VASODILATORS























Overview
  • Hydralazine and isosorbide dinitrate have been used in combination to treat heart failure
  • The V-HeFT I and II trials compared hydralazine/isosorbide to prazosin, enalapril, and placebo. A post-hoc analysis of these 2 trials found that black patients had a better response to hydralazine/isosorbide than white patients. This finding led to the A-HeFT trial where hydralazine/isosorbide was compared to placebo in black patients only. All 3 trials are detailed below. [10]
V-HeFT I Trial - Hydralazine/Isosorbide vs Prazosin vs Placebo in Heart Failure, 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 Hydralazine/Isosorbide 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, 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 Hydralalzine/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 Blacks with Heart Failure, 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)
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 (composite score, range -6 to +2, higher score better) -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.
AHA recommendations
  • Hydralazine/isosorbide therapy may be added to standard therapy (ACE/ARB + beta blocker + diuretics ± aldosterone antagonist ± Entresto) for patients self-described as African Americans with persistent NYHA class III – IV heart failure
  • Hydralazine/isosorbide can be useful to reduce morbidity and mortality in heart failure patients (regardless of race) who cannot tolerate an ACE inhibitor or ARB [34,37,38]
Summary
  • In the A-HeFT trial, hydralazine/isosorbide therapy improved survival in black patients with NYHA class III - IV heart failure. The hydralazine/isosorbide group achieved a lower blood pressure and this may have contributed to its efficacy. The majority of patients in the trial were receiving standard heart failure therapy with an ACE inhibitor/ARB and beta blocker. The two V-HeFT trials were performed before ACE inhibitors and beta blockers became standard treatment.









Overview
  • Quick-acting nitroglycerin (spray, tablets, intravenous) is widely used in patients experiencing a heart attack
  • Nitroglycerin helps relieve the chest pain associated with a heart attack, and it also helps decrease the workload on the heart through venous dilation
  • The effects of nitrates on clinical outcomes was evaluated in the ISIS trial detailed below
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.
AHA recommendations
  • The AHA 2011 NSTEMI-Unstable angina guidelines state that patients with ongoing chest pain should receive up to 3 doses of sublingual nitroglycerin after which IV nitroglycerin may be started if chest pain persists. IV nitroglycerin is indicated in the first 48 hours for persistent decreased blood flow to the heart, heart failure, or hypertension. Nitrates should not be given to patients with any of the following: SBP < 90 (or ≥ 30 below baseline), bradycardia (< 50 bpm), tachycardia (> 100 bpm), absence of symptomatic heart failure, treatment with a phosphodiesterase inhibitor for ED within 24 h of sildenafil or 48 h of tadalafil, right ventricular infarction [22]
  • The AHA 2013 STEMI guidelines state that nitrates may help relieve the symptoms of ischemia, but they do not attenuate myocardial injury unless vasospasm plays a significant role [36]
Summary
  • Nitroglycerin is used almost universally in acute heart attacks because it relieves chest pain and helps decrease the workload on the heart
  • There is no evidence that nitrates improve survival or other important outcomes in ACS



Headache

Gastrointestinal side effects

Rapid heart rate (tachycardia)

Palpitations

Dizziness / lightheadedness

Drug-induced lupus
Overview
  • Lupus erythematosus is an autoimmune disease that can lead to joint inflammation and organ damage
  • Hydralazine can cause a lupus erythematosus-like syndrome to develop in some individuals
  • When drugs cause lupus, it is often referred to as "drug-induced lupus"
Incidence
  • A study in the British Medical Journal followed 281 patients taking hydralazine for hypertension
  • Patients were monitored for the development of drug-induced lupus, and the following was observed:
    • The overall incidence of drug-induced lupus was 6.7% at 3 years of therapy
    • Drug-induced lupus was diagnosed at an average of 24 months after therapy was started (earliest 9 months)
    • The incidence was higher for higher doses of hydralazine (100 mg/day - 5.4%, 200 mg/day - 10.4%)
    • Women had a higher incidence than men ( 11.6% for women overall vs 2.8% for men) [18]
Symptoms
  • Symptoms of hydralazine-induced lupus are similar to what is seen in the typical disease and may include:
    • Joint pain and swelling
    • Muscle pain
    • Fever
    • Rash
    • Weight loss
    • Blood abnormalities (anemia, low white count, low platelets) [18,30,31]
Diagnosis
  • Diagnosis of drug-induced lupus is based on clinical symptoms and the following lab tests:
    • A positive ANA (antinuclear antibody) test - typically present in drug-induced lupus - about 50% of patients taking hydralazine will develop a positive ANA test
    • ANA pattern is often homogenous in drug-induced lupus
    • Anti-histone antibodies are positive in up to 95% of patients
    • Anti-ssDNA (single stranded DNA) antibodies are often present
    • anti-dsDNA (double stranded DNA) antibodies are rare
    • Complement levels are typically normal in drug-induced lupus [18,30,31]
Treatment
  • Symptoms typically resolve once hydralazine is stopped
  • In severe cases, steroids may be used
Summary
  • Hydralazine-induced lupus can be a significant problem, particularly in women and people taking higher doses
  • The manufacturer recommends that a blood cell count and ANA titer be performed before therapy and "periodically" thereafter in prolonged therapy
  • Because the ANA titer can turn positive in 50% of patients taking hydralazine, checking ANA titers periodically may be of little utility
  • A more prudent approach is to check an ANA titer and blood cell count before therapy to establish a baseline, and then repeat the tests if symptoms occur
  • Patients should be maintained on the lowest dose of hydralazine that is effective



Fluid retention

Rapid heart rate (tachycardia)

Chest pain (angina)

Hair growth (hypertrichosis)

Pericardial effusion

EKG changes

Lab changes



Headache

Dizziness / lightheadedness / weakness

Methemoglobinemia

Rebound chest pain when stopping









Kidney disease
Hydralazine
  • In one study, severe kidney disease did not affect blood levels of hydralazine
  • Manufacturer makes no specific dosage recommendations [32]
Minoxidil
  • Minoxidil should be used with caution in patients with significant kidney disease
  • Lower doses should be used
  • Manufacturer makes no specific dosage recommendations [1]
Nitrates
  • Adjustments are not necessary in patients with kidney disease

Liver disease
Hydralazine
  • Hydralazine undergoes extensive liver metabolism
  • Liver disease would be expected to affect its clearance
  • Manufacturer makes no specific dosage recommendations
Isosorbide dinitrate
  • Isosorbide dinitrate undergoes extensive first-pass liver metabolism
  • Isosorbide dinitrate undergoes metabolism in the liver and at sites outside of the liver
  • The manufacturer makes no specific dosage recommendations in liver disease
Isosorbide mononitrate
  • Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism
  • Liver disease does not appear to affect the clearance of isosorbide mononitrate
Minoxidil
  • Lower doses should be used
  • Manufacturer makes no specific dosage recommendations [1]
Nitroglycerin
  • Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver
  • The manufacturer makes no specific dosage recommendations in liver disease

Coronary artery disease (hydralazine and minoxidil)

Heart failure (minoxidil)

Hypertrophic cardiomyopathy (nitrates)

Peripheral neuritis (hydralazine)

Mitral valve heart disease (hydralazine)



Hydralazine

  • MAO inhibitors - MAO inhibitors should be used with caution in patients receiving hydralazine

Nitrates

  • Alcohol - beverage alcohol may potentiate the blood pressure-lowering effect of nitrates
  • Aspirin - aspirin has been shown to significantly increase blood levels of nitroglycerin. Vasodilatory and hemodynamic properties of nitroglycerin may be enhanced when taken with aspirin.
  • Calcium channel blockers - marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination
  • Dihydroergotamine (Migranal®) - nitrates may increase blood levels of dihydroergotamine and they should not be taken together [20]
  • Heparin - IV nitroglycerin may decrease the effect of heparin [25, 26]
  • Phosphodiesterase type 5 inhibitors (Viagra®, Cialis®, sildenafil, etc.)- Erectile dysfunction (ED) medications and drugs used to treat pulmonary hypertension should not be taken with nitrates. Dangerously low blood pressure may occur.
    • The AHA/ACC makes the following statements about nitrates and ED medications:
      • Nitrates should not be taken within 24 hours of sildenafil (Viagra®)
      • Nitrates should not be taken within 48 hours of tadalafil (Cialis®)
      • The suitable time for the administration of nitrates after vardenafil (Levitra®) has not been determined [22]
    • Avanafil (Stendra®) - the avanafil PI states that when nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered
  • Riociguat (Adempas®) - DO NOT USE nitrates in patients who are taking riociguat. Riociguat stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide. When taken with nitrates, severe hypotension may occur
  • Tissue plasminogen activator (t-PA, Activase®, Alteplase®) - IV nitroglycerin has been shown to decrease the effectiveness and blood levels of t-PA. [23, 24]

Metabolism and clearance
Hydralazine (Apresoline®)
Isosorbide dinitrate (Isordil®)
Isosorbide mononitrate (ISMO®)
Minoxidil (Loniten®)
  • Primarily metabolized by glucuronidation
Nitroglycerin (Nitrostat®, etc.)
  • Nitroglycerin is metabolized by a reductase enzyme in the liver
  • Nitroglycerin also undergoes extrahepatic metabolism in red blood cells and vascular walls



  • 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