# Presentation: 713987

## V-HeFT I and V-HeFT II Trials―The Path to A-HeFT

**Jay N. Cohn, MD**
**Professor of Medicine****University of Minnesota Medical School**

**26**

## Major Entry CriteriaV-HeFT I and V-HeFT II

**Inclusion criteria**
**Men, 18 to 75 yr old**
**Heart failure ≥ 3 mo**
**Reduced exercise capacity (VO****2****max < 25 mL/kg/min)**
**Symptomatic despite digitalis and diuretics**
**CT ratio > 0.55, LVEF < 0.45 or LVIDD > 2.7 cm/m****2**
**Exclusion criteria**
**Hypertension requiring drugs other than diuretics**
**Angina requiring frequent or chronic nitrates**
**Use of beta-blockers or non-nitrate vasodilators**
**Myocardial infarction or cardiac surgery within 3 mo**
**Hypertrophic cardiomyopathy or significant valvular disease**
**Severe primary lung, liver, or kidney disease**

**26**

** ****DV BiDil FDA slides10.ppt **

## Study PlanV-HeFT I and V-HeFT II

**Placebo**

**Isosorbide dinitrate 40 mg qid**

**Enalapril 10 mg bid**

**Prazosin 5 mg qid**

**V-HeFT I**

**V-HeFT II**

**2.3 yr**
**(0.5 - 5.7 yr)**

**2.5 yr**
**(0.5 - 4.9 yr)**

**Study Plan****V-HeFT I and V-HeFT II**

**Hydralazine 75 mg qid**

**Isosorbide dinitrate 40 mg qid**

**Hydralazine 75 mg qid**

**26**

**DV BiDil FDA slides10.ppt **

**n = 276**

**n = 183**

**n = 186**

**n = 403**

**n = 401**

## Study EndpointsV-HeFT I and V-HeFT II

**Study Endpoints****V-HeFT I and V-HeFT II**

**Major endpoints**
**All-cause mortality during entire study**
**All-cause mortality at 2 yr**
**Number and duration of cardiovascular hospitalizations**
**Maximum oxygen consumption at peak exercise**
**Quality of life (V-HeFT II)**

**26**

**DV BiDil FDA slides10.ppt **

## Survival in All PatientsV-HeFT I

**ISDN/HYD,****	****n =****	****186****	****148****	****109****	****71****	****37****	****16****Placebo,****	****n =****	****276****	****202****	****135****	****84****	****41****	****10****Prazosin,****	****n =****	****183****	****135****	****94****	****58****	****27****	****7**

**25**

**50**

**75**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

***P***** = 0.093**
**ISDN/HYD vs placebo**

**ISDN/HYD****Placebo****Prazosin**

**Days since randomization date**

**9**

## Survival in All Patients V-HeFT I

**DV **Final NDA20-727_BD.pdf T 3 and pg 26, 24T3

**Survival in All Patients**** ****V-HeFT I**

**26**

| V-HeFT I, overall |  |  |  |  |
| --- | --- | --- | --- | --- |
| Treatment | Placebo,n (%) | Drug,n (%) | Hazard ratio(95% CI) | Log-rankP value |
| ISDN/HYD | 120 (44.0) | 72 (38.7) | 0.78 (0.58, 1.04) | 0.093 |
| Prazosin | 120 (44.0) | 91 (49.7) | 1.11 (0.85, 1.46) | 0.441 |

| V-HeFT I, endpoint of 2 yr |  |  |
| --- | --- | --- |
| Placebo, % | ISDN/HYD, % | P value |
| 34.3 | 25.6 | 0.053 |

## Survival in All Patients V-HeFT II

**26**

**DV **Final NDA20-727_Brief_Document.pdf F 8

**Survival in All Patients**** ****V-HeFT II**

**ISDN/HYD,****	****n = ****	****401****	****332****	****242****	****157****	****86****	****3**
**Enalapril,****	****n = 403****	****346****	****265****	****169****	****89****	****1**

**ISDN/HYD****Enalapril**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

**Time, days since randomization**

**HR = 1.23 (0.97, 1.55)**
**Log-rank***** P***** = 0.083**

## Survival in All PatientsV-HeFT II

| V-HeFT II, overall |  |  |  |
| --- | --- | --- | --- |
| Enalapriln = 403 | ISDN/HYDn = 401 | Hazard ratio(95% CI) | Log-rankP value |
| 132 (32.8%) | 153 (38.2%) | 1.23 (0.97, 1.55) | 0.083 |

**26**

| V-HeFT II, endpoint of 2 yr |  |  |
| --- | --- | --- |
| Enalapril, % | ISDN/HYD, % | P value |
| 18.0 | 25.0 | 0.016 |

**DV **Final NDA20-727_Brief_Document.pdf page 46

## Subgroup Analysis

## Survival in Black Patientsand White PatientsV-HeFT II

**Black patients**

**White patients**

**DV **Final NDA20-727_Brief_Document.pdf F 10

**ISDN/HYD****Enalapril**

**Time, days since randomization**

**Patients, n**
**ISDN/HYD****	****109****	****92****	****67****	****49****	****29****	****1****	****282****	****231****	****171****	****105****	****55****	****1**
**Enalapril****	****106****	****93****	****69****	****47****	****24****	****2****	****292****	****251****	****194****	****123****	****66****	****1**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

**HR = 1.01 (0.65, 1.58)*****P***** = 0.96 **

**HR = 1.39 (1.05, 1.83)**
***P***** = 0.02**

## Survival in Black Patientsand White PatientsV-HeFT I

**DV **Final NDA20-727_Brief_Document.pdf F 3

**Black patients**

**Patients, n**
**ISDN/HYD****	****49****	****43****	****36****	****28****	****16****	****8****	****132****	****102****	****71****	****42****	****22****	****9**
**Placebo****	****79****	****61****	****44****	****29****	****14****	****3****	****192****	****140****	****91****	****55****	****27****	****8**

**HR = 0.53 (0.29, 0.98)*****P***** = 0.04**

**Time, days since randomization**

**White patients**

**HR = 0.88 (0.63, 1.24)*****P***** = 0.47**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**365**

**730**

**1095**

**1460**

**1825**

**Survival, %**

## V-HeFT I—Conclusions (1)

**ISDN/HYD compared to placebo was associated with**
**A 22% lower risk of death overall (*****P***** = 0.09)**
**A 12% lower risk of death in white patients (*****P***** = 0.47)**
**A 47% lower risk of death in black patients (*****P***** = 0.04)**

## V-HeFT II—Conclusions (2)

**Enalapril compared to ISDN/HYD was associated with**
**A 23% lower mortality overall (*****P***** = 0.08) **
**A 39% lower mortality in white patients ****(*****P***** = 0.02)**
**No difference in mortality in blacks**

## From V-HeFT I and V-HeFT II to A-HeFT 

**Based on V-HeFT I and V-HeFT II, a clinical study was needed to confirm the hypothesis that the ISDN/HYD combination benefits outcomes in black HF patients**
**A-HeFT was designed as a prospective, placebo-controlled study with the objective of testing BiDil’s effects on survival, heart failure hospitalizations, and quality of life in patients receiving contemporary therapy for heart failure**