Use of Isosorbide Dinitrate and Hydralazine in African-Americans With Heart Failure 9 Years After the African-American Heart Failure Trial
2014; Elsevier BV; Volume: 114; Issue: 1 Linguagem: Inglês
10.1016/j.amjcard.2014.04.018
ISSN1879-1913
AutoresKeith C. Ferdinand, Uri Elkayam, Donna Mancini, Elizabeth Ofili, Ileana L. Piña, Inder S. Anand, Arthur M. Feldman, Dennis M. McNamara, Christopher Leggett,
Tópico(s)Transplantation: Methods and Outcomes
ResumoThe 2013 American College of Cardiology Foundation/American Heart Association guidelines recommend combined isosorbide dinitrate (ISDN) and hydralazine to reduce mortality and morbidity for African-Americans with symptomatic heart failure (HF) and reduced ejection fraction, currently receiving optimal medical therapy (class I, level A). Nitrates can alleviate HF symptoms, but continuous use is limited by tolerance. Hydralazine may mitigate nitrate tolerance, and the ISDN–hydralazine combination in the Vasodilators in Heart Failure Trial (V-HeFT) I improved survival and exercise tolerance in men with dilated cardiomyopathy or HF with reduced ejection fraction, most notably in self-identified black participants. In the subsequent V-HeFT II, survival was greater with enalapril than with ISDN–hydralazine in the overall cohort, but mortality rate was similar in the enalapril and ISDN–hydralazine groups in the self-identified black patients. Consequently, in the African-American Heart Failure Trial (A-HeFT) in self-identified black patients with symptomatic HF, adding a fixed-dose combination ISDN–hydralazine to modern guideline-based care improved outcomes versus placebo, including all-cause mortality, and led to early trial termination. Hypertension underlies HF, especially in African-Americans; the A-HeFT and its substudies demonstrated not only improvements in echocardiographic parameters, morbidity, and mortality but also a decrease in hospitalizations, potentially affecting burgeoning HF health-care costs. Genetic characteristics may, therefore, determine response to ISDN–hydralazine, and the Genetic Risk Assessment in Heart Failure substudy demonstrated important hypothesis-generating pharmacogenetic data. The 2013 American College of Cardiology Foundation/American Heart Association guidelines recommend combined isosorbide dinitrate (ISDN) and hydralazine to reduce mortality and morbidity for African-Americans with symptomatic heart failure (HF) and reduced ejection fraction, currently receiving optimal medical therapy (class I, level A). Nitrates can alleviate HF symptoms, but continuous use is limited by tolerance. Hydralazine may mitigate nitrate tolerance, and the ISDN–hydralazine combination in the Vasodilators in Heart Failure Trial (V-HeFT) I improved survival and exercise tolerance in men with dilated cardiomyopathy or HF with reduced ejection fraction, most notably in self-identified black participants. In the subsequent V-HeFT II, survival was greater with enalapril than with ISDN–hydralazine in the overall cohort, but mortality rate was similar in the enalapril and ISDN–hydralazine groups in the self-identified black patients. Consequently, in the African-American Heart Failure Trial (A-HeFT) in self-identified black patients with symptomatic HF, adding a fixed-dose combination ISDN–hydralazine to modern guideline-based care improved outcomes versus placebo, including all-cause mortality, and led to early trial termination. Hypertension underlies HF, especially in African-Americans; the A-HeFT and its substudies demonstrated not only improvements in echocardiographic parameters, morbidity, and mortality but also a decrease in hospitalizations, potentially affecting burgeoning HF health-care costs. Genetic characteristics may, therefore, determine response to ISDN–hydralazine, and the Genetic Risk Assessment in Heart Failure substudy demonstrated important hypothesis-generating pharmacogenetic data. The 2013 American College of Cardiology Foundation and American Heart Association (AHA) guidelines recommend the combination of isosorbide dinitrate (ISDN) and hydralazine to reduce mortality and morbidity for African-Americans with New York Heart Association class III or IV heart failure (HF) and HF with reduced ejection fraction (EF) who are currently receiving optimal medical therapy with angiotensin-converting enzyme inhibitors and β blockers (class I, level A).1Yancy C.W. Jessup M. Bozkurt B. Masoudi F.A. Butler J. McBride P.E. Casey Jr., D.E. McMurray J.J. Drazner M.H. Mitchell J.E. Fonarow G.C. Peterson P.N. Geraci S.A. Horwich T. Januzzi J.L. Johnson M.R. Kasper E.K. Levy W.C. Riegel B. Sam F. Stevenson L.W. Tang W.H. Tsai E.J. Wilkoff B.L. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013; 62: e147-e239Abstract Full Text Full Text PDF PubMed Scopus (4470) Google Scholar The guidelines also state that the combination of ISDN and hydralazine can be useful to reduce morbidity and mortality in patients with current or previous symptomatic HF who are not able to take angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (class IIa, level B).1Yancy C.W. Jessup M. Bozkurt B. Masoudi F.A. Butler J. McBride P.E. Casey Jr., D.E. McMurray J.J. Drazner M.H. Mitchell J.E. Fonarow G.C. Peterson P.N. Geraci S.A. Horwich T. Januzzi J.L. Johnson M.R. Kasper E.K. Levy W.C. Riegel B. Sam F. Stevenson L.W. Tang W.H. Tsai E.J. Wilkoff B.L. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013; 62: e147-e239Abstract Full Text Full Text PDF PubMed Scopus (4470) Google Scholar Nevertheless, African-Americans remain more likely than whites to die from diseases of the heart (Figure 1),2Roger V.L. Go A.S. Lloyd-Jones D.M. Benjamin E.J. Berry J.D. Borden W.B. Bravata D.M. Dai S. Ford E.S. Fox C.S. Fullerton H.J. Gillespie C. Hailpern S.M. Heit J.A. Howard V.J. Kissela B.M. Kittner S.J. Lackland D.T. Lichtman J.H. Lisabeth L.D. Makuc D.M. Marcus G.M. Marelli A. Matchar D.B. Moy C.S. Mozaffarian D. Mussolino M.E. Nichol G. Paynter N.P. Soliman E.Z. Sorlie P.D. Sotoodehnia N. Turan T.N. Virani S.S. Wong N.D. Woo D. Turner M.B. Heart disease and stroke statistics—2012 update: a report from the American Heart Association.Circulation. 2012; 125: e2-e220Crossref PubMed Scopus (0) Google Scholar, 3National Center for Health StatisticsHealth, United States, 2012: With Special Feature on Emergency Care.2013http://www.cdc.gov/nchs/data/hus/2012/026.pdfGoogle Scholar and many patients who may benefit from ISDN–hydralazine are not receiving it. This review details the rationale for using ISDN–hydralazine in African-Americans with HF as discussed at a roundtable meeting of cardiologists in November 2012. As HF is the primary diagnosis in >1 million hospitalizations annually and annual costs related to HF in the United States exceed $40 billion, advances in the treatment of HF would have significant economic benefits.1Yancy C.W. Jessup M. Bozkurt B. Masoudi F.A. Butler J. McBride P.E. Casey Jr., D.E. McMurray J.J. Drazner M.H. Mitchell J.E. Fonarow G.C. Peterson P.N. Geraci S.A. Horwich T. Januzzi J.L. Johnson M.R. Kasper E.K. Levy W.C. Riegel B. Sam F. Stevenson L.W. Tang W.H. Tsai E.J. Wilkoff B.L. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013; 62: e147-e239Abstract Full Text Full Text PDF PubMed Scopus (4470) Google Scholar Organic nitrates, including ISDN, activate the intracellular enzyme soluble guanylyl cyclase and subsequently elevate cyclic guanosine 3′,5′-monophosphate levels. The elevated cyclic guanosine 3′,5′-monophosphate level leads to activation of cyclic guanosine 3′,5′-monophosphate–dependent protein kinase, which in turn mediates vasorelaxation by phosphorylating proteins that regulate intracellular calcium mobilization.4Sydow K. Daiber A. Oelze M. Chen Z. August M. Wendt M. Ullrich V. Mulsch A. Schulz E. Keaney Jr., J.F. Stamler J.S. Munzel T. Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.J Clin Investig. 2004; 113: 482-489Crossref PubMed Scopus (277) Google Scholar However, within several hours of sustained exposure, nitrates (including ISDN) lose efficacy quickly as tolerance develops,5Elkayam U. Roth A. Mehra A. Ostrzega E. Shotan A. Kulick D. Jamison M. Johnston J.V. Rahimtoola S.H. Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure.Circulation. 1991; 84: 2040-2048Crossref PubMed Scopus (41) Google Scholar, 6Roth A. Kulick D. Freidenberger L. Hong R. Rahimtoola S.H. Elkayam U. Early tolerance to hemodynamic effects of high dose transdermal nitroglycerin in responders with severe chronic heart failure.J Am Coll Cardiol. 1987; 9: 858-864Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 7Elkayam U. Kulick D. McIntosh N. Roth A. Hsueh W. Rahimtoola S.H. Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure.Circulation. 1987; 76: 577-584Crossref PubMed Scopus (191) Google Scholar leading to marked attenuation of hemodynamic effects. Hydralazine prevents and reverses nitrate tolerance—preserving its capacity to reduce venous pressure—probably by reducing superoxide production in vascular tissues and possibly also by scavenging reactive oxygen species to mitigate both vascular tolerance and cross-tolerance.8Roth A. Shotan A. Elkayam U. A randomized comparison between the hemodynamic effects of hydralazine and nitroglycerin alone and in combination at rest and during isometric exercise in patients with chronic mitral regurgitation.Am Heart J. 1993; 125: 155-163Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 9Gogia H. Mehra A. Parikh S. Ramin M. Ajit-Uppal J. Johnson J. Elkayam U. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure.J Am Coll Cardiol. 1995; 26: 1575-1580Abstract Full Text PDF PubMed Scopus (115) Google Scholar, 10Bauer J.A. Fung H.L. Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure.Circulation. 1991; 84: 35-39Crossref PubMed Scopus (99) Google Scholar, 11Leiro J.M. Alvarez E. Arranz J.A. Cano E. Orallo F. Antioxidant activity and inhibitory effects of hydralazine on inducible NOS/COX-2 gene and protein expression in rat peritoneal macrophages.Int Immunupharmacol. 2004; 4: 163-177Crossref PubMed Scopus (53) Google Scholar, 12Munzel T. Kurz S. Rajagopalan S. Thoenes M. Berrington W.R. Thompson J.A. Freeman B.A. Harrison D.G. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug.J Clin Investig. 1996; 98: 1465-1470Crossref PubMed Scopus (277) Google Scholar, 13Hare J. Nitroso-redox balance in the cardiovascular system.New Engl J Med. 2004; 351: 2112-2114Crossref PubMed Scopus (138) Google Scholar Nitric oxide (NO) is an endogenous vasodilator that also directly affects the myocardium to modulate contractility, diastolic distensibility, mitochondrial respiration, substrate metabolism, ion channel function, cell growth (hypertrophy), and postinfarction remodeling.14Loscalzo J. Welch G. Nitric oxide and its role in the cardiovascular system.Prog Cardiovasc Dis. 1995; 38: 87-104Abstract Full Text PDF PubMed Scopus (504) Google Scholar, 15Massion P.B. Feron O. Dessy C. Balligand J.L. Nitric oxide and cardiac function: ten years after, and continuing.Circ Res. 2003; 93: 388-398Crossref PubMed Scopus (484) Google Scholar, 16Pacher P. Beckman J.S. Liaudet L. Nitric oxide and peroxynitrite in health and disease.Physiol Rev. 2007; 87: 315-424Crossref PubMed Scopus (4450) Google Scholar, 17Saraiva R.M. Hare J.M. Nitric oxide signaling in the cardiovascular system: implications for heart failure.Curr Opin Cardiol. 2006; 21: 221-228Crossref PubMed Scopus (62) Google Scholar In the presence of superoxide and other reactive oxygen species, NO is converted to peroxynitrite, reducing its capacity to relax the endothelium. Peroxynitrite itself can interact with proteins and genes to damage the endothelium and elicit endothelial dysfunction.16Pacher P. Beckman J.S. Liaudet L. Nitric oxide and peroxynitrite in health and disease.Physiol Rev. 2007; 87: 315-424Crossref PubMed Scopus (4450) Google Scholar Data from animal models18Boerrigter G. Burnett Jr., J.C. Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease.Cardiovasc Drug Rev. 2007; 25: 30-45Crossref PubMed Scopus (46) Google Scholar, 19Fraccarollo D. Widder J.D. Galuppo P. Thum T. Tsikas D. Hoffmann M. Ruetten H. Ertl G. Bauersachs J. Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction.Circulation. 2008; 118: 818-827Crossref PubMed Scopus (103) Google Scholar, 20Janssens S. Pokreisz P. Schoonjans L. Pellens M. Vermeersch P. Tjwa M. Jans P. Scherrer-Crosbie M. Picard M.H. Szelid Z. Gillijns H. Van de Werf F. Collen D. Bloch K.D. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction.Circ Res. 2004; 94: 1256-1262Crossref PubMed Scopus (193) Google Scholar, 21Kass D.A. Takimoto E. Nagayama T. Champion H.C. Phosphodiesterase regulation of nitric oxide signaling.Cardiovasc Res. 2007; 75: 303-314Crossref PubMed Scopus (123) Google Scholar, 22Rohde D. Ritterhoff J. Voelkers M. Katus H.A. Parker T.G. Most P. S100A1: a multifaceted therapeutic target in cardiovascular disease.J Cardiovasc Transl Res. 2010; 3: 525-537Crossref PubMed Scopus (48) Google Scholar, 23Scherrer-Crosbie M. Ullrich R. Bloch K.D. Nakajima H. Nasseri B. Aretz H.T. Lindsey M.L. Vancon A.C. Huang P.L. Lee R.T. Zapol W.M. Picard M.H. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice.Circulation. 2001; 104: 1286-1291Crossref PubMed Scopus (257) Google Scholar and clinical studies24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar, 25Lapp H. Mitrovic V. Franz N. Heuer H. Buerke M. Wolfertz J. Mueck W. Unger S. Wensing G. Frey R. Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure.Circulation. 2009; 119: 2781-2788Crossref PubMed Scopus (104) Google Scholar, 26Lewis G.D. Lachmann J. Camuso J. Lepore J.J. Shin J. Martinovic M.E. Systrom D.M. Bloch K.D. Semigran M.J. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure.Circulation. 2007; 115: 59-66Crossref PubMed Scopus (275) Google Scholar suggest that correction of NO bioavailability and/or signaling capacity or reduction in oxidative stress favorably alters HF end points. This hypothesis was tested using the combination of ISDN and hydralazine in patients with HF and HF with reduced EF in the Vasodilators in Heart Failure Trial (V-HeFT) I and V-HeFT II.27Cohn J.N. Archibald D.G. Ziesche S. Franciosa J.A. Harston W.E. Tristani F.E. Dunkman W.B. Jacobs W. Francis G.S. Flohr K.H. Goldman S. Cobb F.R. Shah P.M. Saunders R. Fletcher R.D. Loeb H.S. Hughes V.C. Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2034) Google Scholar, 28Cohn J.N. Johnson G. Ziesche S. Cobb F. Francis G. Tristani F. Smith R. Dunkman W.B. Loeb H. Wong M. Bhat G. Goldman S. Fletcher R.D. Doherty J. Hughes C.V. Carson P. Cintron G. Shabetai R. Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.New Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2513) Google Scholar Compared with placebo, treatment with ISDN and hydralazine reduced the relative risk of death by 36% after 3 years with minimal background therapy (digoxin and diuretics) in V-HeFT I.27Cohn J.N. Archibald D.G. Ziesche S. Franciosa J.A. Harston W.E. Tristani F.E. Dunkman W.B. Jacobs W. Francis G.S. Flohr K.H. Goldman S. Cobb F.R. Shah P.M. Saunders R. Fletcher R.D. Loeb H.S. Hughes V.C. Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2034) Google Scholar Furthermore, ISDN and hydralazine improved survival in black or African-American patients, although the effect was not significant in white patients (Figure 2).29Carson P. Ziesche S. Johnson G. Cohn J.N. 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: 178-187Abstract Full Text PDF PubMed Scopus (411) Google Scholar In V-HeFT II, treatment with ISDN and hydralazine did not improve survival compared with enalapril,28Cohn J.N. Johnson G. Ziesche S. Cobb F. Francis G. Tristani F. Smith R. Dunkman W.B. Loeb H. Wong M. Bhat G. Goldman S. Fletcher R.D. Doherty J. Hughes C.V. Carson P. Cintron G. Shabetai R. Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.New Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2513) Google Scholar although the effects on all-cause mortality were equivalent to those of enalapril in black patients and inferior to enalapril in white patients.29Carson P. Ziesche S. Johnson G. Cohn J.N. 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: 178-187Abstract Full Text PDF PubMed Scopus (411) Google Scholar These findings led to the design of an outcomes study with fixed-dose (FD) ISDN–hydralazine (BiDil; Arbor Pharmaceuticals, Inc, Atlanta, Georgia) in self-identified black patients.30Taylor A.L. The African-American Heart Failure Trial (A-HeFT): rationale and methodology.J Card Fail. 2003; 9: S216-S219Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The African-American Heart Failure Trial (A-HeFT) enrolled 1,050 patients with New York Heart Association class III or IV HF receiving guideline-based care, including β blockers, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar The primary outcome of A-HeFT was a composite score of mortality, hospitalization, and quality of life (QOL), and the clear survival benefit of FD ISDN–hydralazine over placebo led to termination of the study after 3 years (Figure 3). With a median follow-up period of 10 months, FD ISDN–hydralazine in combination with neurohormonal blockade reduced mortality by 43%.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar In addition, in A-HeFT, adding FD ISDN–hydralazine to standard therapy decreased the number of hospitalizations and reduced length of hospital stay compared with standard therapy alone.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar, 31Angus D.C. Linde-Zwirble W.T. Tam S.W. Ghali J.K. Sabolinski M.L. Villagra V.G. Winkelmayer W.C. Worcel M. Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure.Circulation. 2005; 112: 3745-3753Crossref PubMed Scopus (36) Google Scholar The relative risk of an HF-related hospitalization during the first 2 years of treatment was equal to placebo in V-HeFT I and to enalapril in V-HeFT II.28Cohn J.N. Johnson G. Ziesche S. Cobb F. Francis G. Tristani F. Smith R. Dunkman W.B. Loeb H. Wong M. Bhat G. Goldman S. Fletcher R.D. Doherty J. Hughes C.V. Carson P. Cintron G. Shabetai R. Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.New Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2513) Google Scholar, 29Carson P. Ziesche S. Johnson G. Cohn J.N. 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: 178-187Abstract Full Text PDF PubMed Scopus (411) Google Scholar In A-HeFT, improvements in functional parameters included EF, left ventricular (LV) remodeling, and significant reduction in B-type natriuretic peptide (BNP).24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar, 32Cohn J.N. Tam S.W. Anand I.S. Taylor A.L. Sabolinski M.L. Worcel M. Isosorbide dinitrate and hydralazine in a fixed-dose combination produces further regression of left ventricular remodeling in a well-treated black population with heart failure: results from A-HeFT.J Card Fail. 2007; 13: 331-339Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Additionally, based on the Minnesota Living with Heart Failure questionnaire, patients in A-HeFT reported improved QOL with FD ISDN–hydralazine.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar, 33Carson P. Tam S.W. Ghali J.K. Archambault W.T. Taylor A. Cohn J.N. Braman V.M. Worcel M. Anand I.S. Relationship of quality of life scores with baseline characteristics and outcomes in the African-American Heart Failure Trial.J Card Fail. 2009; 15: 835-842Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar The first hospitalization for HF was a component of the primary composite score in A-HeFT. With a mean follow-up of 10 months (range 0 to 18), 130 patients (24.4%) in the placebo group and 85 (16.4%) in the FD ISDN–hydralazine group (p = 0.001) were hospitalized.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar Relative risk of first HF hospitalization was reduced by 39% with FD ISDN–hydralazine compared with placebo (hazard ratio 0.61, 95% confidence interval 0.46 to 0.80, p <0.001; Figure 4).34Taylor A.L. Ziesche S. Yancy C.W. Carson P. Ferdinand K. Taylor M. Adams K. Olukotun A.Y. Ofili E. Tam S.W. Sabolinski M.L. Worcel M. Cohn J.N. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial.Circulation. 2007; 115: 1747-1753Crossref PubMed Scopus (74) Google Scholar The treatment effect appeared early, approximately 50 days after starting treatment, and remained significant throughout the study. A similar beneficial effect of FD ISDN–hydralazine was observed in all the subgroups analyzed, including age (< or >65 years), gender, ischemic HF etiology, baseline blood pressure (BP; systolic BP >126 mm Hg), presence of diabetes mellitus, history of chronic renal insufficiency, and baseline medication usage. Nevertheless, race is a social construct and not a physiologic concept and is an imprecise surrogate for genetic-related differences among subjects. Results of A-HeFT, therefore, will be clarified with continued genetic-based research, and clinicians should recognize the significant heterogeneity among prespecified groups, with perhaps greater genetic differences within than between certain racial or ethnic groups. Combined treatment with ISDN and hydralazine has shown good tolerability. In V-HeFT I, discontinuation rates were identical for ISDN and hydralazine versus placebo (22% in both groups).27Cohn J.N. Archibald D.G. Ziesche S. Franciosa J.A. Harston W.E. Tristani F.E. Dunkman W.B. Jacobs W. Francis G.S. Flohr K.H. Goldman S. Cobb F.R. Shah P.M. Saunders R. Fletcher R.D. Loeb H.S. Hughes V.C. Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2034) Google Scholar The main adverse events leading to discontinuation of ISDN and hydralazine were headache (12%), dizziness (6%), gastrointestinal effects (4%), and nervous system effects (4%); 3 patients (2%) discontinued because of arthralgia and 3 because of possible lupus.27Cohn J.N. Archibald D.G. Ziesche S. Franciosa J.A. Harston W.E. Tristani F.E. Dunkman W.B. Jacobs W. Francis G.S. Flohr K.H. Goldman S. Cobb F.R. Shah P.M. Saunders R. Fletcher R.D. Loeb H.S. Hughes V.C. Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2034) Google Scholar Headache was the only adverse event observed more frequently with ISDN and hydralazine than with enalapril in V-HeFT II (73% vs 54% of patients, p <0.05).28Cohn J.N. Johnson G. Ziesche S. Cobb F. Francis G. Tristani F. Smith R. Dunkman W.B. Loeb H. Wong M. Bhat G. Goldman S. Fletcher R.D. Doherty J. Hughes C.V. Carson P. Cintron G. Shabetai R. Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.New Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2513) Google Scholar In A-HeFT, in which patients had been receiving standard HF therapy for 3 months, headache and dizziness were significantly more frequent in the ISDN plus hydralazine group, whereas exacerbations of congestive HF (both moderate and severe) were significantly more frequent in the placebo group.24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar Potential adverse events associated with FD ISDN–hydralazine that may require specific attention include hypotension and lupus-like syndrome.35Arbor Pharmaceuticals, LLC. BiDil prescribing information. Available at: http://bidil.com/PI.pdf. 2013. Accessed on May 6, 2014.Google Scholar Different ISDN and hydralazine preparations were used for V-HeFT I,27Cohn J.N. Archibald D.G. Ziesche S. Franciosa J.A. Harston W.E. Tristani F.E. Dunkman W.B. Jacobs W. Francis G.S. Flohr K.H. Goldman S. Cobb F.R. Shah P.M. Saunders R. Fletcher R.D. Loeb H.S. Hughes V.C. Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2034) Google Scholar V-HeFT II,28Cohn J.N. Johnson G. Ziesche S. Cobb F. Francis G. Tristani F. Smith R. Dunkman W.B. Loeb H. Wong M. Bhat G. Goldman S. Fletcher R.D. Doherty J. Hughes C.V. Carson P. Cintron G. Shabetai R. Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.New Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2513) Google Scholar and A-HeFT,24Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino R. Ferdinand K.C. Taylor M. Adams K. Sabolinski M.L. Worcel M. Cohn J.N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.New Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1353) Google Scholar and it has been postulated that differences in the efficacy results might be related to pharmacokinetic differences among the drug formulations. To evaluate the different formulations, a 3-arm bioequivalence study was conducted in 56 healthy volunteers who were slow acetylators.36Tam S.W. Sabolinski M.L. Worcel M. Packer M. Cohn J.N. Lack of bioequivalence between different formulations of isosorbide dinitrate and hydralazine and the fixed-dose combination of isosorbide dinitrate/hydralazine: the V-HeFT paradox.Clin Pharmacokinet. 2007; 46: 885-895Crossref PubMed Scopus (14) Google Scholar Subjects were randomized to receive a single oral dose (10 mg/37.5 mg) of ISDN tablet plus hydralazine capsule, ISDN tablet plus hydralazine tablet, or a FD ISDN–hydralazine tablet (10 mg/37.5 mg, which differs from the A-HeFT formulation 20-mg/37.5-mg tablet in current clinical use35Arbor Pharmaceuticals, LLC. BiDil prescribing information. Available at: http://bidil.com/PI.pdf. 2013. Accessed
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