of observations and publications by this and other authors that heart failure in African Americans appeared to have certain nuances that were disconcerting. At least one large randomized controlled clinical trial yielded convincing evidence of a dramatic difference in drug responsiveness as a function of race. Such a discovery leads most investigators to interrogate additional data sources to seek corroboration of the finding or to challenge the finding. The body of published work consistently demonstrated that African Americans had a suspected lesser responsiveness to standard therapies. However, when the original investigators involved in the Vasodilator Heart Failure Trials engaged in the same exercise, the use of combined vasodilator therapy was associated with an unexpected but exaggerated responsiveness in African Americans and virtually no response in non-African Americans. This was not 'data dredging'; rather it represents the process of question, discovery and the generation of hypotheses that has driven the vast majority of discoveries in medicine. Much more has been discovered via serendipity than by directed investigation. That all of these observations regarding potential differences in responsiveness to proven therapies for heart failure in African Americans were published in highly regarded peer review journals attests to the credibility and importance of these findings.
What was the African American Heart Failure Trial?
The African American Heart Failure Trial [A-HeFT] was a prospective study of the potential benefit of combined vasodilator therapy in African Americans with heart failure. An African American only cohort was studied as it was within the African American group where the signal was seen. To be clear, the same process of review and question in the prior vasodilator trials database demonstrated no statistically significant benefit in the non-African American group. The results seen in A-HeFT are indeed compelling. All should be reminded that the trial was stopped prematurely because the magnitude of benefit of combined vasodilator therapy made it unethical to continue a blinded trial and imperative to offer the benefit of therapy to all participants. An additional 43% reduction in the risk of death was noted in A-HeFT. To put this is context, the magnitude of benefit of combined vasodilator therapy for heart failure beyond that seen with now standard background therapy exceeds all other approved adjunctive therapies for heart failure by a wide margin. To make this clinically relevant, survival benefits and hospitalization advantages of medical therapies are interpreted as how many patients would need to be treated with the new therapy over a year to save one life or reduce a hospitalization. Most preventive therapies, for example drugs to lower blood pressure or lower cholesterol prior to a stroke or heart attack, would need to used in hundreds of patients over a year to save a life. However, BiDil when added to standard therapy only needs to be exposed to 17 patients over one year to save one life and only 8 patients over one year to save a hospitalization. Since the publication of the primary results of A-HeFT, eleven additional publications and 30 abstracts from A-HeFT have appeared in major peer-reviewed medical journals and/or been presented at major medical meetings. Moreover, the two most respected bodies charged with writing guidelines, i.e., the responsibility to referee all available clinical research and reach a decision as to what therapies are most highly regarded and should be done versus which therapies are not helpful and should be avoided, have favorably adjudicated the A-HeFT data. The data are reflected as either the top tier or second highest tier recommendation. This most rigorous process is devoid of conflicted input or commercial bias and reflects the directives to practicing physicians throughout the country. Without question, the A-HeFT data are respected and accepted throughout medicine and have repeatedly withstood the scrutiny of peer-review. There is no higher standard for clinical research. It should be emphasized that the guidelines are not product specific and support both the use of the generic combinations and the proprietary compound.
In the face of these data, what is the current state of the art for treatment of heart failure in African Americans?
The treatment of African Americans with heart failure continues to be problematic as these data have not resulted in widespread uptake and multiple data sources now demonstrate that fewer than 10 percent of African American patients with heart failure are receiving this life altering therapy whether it is the proprietary drug or by substituting with the individual components. This is an unacceptable situation. Without question there are practical issues of note: there is a side effect profile and the therapy must be given three times a day (although patients within the trial were highly compliant); the retail price is expensive but the vast majority of insurance supported formularies now give this therapy a preferred status and the individual compounds are available (but the use of those compounds has been minimal as well); and there is a requirement for concomitant use of other indicated therapies which remains a challenge. However, a greater concern is the very debate in which we are embroiled. Lay citizens, black and white, are aware of these issues and the rhetoric has unfortunately penetrated the physician community as well. On this issue, rhetoric has superseded science and there has been little use of this therapy. To be clear, this is not a benign illness that is being addressed for which the consequences of inadequate care are only cosmetic; this is about a life-threatening disease with an inexorable rate of death and an increasing rate of hospitalization. I have witnessed death and despair due to heart failure, it is not pretty. Unless there are defensible concerns regarding safety or appropriateness of care, it is time for the negative rhetoric to pass and for effective therapy to be embraced and utilized.
What are the future directions?
None of us are comfortable with race as a descriptor of drug efficacy. If nothing else, the BiDil experience has demonstrated how persistently inflammatory and polarizing race remains. Efforts are ongoing within the A-HeFT investigator group and by independent investigators to better understand what is unique about some African Americans that predicts remarkable responsiveness to this therapy and might be found in other Americans so that all might take advantage of this remarkable step forward in the treatment of severe heart disease. Indeed genetics is the target but the data are too premature for clinical use and much more work needs to ensue.
The process of review, question and challenge to new and/or established paradigms is healthy and keeps all of us honest and humble but the passion directed against this paradigm is misguided as the consequences of persistent argument and debate unfortunately are persistent disease and premature death. We should redirect our passion into more research and optimal utilization of truly effective therapies for patients with this very serious disease.
Clyde W. Yancy, M.D., FACC, FAHA, FACP
On behalf of: The Association of Black Cardiologists
Disclosure: Yancy is a member of the steering committee for A-HeFT; member, Association of Black Cardiologist, consultant for Nitromed, Inc.