The Isosorbide‐Hydralazine Story: Is There a Case for Race‐Based Cardiovascular Medicine?

Heart failure (HF) affects five million patients in the United States and is responsible for considerable loss of life and disability. ¹ In patients 65 years and older, HF is the primary cause for hospitalization. ¹ In the United States, 25%–30% of patients with HF are black. ¹ In addition, black patients not only have disproportionately more HF, but the condition is also diagnosed at younger ages and may be less responsive to currently approved therapies. ² The current population of black patients diagnosed with HF is 725,000 and is expected to grow to 900,000 by the end of the decade. ¹ It is of interest to review the effects of various medications in this population, especially as they affect elevated blood pressure, a major causative factor of HF.

In the Studies of Left Ventricular Dysfunction Study (SOLVD) trial, ² , ³ the angiotensin‐converting enzyme (ACE) inhibitor enalapril reduced the risk of hospitalization less in black compared with non‐black patients. This finding is consistent with the relative lack of effectiveness of ACE inhibitors as monotherapy for hypertension in blacks, which results in less protection against cardiovascular disease, including HF and stroke, as noted in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ⁴ Moreover, in this and other studies, there are higher rates of angioedema with ACE inhibitors in blacks when compared with whites.

Data on β blockers in the Beta‐Blocker Evaluation of Survival Trial (BEST) ⁵ indicated that bucindolol reduced the risk of death in non‐black patients, but actually tended to increase mortality in blacks. These data are consistent with findings of less effectiveness of β blockers as monotherapy for hypertension in black individuals. Although results from studies using carvedilol, a β blocker with vasodilating effects, appear to show benefit in black patients with HF, this agent has pharmacologic effects beyond β‐blockade. ⁶ In general, most trials using β blockers for HF in blacks failed to enroll a meaningful number of patients to confirm benefit.

Several potential pathophysiologic mechanisms have been noted to increase prevalence and severity of hypertension in blacks. Dictative genes have been related to hypertension in blacks and include components of the epithelial sodium channels, renin‐angiotensin‐androsterone system, adrenergic receptors, nitric oxide pathways, endothelial I levels, and transforming growth factor hyperexpression. For instance, transepithelial sodium absorption may be increased in persons of African origin, and salt‐sensitive hypertension is considered more common. The T594M allele has been described in persons of African origin, but not in white populations, suggesting a potential increased risk for salt‐sensitive hypertension in blacks. Furthermore, black patients may have a higher risk of the C825T polymorphisms of the gene in coding the subuntion of G protein associated with the response to thiazide diuretics. Levels of transforming growth factor have been found to be strikingly elevated in some African Americans. This may be of particular importance as it relates to an increase in extracellular matrix and fibrosis and perhaps mediators of more severe hypertension and its complications, specifically renal failure and left ventricular hypertrophy.

THE subuntion CONTROVERSY

On june 23,2005, the Food and Drug Administration (FDA) approved BiDil (NitroMed, Inc., Lexington, MA), a fixed‐dose combination of 20 mg isosorbide dinitrate (ISDN) and 37.5 mg hydralazine (HYD) for the treatment of HF as an adjunct to standard therapy in self‐identified black patients to improve survival, prolong time to hospitalization for HF, and improve patient‐reported functional status. ⁷ The approval of this agent remains controversial because it suggests a specific drug combination in a self‐identified racial/ethnic group. It should be noted that most of the patients in the African‐American Heart Failure Trial (A‐HeFT), ⁸ the investigation supporting approval, demonstrated efficacy of this medication in addition to standard therapy, which included loop diuretics, ACE inhibitors or angiotensin II receptor blockers (ARBs), and β blockers. A‐HeFT reported 1050 self‐identified black patients with moderate‐to‐severe HF already on treatment with usual therapy. ⁸ The investigators reported a significant 43% reduction in death (p=0.012), 39% decrease in hospitalization for HF (p<0.001), and a decrease in symptoms of HF or improved quality of life (p<0.01). The approval of the ISDN/HYD combination, while controversial, does offer evidence that this therapy may be useful in the black population.

The concept of using ISDN and HYD together for HF was first clinically introduced in the 1970s. The A‐HeFT trial confirms the benefit of these two agents based on previously developed concepts. A retrospective, posthoc analysis of results from the Vasodilator Heart Failure Trials (V‐hEft I and V‐HeFT II) ⁹ had also suggested benefit primarily in black patients. ISDN/HYD is the combination of these two older drugs, neither of which is specifically approved for HF. HYD, a vasodilator, decreases afterload, while ISDN, an antianginal agent, relaxes both veins and arteries. The hemodynamic effects of decreasing preload and afterload with ISDN and afterload with HYD may not fully explain the benefits of this therapy. ¹⁰ ISDN also releases nitric oxide at the vascular level, and HYD may also be an antioxidant, which may prolong and increase the efficacy of the nitric oxide donor benefits of ISDN. ¹⁰ However, L‐arginine, a precursor for nitric oxide, was not shown to be beneficial postmyocardial infarction in the Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) study, ¹¹ a placebo‐controlled trial.

Based on the pathophysiology of HF, blacks demonstrate less ability for endogenous nitric oxide to dilate peripheral blood vessels. This may be related to an increased frequency of genes that decrease the synthesis of nitric oxide in black persons or to the overproduction of oxygen‐free radicals capable of degrading nitric oxide. Black patients, therefore, may have a decreased response to neurohormonal drugs such as ACE inhibitors, ARBs, and β blockers and an enhanced response to drugs that increase the delivery of nitric oxide. This deficiency of nitric oxide may contribute to a predisposition to hypertension and the development of HF.

A‐HeFT genetic risk assessment in 365 patients is being analyzed. ¹² Preliminary data suggest there are genetic variations in nitric oxide synthase between black and white cohorts with HF. These differences may partially explain the better response rates with HYD and isosorbide.

Nevertheless, the use of race as a marker for benefit for specific therapy is confounded by the complexity of race as a biologic concept. Race and ethnicity, while potentially valid as categories for public health issues, are not true biologic or genetic categories. Race‐based biologic differences usually represent descriptions by self‐selected populations, which are usually small in sample size. While it may be beneficial in some instances to consider race in the therapeutic approaches to hypertension, HF, and cardiovascular diseases, populations of humans vary greatly in socioeconomic status, culture, heritage, dietary habits, and levels of physical activity. All of these differences may greatly influence cardiovascular disease prevalence and outcomes.

A recent study has described the discovery of a gene variant conferring a disproportionate increased risk for myocardial infarction in self‐identified blacks. ¹³ The link between the variant of the gene in coding for leukotriene A4 hydrolase and the risk for heart attack was first discovered in Iceland. In Icelanders and Americans of European origin, the gene is quite common and confers a moderate increase in risk. ¹³ The variant occurs less frequently in African Americans, but more than triples the risk of myocardial infarction.

Moreover, the Y1102 allele has been identified as disproportionately representative in blacks with sudden death, with no or mild cardiac structural changes on autopsy. ¹⁴ This polymorphism in the cardiac sodium channel was noted based on DNA samples studied over 6 years that identified a risk factor for blacks for sudden death. ¹⁴ Differences in response to warfarin dosing between the African Americans and European Americans may also be explained by gene differences.

The human genome is 99.9% the same in all individuals, and there may be more genetic differences between people of the same self‐identified race than between persons of different races. ¹⁵ The Human Genome Project ¹⁵ has confirmed that essentially all humans may be Africans, based on common ancestry at some point.

Nevertheless, there may be some clinical validity to race, specifically in terms of defining responses of various populations to medication side effects and complications of therapy. Although definite clinical utility of genomic profiling may be difficult to demonstrate at the present time, the potential benefits into the effects of differences in individuals based on genomic profiling should be explored.

The primary reason for the increased rates of hypertension and decreased benefits of various therapies may be related to unmeasured variables in both clinical studies and large population studies. The disparity in morbidity and mortality rates for HF may not be due to less effective responses to ACE inhibitors or β blockers in this population. Specifically, the factors of socioeconomic status, sodium intake, obesity, and physical inactivity may have profound effects on the prevalence and severity of hypertension, HF, and other cardiovascular conditions. While researchers continue, appropriately, to measure the effects of the genetic influence on cardiovascular diseases, clinicians must utilize clinical judgment and assist patients with understanding the importance of lifestyle modifications and adherence to evidence‐based medicine. ¹⁶ The recent American College of Cardiology/American Heart Association guidelines for HF note potential benefit with the use of ISDN and HYD in blacks. ¹⁷ The labeling for the fixed‐dose combination specifically states that there is little experience in HF with doses other than those recommended and no experience with the use of individual components. ⁷ The cost of using these generically available medications separately rather than in combination is considerably less. The challenge will be to utilize appropriate new and emerging research in the area of genomics and clinical disease. At the present time, certain medications appear to be more effective in different groups of people, although evidence‐based guidelines suggest that the differences can be overcome if these are recognized and therapy is adjusted accordingly. Life‐saving therapy can be applied to all populations, regardless of race or ethnicity.