isosorbide dinitrate and hydralazine as therapy for african americans with heart failure; a failed...

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Despite significant advances in the management of heart is burden of e African e use of ISDN/HYD was incorporated in the 2005 ACC/AHA as a Class IIA recommendation; later in the ese guideline statements are concordant, treatment regimen for heart failure in African Americans. At e manufacturer of the proprietary e likelihood HYD is directly related antihypertensive effect. Regardless of the blood pressure change, and indeed A-HeFT confirmed Moreover, when the A-HeFT data were subjected to the A-HeFT tested a proprietary, rather than a generic, HYD. Data have since emerged that e clinical any Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm? , 309 Despite signif icant 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 is burden of heart failure in African Americans has been recently highlighted by provocative findings from the CARDIA database. 3,4 e African American Heart Failure Trial (A-HeFT) established the benet of adjunctive administration of isosorbide dinitrate / hydralazine (ISDN / HYD) in addition to standard therapy for African American patients with symptomatic heart failure. e risk of death was reduced by 43%, the need for rst hospitalization was reduced by 33%, and markers of quality of life were improved. 5 e 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 ACC / AHA Heart Failure Guidelines now recognized as a Class I recommendation. 6–8 ese 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 e manufacturer of the proprietary combination, BiDil ® , suspended its sales and marketing team with no further product development planned. 10 e likelihood that a signicant increase in the use of ISDN / HYD will occur is nil. What happened? Certainly, there is an oſten 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 eects, 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. e primary A-HeFT data have not been uniformly accepted. e 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 ver y 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 ndings persist when the data are controlled for the presence of hypertension. e 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 eect. 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 conrm 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. e 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 nding in the setting of prevailing standard background medical therapy (at the time of each trial) for heart failure that confirms this treatment eect. 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 ndings were again remarkably consistent and strikingly positive. 14 A-HeFT tested a proprietar y, rather than a generic, combination of ISDN / HYD. Data have since emerged that potentially important pharmacokinetic dierences 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 proprietar y compound. Such is not the case for generic ISDN and HYD. e pharmacokinetic profile of BiDil ® was not bioequivalent to the formulation used in V-HeFT I or V-HeFT II. 15 e clinical importance of t hese pharmacokinetic differences between ISDN / HYD and BiDi l ® remains to be cl arif ied. 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. us, 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 signicant Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm? Clyde W. Yancy, M.D. 1 and Arthur Feldman, M.D., Ph.D. 2 , Editor-in-Chief, CTS 1 Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; 2 Department of Medicine, Thomas Jefferson University, Philadelphia, USA. Correspondence: CW Yancy (clyd[email protected]du) DOI: 10.1111/j.1752-8062.2009.00130.x WWW.CTSJOURNAL.COM 309 VOLUME 2 • ISSUE 4

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Page 1: 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 aff ected 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 Th is burden of heart failure in African Americans has been recently highlighted by provocative fi ndings from the CARDIA database.3,4 Th e African American Heart Failure Trial (A-HeFT) established the benefi t of adjunctive administration of isosorbide dinitrate/hydralazine (ISDN/HYD) in addition to standard therapy for African American patients with symptomatic heart failure. Th e risk of death was reduced by 43%, the need for fi rst hospitalization was reduced by 33%, and markers of quality of life were improved.5

Th e 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 ACC/AHA Heart Failure Guidelines now recognized as a Class I recommendation.6–8 Th ese 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 Th e manufacturer of the proprietary combination, BiDil®, suspended its sales and marketing team with no further product development planned.10 Th e likelihood that a signifi cant increase in the use of ISDN/HYD will occur is nil. What happened?

Certainly, there is an oft en 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 eff ects, 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.

Th e primary A-HeFT data have not been uniformly accepted. Th e data have been attributed to an antihypertensive eff ect; 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 eff ect of disparate healthcare.

Recent analyses of the original A-HeFT database have demonstrated convincingly that positive fi ndings persist when the data are controlled for the presence of hypertension. Th e blood pressure lowering eff ect 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 eff ect. Regardless of the blood pressure change, the magnitude of benefi t of ISDN/HYD was similar. For the entire A-HeFT cohort, the blood pressure lowering eff ect of ISDN/HYD was approximately 2 mmHg.11

A-HeFT was designed to confi rm 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 confi rmed the benefi t of ISDN/HYD. Th e 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 fi nding in the setting of prevailing standard background medical therapy (at the time of each trial) for heart failure that confi rms this treatment eff ect. 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 fi ndings 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 diff erences 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. Th e pharmacokinetic profi le of BiDil® was not bioequivalent to the formulation used in V-HeFT I or V-HeFT II.15 Th e 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.

Th us, the race issue remains. Importantly, A-HeFT did not prospectively investigate the benefi t of ISDN/HYD in a non-African American population—a frequently cited critique and source of consternation. However, a statistically signifi cant

Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm?Clyde W. Yancy, M.D.1 and Arthur Feldman, M.D., Ph.D.2, Editor-in-Chief, CTS

1Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; 2Department of Medicine, Thomas Jefferson University, Philadelphia, USA.Correspondence: CW Yancy ([email protected])

DOI: 10.1111/j.1752-8062.2009.00130.x

WWW.CTSJOURNAL.COM 309VOLUME 2 • ISSUE 4

Despite significant advances in the management of heart failure (HF), African Americans with HF remain a problematic patient cohort. When aff ected 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 Th is burden of heart failure in African Americans has been recently highlighted by provocative fi ndings from the CARDIA database.3,4 Th e African American Heart Failure Trial (A-HeFT) established the benefi t of adjunctive administration of isosorbide dinitrate/hydralazine (ISDN/HYD) in addition to standard therapy for African American patients with symptomatic heart failure. Th e risk of death was reduced by 43%, the need for fi rst hospitalization was reduced by 33%, and markers of quality of life were improved.5

Th e 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 ACC/AHA Heart Failure Guidelines now recognized as a Class I recommendation.6–8 Th ese 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 Th e manufacturer of the proprietary combination, BiDil®, suspended its sales and marketing team with no further product development planned.10 Th e likelihood that a signifi cant increase in the use of ISDN/HYD will occur is nil. What happened?

Certainly, there is an oft en 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 eff ects, 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.

Th e primary A-HeFT data have not been uniformly accepted. Th e data have been attributed to an antihypertensive eff ect; 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 eff ect of disparate healthcare.

Recent analyses of the original A-HeFT database have demonstrated convincingly that positive fi ndings persist when the data are controlled for the presence of hypertension. Th e blood pressure lowering eff ect of ISDN/HYD is directly relatedto 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 eff ect. Regardless of the blood pressure change, the magnitude of benefi t of ISDN/HYD was similar. For the entireA-HeFT cohort, the blood pressure lowering eff ect of ISDN/HYD was approximately 2 mmHg.11

A-HeFT was designed to confi rm 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 confi rmed the benefi t of ISDN/HYD. Th e 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 fi nding in the setting of prevailing standard background medical therapy (at the time of each trial) for heart failure that confi rms this treatment eff ect. 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 themore rigorous clinical trial endpoint of freedom from death or hospitalization, the fi ndings 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 thatpotentially important pharmacokinetic diff erences 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. Th e pharmacokinetic profi le of BiDil® was not bioequivalent tothe formulation used in V-HeFT I or V-HeFT II.15 Th e clinicalimportance 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 iterationof ISDN/HYD.

Th us, the race issue remains. Importantly, A-HeFT did not prospectively investigate the benefi t of ISDN/HYD in a non-African American population—a frequently cited critique and source of consternation. However, a statistically signifi cant

Isosorbide Dinitrate and Hydralazine as Therapy for African Americanswith Heart Failure; a Failed Paradigm?Clyde W. Yancy, M.D.1 and Arthur Feldman, M.D., Ph.D.2, Editor-in-Chief, CTS

1Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; 2Department of Medicine, Thomas Jefferson University, Philadelphia, USA.Correspondence: CW Yancy ([email protected])

DOI: 10.1111/j.1752-8062.2009.00130.x

WWW.CTSJOURNAL.COM 309VOLUME 2 • ISSUE 4

Page 2: Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm?

Yancy et al. � Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure

signal of effi cacy for ISDN/HYD was absent in the non-African American groups in retrospective analyses of the prior trials. Th ough 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 benefi t 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 eff ect of disparate healthcare—a real but immeasurable impediment. Disparate healthcare does not merely refl ect aggregate diff erences in treatments or outcomes for a given group, but rather it refl ects those diff erences in treatment and outcome that persist aft er accounting for issues of appropriate indication, patient preference, or physiological variances.16 Th ese diff erences 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 benefi t of ISDN/HYD was merely cosmetic, the arguments regarding race-based therapy could persist ad infi nitum. However, the sum total of all impediments limiting the uptake of ISDN/HYD has prevented full realization of the benefi t 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 Th ese missed opportunities are unacceptable consequences of the hesitant uptake of adjunctive ISDN/HYD use in heart failure.

Th ere 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. Th ere is a certain disquiet caused by the incorporation of race in any diagnostic or treatment algorithm. Race is a poor proxy for any scientifi c 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 infl uences, 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. Th e 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-HeFT.20 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

Th ese early genomic observations in African Americans are not defi nitive and will require confi rmation 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 profi le. 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 fi ndings 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 profi ling” but the upside of the measured and appropriate application of genomic medicine is greater than the apparent risks yet identifi ed. Gaining a better understanding of how pharmacogenomics and other nongenetic factors can be used to predict therapeutic eff ectiveness in individual patients represents an exciting future in medicine and all reasonable eff orts must and should continue as we develop this important but delicate nuance in cardiovascular care.

References1. Yancy CW. Heart failure in African Americans. Am J Cardiol. 2005; 96(7B): 3i–12i.

2. Kamath SA, Drazner MH, Wynne J, Fonarow GC, Yancy CW. Characteristics and outcomes in Afri-can Americans with decompensated heart failure. Arch Intern Med. 2008; 168(11): 1152–1158.

3. Bibbins-Domingo K, Pletcher MJ, Lin F, Vittinghoff E, Gardin JM, Arynchyn A, Lewis CE, Williams OD, Hulley SB. Racial differences in incident heart failure among young adults.N Engl J Med. 2009; 360(12): 1179–1190.

4. Peterson E, Yancy CW. Eliminating racial and ethnic disparities in cardiac care. N Engl J Med.2009; 360(12): 1172–1174.

5. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351(20): 2049–2057.

6. Heart Failure Society of America. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006; 12(1): e1–e2.

7. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Manage-ment of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/Ameri-can Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Trans-plantation: endorsed by the Heart Rhythm Society. Circulation. 2005; 112(12): e154–e235.

8. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009; 119(14): 1977–2016.

9. Yancy CW, Abraham WT, Albert NM, Clare R, Stough WG, Gheorghiade M, Greenberg BH, O’Connor CM, She L, Sun JL, Young JB, Fonarow GC. Quality of Care and Outcomes for African Americans Hospitalized with Heart Failure. J Am Coll Cardiol. 2008; 51: 1675–1684.

10. Huggett B. BiDil fl ops. Nat Biotechnol. 2008; 26(3):252.

11. Anand IS, Tam SW, Rector TS, Taylor AL, Sabolinski ML, Archambault WT, Adams KF, Olukotun AY, Worcel M, Cohn JN. Infl uence of blood pressure on the effectiveness of a fi xed-dose combina-tion of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial. J Am Coll Cardiol. 2007; 49(1): 32–39.

12. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999; 5(3): 178–187.

310 VOLUME 2 • ISSUE 4 WWW.CTSJOURNAL.COM

signal of effi cacy for ISDN/HYD was absent in the non-African tAmerican groups in retrospective analyses of the prior trials. Th ough 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 benefi t 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 eff ect of disparate healthcare—a real but immeasurable impediment. Disparate healthcare does not merely refl ect aggregate diff erences in treatments or outcomes for a given group, but rather it refl ects those diff erences in treatment and outcome that persist aft er accounting for issues of appropriate indication, patient preference, or physiological variances.16 Th ese diff erences 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 benefi t of ISDN/HYD was merely cosmetic, the arguments regarding race-based therapy could persist ad infi nitum. However, the sum total of all impediments limiting the uptake of ISDN/HYD has prevented full realization of the benefi t 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 Th ese missed opportunities are unacceptable consequences of the hesitant uptake of adjunctive ISDN/HYD use in heart failure.

Th ere 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. Th ere is a certain disquiet caused by the incorporation of race in any diagnostic or treatment algorithm. Race is a poor proxy for any scientifi c 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 infl uences, 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. Th e 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/HYDin A-HeFT.20 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

Th ese early genomic observations in African Americans are not defi nitive and will require confi rmation 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 profi le. 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 fi ndings 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 profi ling” but the upside of the measured and appropriate application of genomic medicine is greater than the apparent risks yet identifi ed. Gaining a better understanding of how pharmacogenomics and other nongenetic factors can be used to predict therapeutic eff ectiveness in individual patients represents an exciting future in medicine and all reasonable eff orts must and should continue as we develop this important but delicate nuance in cardiovascular care.

References1. Yancy CW. Heart failure in African Americans. Am J Cardiol. 2005; 96(7B): 3i–12i.

2. Kamath SA, Drazner MH, Wynne J, Fonarow GC, Yancy CW. Characteristics and outcomes in Afri-can Americans with decompensated heart failure. Arch Intern Med. 2008; 168(11): 1152–1158.

3. Bibbins-Domingo K, Pletcher MJ, Lin F, Vittinghoff E, Gardin JM, Arynchyn A, Lewis CE, Williams OD, Hulley SB. Racial differences in incident heart failure among young adults.N Engl J Med. 2009; 360(12): 1179–1190.

4. Peterson E, Yancy CW. Eliminating racial and ethnic disparities in cardiac care. N Engl J Med.2009; 360(12): 1172–1174.

5. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351(20): 2049–2057.

6. Heart Failure Society of America. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006; 12(1): e1–e2.

7. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Manage-ment of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/Ameri-can Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Trans-plantation: endorsed by the Heart Rhythm Society. Circulation. 2005; 112(12): e154–e235.

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10. Huggett B. BiDil fl ops. Nat Biotechnol. 2008; 26(3):252.

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12. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999; 5(3): 178–187.

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Yancy et al. � Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure

13. Yancy CW, Ghali JK, Braman VM, Sabolinski ML, Worcel M, Archambault WT, Franciosa JA. Evidence for the continued safety and tolerability of fi xed-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial). Am J Cardiol. 2007; 100(4): 684–689.

14. Taylor AL, Ziesche S, Yancy CW, Carson P, Ferdinand K, Taylor M, Adams K, Olukotun AY, Ofi li E, Tam SW, Sabolinski ML, Worcel M, Cohn JN. Early and sustained benefi t on event-free survival and heart failure hospitalization from fi xed-dose combination of isosorbide dinitrate/hy-dralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation. 2007; 115(13): 1747–1753.

15. Tam SW, Sabolinski ML, Worcel M, Packer M, Cohn JN. Lack of bioequivalence between differ-ent formulations of isosorbide dinitrate and hydralazine and the fi xed-dose combination of isosor-bide dinitrate/hydralazine: the V-HeFT paradox. Clin Pharmacokinet. 2007; 46(10): 885–895.

16. Unequal Treatment: confronting racial and ethnic disparities in health care. Smedley BD, Stith AY, Nelson AR, eds. Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care, Institute of Medicine, 2003 by the National Academy of Sciences. Washington, DC: The National Academies Press, 2003.

17. Angus DC, Linde-Zwirble WT, Tam SW, Ghali JK, Sabolinski ML, Villagra VG, Winkelmayer WC, Worcel M. Cost-effectiveness of fixed-dose combination of isosor-

bide dinitrate and hydralazine therapy for blacks with heart failure. Circulation. 2005; 112(24): 3745–3753.

18. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002; 347(15): 1135–1142.

19. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, Bristow MR. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart fail-ure. Proc Natl Acad Sci USA. 2006; 103(30): 11288–11293.

20. McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Taylor AL, Cohn JN, Feldman AM, Worcel M. Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: results from the A-HeFT Trial. J Am Coll Cardiol. 2006; 48(6): 1277–1282.

21. McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L, Ofi li E, Yancy C, Feldman AM, Ghali JK, Taylor AL, Cohn JN, Worcel M. Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial.J Card Failure. 2009;15(3): 191–198.

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13. Yancy CW, Ghali JK, Braman VM, Sabolinski ML, Worcel M, Archambault WT, Franciosa JA.Evidence for the continued safety and tolerability of fi xed-dose isosorbide dinitrate/hydralazinein patients with chronic heart failure (the extension to African-American Heart Failure Trial). Am JCardiol. 2007; 100(4): 684–689.

14. Taylor AL, Ziesche S, Yancy CW, Carson P, Ferdinand K, Taylor M, Adams K, Olukotun AY,Ofi li E, Tam SW, Sabolinski ML, Worcel M, Cohn JN. Early and sustained benefi t on event-freesurvival and heart failure hospitalization from fi xed-dose combination of isosorbide dinitrate/hy-dralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation.2007; 115(13): 1747–1753.

15. Tam SW, Sabolinski ML, Worcel M, Packer M, Cohn JN. Lack of bioequivalence between differ-ent formulations of isosorbide dinitrate and hydralazine and the fi xed-dose combination of isosor-bide dinitrate/hydralazine: the V-HeFT paradox. Clin Pharmacokinet. 2007; 46(10): 885–895.

16. Unequal Treatment: confronting racial and ethnic disparities in health care. SmedleyBD, Stith AY, Nelson AR, eds. Committee on Understanding and Eliminating Racial andEthnic Disparities in Health Care, Institute of Medicine, 2003 by the National Academy of Sciences. Washington, DC: The National Academies Press, 2003.

17. Angus DC, Linde-Zwirble WT, Tam SW, Ghali JK, Sabolinski ML, Villagra VG,Winkelmayer WC, Worcel M. Cost-effectiveness of fixed-dose combination of isosor-

bide dinitrate and hydralazine therapy for blacks with heart failure. Circulation. 2005; 112(24): 3745–3753.

18. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002; 347(15): 1135–1142.

19. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, Bristow MR. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart fail-ure. Proc Natl Acad Sci USA. 2006; 103(30): 11288–11293.

20. McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Taylor AL, Cohn JN,Feldman AM, Worcel M. Aldosterone synthase promoter polymorphism predicts outcome inAfrican Americans with heart failure: results from the A-HeFT Trial. J Am Coll Cardiol. 2006; 48(6): 1277–1282.

21. McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L, Ofi li E,Yancy C, Feldman AM, Ghali JK, Taylor AL, Cohn JN, Worcel M. Endothelial nitric oxide synthase(NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial.J Card Failure. 2009;15(3): 191–198.

WWW.CTSJOURNAL.COM 311VOLUME 2 • ISSUE 4