CC-1 Integrated Summary of V-HeFT and A-HeFT Trials Milton Packer, MD University of Texas Southwestern Medical Center at Dallas

CC-2 Characteristics of Major Trials With Isosorbide Dinitrate and Hydralazine in Heart Failure V-HeFT I ( )V-HeFT II ( )A-HeFT ( ) SponsorVeterans Affairs NitroMed Number of patients SexMale Male and female RaceAll races Blacks Drugs studiedPlacebo ISDN/HYD Prazosin Enalapril ISDN/HYD Placebo ISDN/HYD Target doses of ISDN/HYD ISDN 40 mg QID HYD 75 mg QID ISDN 40 mg QID HYD 75 mg QID ISDN 40 mg TID HYD 75 mg TID ISDN/HYDAs individual products As individual products As fixed-dose combination tablet (BiDil ® ) Severity of HFMild-to-severe Moderate-to-severe Background therapy for HF Digoxin Diuretics Digoxin Diuretics Digoxin Diuretics ACE inhibitors/ARBs Beta-blockers Aldosterone antagonists DV Final NDA20-727_Brief_Document.pdf T 1

CC-3 BiDil ® Effects in Black Patients With Heart Failure  Mortality  Hospitalization for heart failure  Quality of life DV NitroMed BB pp 11, 12

CC-4 Primary Endpoint—Composite Score † P = DV A-HeFT CSR T 24 † Composite score range, –6 to +2. –0.16 –0.47 Mean ± SEM

CC-5 Components of Primary Endpoint DeathFirst HF hospitalizationChange in QoL at 6 mo A-HeFT T 26 pg 109, 116, 120; A-HeFT PTT 16.1 BiDil ® Placebo n = 32n = 54n = 85n = 130 Percent

CC-6 BiDil ® Effects in Black Patients With Heart Failure  Mortality  Hospitalization for heart failure  Quality of life DV NitroMed BB pp 11, 12

CC-7 BiDil Placebo Effect on Mortality A-HeFT BiDil ® Placebo HR = 0.57 (0.37, 0.89) P = Patients at risk, n Survival, % Time since baseline visit, days DV NitroMed BB F 16

CC-8 Effect on Mortality in Black Patients V-HeFT I Patients, n ISDN/HYD Placebo Survival, % Time since randomization date, days DV NitroMed BB F3 HR = 0.53 (0.29, 0.98) P = 0.04

CC Effect on CHF Hospitalization A-HeFT DV NitroMed BB T22, F18 Placebo BiDil ® HR = 0.61 (0.46, 0.80) P < BiDil Placebo Patients at risk Without hospitalization, % Time since baseline visit date, days

CC-10 Effect on CHF Hospitalization in Black Patients V-HeFT I and V-HeFT II Without HF hospitalization, % V-HeFT IV-HeFT II Time since randomization date, days Placebo ISDN/HYD Enalapril ISDN/HYD DV NitroMed BB F6, F13

CC-11 † Minnesota Living With HF questionnaire. Lower QoL score indicates better QoL. Mean ± SEM. MLHF Questionnaire Change in QoL From Baseline † DV A-HeFT CSR PTT 16.1 Improvement P = Month P = 0.129P = 0.053P = 0.011P = 0.039P = 0.024P = n =

CC-12 Quality of Life in Black Patients V-HEFT II P = DV V-HeFT II PTT 35

CC-13 Overview  Concordance of data within and across trials support proposed indication: “BiDil ® is indicated for the treatment of heart failure as an adjunct to standard therapy in black patients to improve survival, prolong time to hospitalization for heart failure, and improve quality of life.”