VASODILATORS



















V-HeFT I Trial - Hydralazine/Isosorbide vs Prazosin vs Placebo in Heart Failure with Reduced EF , NEJM (1986) [PubMed abstract]
  • The V-HeFT trial enrolled 642 men with symptomatic heart failure (average ejection fraction 30%)
Main inclusion criteria
  • Receiving diuretic and digoxin
  • EF < 45% or evidence of enlarged heart on chest X-ray or ECHO
  • Reduced exercise tolerance
Main exclusion criteria
  • Myocardial infarction within 3 months
  • Obstructive valvular disease or myocardial obstructive disease
  • Taking long-acting nitrates, calcium channel blockers, beta blockers, or antihypertensives other than diuretics
Baseline characteristics
  • Average age 58 years
  • Previous myocardial infarction - 41%
  • Average EF - 30%
  • CAD - 44%
Patients were randomized to 1 of 3 groups:
  • Group 1 (186 patients) - Hydralazine 75 mg + Isosorbide dinitrate 40 mg four times a day (average daily dose hydralazine/isosorbide 270 mg/136 mg)
  • Group 2 (186 patients) - Prazosin 5 mg four times a day (average dose 18.6 mg/day)
  • Group 3 (273 patients) - Placebo 4 times a day
  • Study medications were started at half the target dose and doubled after 2 weeks if tolerated
Primary outcome: Overall mortality
Results

Duration: Average of 2.3 years
Outcome Hyd/Iso Prazosin Placebo Comparisons
Primary outcome 38.7% 49.7% 44% 1 vs 3 p=0.046 | 2 vs 3 p>0.05
Cumulative mortality at 2 years 25.6% ∼34% 34.3% 1 vs 2 or 3 p<0.05
Drug discontinuation 22% 27% 22% N/A
Change in BP at 1 year (mmHg) +0.6/-1 -4.6/-2.7 -0.3/-0.3 N/A

Findings: Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality
V-HeFT II Trial - Hydralazine/Isosorbide vs Enalapril in Heart Failure with Reduced EF, NEJM (1991) [PubMed abstract]
  • The V-HeFT II trial enrolled 804 men with heart failure
Main inclusion criteria
  • Receiving diuretic and digoxin
  • EF < 45% or evidence of enlarged heart on chest X-ray or ECHO
  • Reduced exercise tolerance
Main exclusion criteria
  • Myocardial infarction or heart surgery within 3 months
  • Angina requiring treatment
  • Obstructive valvular disease
  • Obstructive lung disease
Baseline characteristics
  • Average age 61 years
  • Average EF - 29%
  • Prior myocardial infarction - 47%
  • Average BP - 125/78
  • NYHA class: I - 6% | II - 51% | III - 42% | IV - 0.3%
Randomized treatment groups
  • Group 1 (401 patients) - Hydralazine 75 mg + Isosorbide dinitrate 40 mg four times a day (average daily dose 199 mg/100 mg)
  • Group 2 (403 patients) - Enalapril 10 mg twice a day (average dose 15 mg/day)
  • Patients were instructed not to take nonstudy vasodilators or antihypertensive drugs
  • There was a run-in phase of at least 4 weeks where all patients were placed on diuretic and digoxin and nonstudy drugs were discontinued
Primary outcome: Overall mortality at 2 years
Results

Duration: Average of 2.5 years
Outcome Hydralazine/Isosorbide Enalapril Comparisons
Primary outcome (overall mortality at 2 years) 25% 18% p=0.016
Overall mortality at 5 years 54% 48% p=0.08
Hospitalization for heart failure 18.4% 18.9% p>0.05
Headache 73% 54% p<0.05
Symptomatic hypotension 20% 28% p<0.05
Change in BP at 13 weeks (mmHg) 0/-1 -5/-4 N/A

Findings: The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.
A-HeFT Trial - Hydralazine/Isosorbide vs Placebo in Black Patients with Heart Failure with Reduced EF, NEJM (2004) [PubMed abstract]
  • The A-HeFT trial enrolled 1050 blacks with heart failure
Main inclusion criteria
  • Self-identified as black
  • NYHA class III or IV heart failure
  • EF ≤ 35% or ≤ 45% with a left ventricular internal end-diastolic diameter of > 2.9 cm
  • Receiving standard therapy for heart failure
Main exclusion criteria
  • Myocardial infarction, ACS, stroke, PCI, or heart surgery within 3 months
  • Hypertrophic or restrictive cardiomyopathy
  • Uncontrolled hypertension
Baseline characteristics
  • Average age 57 years
  • Average EF - 24%
  • Average BP - 126/76
  • NYHA class: III - 96% | IV - 4%
  • Heart failure etiology: Ischemic - 23% | Hypertensive - 39% | Idiopathic - 26% | Valvular - 3%
  • Baseline meds: Diuretic - 89% | ACE/ARB - 87% | Beta blocker - 74% | Carvedilol - 56% | Spironolactone - 38%
Randomized treatment groups
  • Group 1 (518 patients) - Hydralazine 37.5 mg + isosorbide dinitrate 20 mg 1-2 tabs three times a day (average daily dose 142 mg/76 mg)
  • Group 2 (532 patients) - Placebo three times day
  • Hydralazine/isosorbide was started at half the target dose and increased if tolerated
Primary outcome: Composite score made up of weighted values for death from any cause, first hospitalization for heart failure (during 18 months of follow-up), and change in the quality of life (at 6 months). Score ranges from -6 to +2, and higher scores are better.
Results

Duration: After an average follow-up of 10 months, the trial was stopped early due to higher mortality in the placebo group
Outcome Hydralazine/Isosorbide Placebo Comparisons
Primary outcome -0.1 -0.5 p=0.01
Overall mortality 6.2% 10.2% p=0.02
Hospitalization for heart failure 16.4% 24.4% p=0.001
Heart failure exacerbation 8.7% 12.8% p=0.04
Headache 47.5% 19.2% p<0.001
Dizziness 29.3% 12.3% p<0.001
SBP change from baseline at 6 months (mmHg) -1.9 +1.2 p=0.02
DBP change from baseline at 6 months (mmHg) -2.4 +0.8 p<0.001

Findings: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.










ISIS-4 Trial - Captopril vs Isosorbide vs Magnesium vs Placebo in ACS, Lancet (1995) [PubMed abstract]
  • The ISIS-4 trial enrolled 58,050 patients who presented to the ER with suspected myocardial infarction
Main inclusion criteria
  • Presenting to the ER with suspected myocardial infarction
  • Onset of symptoms within 24 hours
Main exclusion criteria
  • Indication for, or contraindication to study medications
  • Cardiogenic shock
  • Severe hypotension
  • Fluid depletion
Baseline characteristics
  • STEMI - 79%
  • Previous myocardial infarction - 17%
  • Symptomatic heart failure - 14%
  • Nonstudy IV nitrate - 47%
Randomized treatment groups
  • Patients were randomized in a 2 X 2 X 2 factorial design
  • Group 1 (29,028 patients): Captopril (target dose 50 mg twice a day) or Placebo for 1 month
  • Group 2 (29,018 patients) Isosorbide mononitrate (target dose 60 mg once daily) or Placebo for 1 month
  • Group 3 (29,011 patients) Magnesium sulfate IV 8 mmol bolus followed by 72 mmol over 24 hours
Primary outcome: Overall mortality at 5 weeks
Results

Duration: 5 weeks
Outcome Drug Corresponding placebo group Comparisons
Primary outcome (captopril) 7.19% 7.69% p=0.02
Primary outcome (isosorbide) 7.34% 7.54% p>0.05
Primary outcome (magnesium) 7.64% 7.24% p>0.05
  • There were no significant interactions between the three treatment groups
  • 60% of patients in the placebo groups received a non-study nitrate. When these patients were excluded, a benefit from nitrate therapy was still not observed.

Findings: Because of its size, ISIS-4 provides reliable evidence about the effects of adding each of these three treatments to established treatments for acute Ml. Intravenous magnesium was ineffective, and although oral nitrate therapy appeared safe it did not produce a clear reduction in 1-month mortality.






































  • In chronic dosing, duration of effect is much shorter due to tolerance
Drug Onset of action Duration of effect
Nitroglycerin spray, tablet. powder 1 - 3 minutes around 25 minutes
Isosorbide dinitrate about 1 hour up to 8 hours after one dose
Isosorbide mononitrate about 1 hour up to 12 hours after one dose
Nitroglycerin ointment not rapid enough for acute angina up to 12 hours
Nitroglycerin patch steady-state reached in 2 hours up to 12 hours