Treatment with Hydralazine and Nitrates Uri Elkayam, MD Professor of Medicine University of Southern California School of Medicine Los Angeles, California elkayam@usc.edu
Hydralazine and Isosorbide Dinitrate in Heart Failure Historical perspective. Mechanisms. When and How to use it. Why use hydralazine? Should it be used in Non African Americans?
Hemodynamic Advantage of Combined Hydralazine and Nitrates Am J Cardiol 1977
Ventricular Function Curve Effect of Hyd-N on LV Function Massie B Am J Cardiol 1977
The V-HeFT I Trial 642 men with chronic HF. Mean EF 30%, mean max VO2 14.5 On digoxin and diuretics. Randomized to either placebo (N=273), prazosin (20 mg/d, N=183) or Hydralazine/ISDN (300/160 mg/d N= 186). Primary end point -2 years all cause death
V-HeFT I Study Effect on all cause mortality Mean F/U 2.3 mortality reduction at 2 years 25% (P<0.028) Dose: Average Dose: Hydralazine 270 mg/d ISDN 136 mg/d
V-HeFT I Study Effect on all cause mortality Mortality reduction over the entire period: P=0.093 log rank test and 0.04 wilcoxon test
253 class IV HF patients randomized to placebo or enalapril 5-20 mg BID
The V-HeFT II Trial 804 men receiving digoxin and diuretics for HF. Randomized to enalapril 20 mg/d or Hyd/ISDN 300 /160 mg Average dose 199/100 mg/d
Identical survival curves on Hyd/N in V-HeFT I and II
Ejection Fraction P < 0.05 Oxygen Consumption P < 0.01 Change in EF and maximum oxygen consumption higher with nitrates BP decrease 5/4 mmhg with enalapril and 0/1 mmhg with Hyd/ISDN
Effect of Enalapril vs. HYD/ISDN on all cause mortality P = 0.016 at 2 years and 0.08 overall Mortality difference due to decreased sudden death Mortality reduction More prominent in class I-II patients
V HeFT Studies Racial Differences in Response to Therapy Annual Mortality Rate V HeFT I 180 AA vs. 450 white male patients. P = 0.04 V HeFT II 215 AA vs. 574 white patients. P= 0.02 Carson P et al J Cardiac Fail 1999;5:178
A-HeFT Trial 1050 AA patients with HFrEF. NYHA III-IV. Randomly to a fixed dose Hyd/ ISDN (Bidil) or placebo in addition to standard HF therapy. Primary end point : A composite of death, hospitalizations and QOL.
A-HeFT First Hospitalization for HF
A-HeFT Hospitalizations
A-HeFT Quality of Life
A-HeFT Effect on Mortality
Effect on Mortality of Various HF Medications
Hyd/ISDN Magnitude of Benefit
HYD+ISDN or ICD? 12% reduction in death and hospitalization P=0.002 4.5 mg/d Vs 33 mg/d 23% survival benefit with ICD in 45 months P<0.001 43% improvement In survival in 10 months P=0.01 SCD - HeFT A - HeFT
Hydralazine and Oral Nitrates When To Use It? A combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality in addition to BB and ACE-inhibitors for African Americans with HF and reduced LVEF: NYHA III or IV HF Strength of Evidence = A NYHA II HF Strength of Evidence = B AHA/ACC 2013 Practice Guideline
Nitrate Therapy for Heart Failure Gupta et al JACC Heart Failure 2013;1:183 Despite proven benefits, the combination hydralazine and nitrate therapy is not commonly used in HF.
Heart Failure Readmission Penalties, Care Quality, and Outcomes Pandey et al. JACC Heart Failure August 2016 N=43,143 GWTG-HF Registry 2008-2011
Hydralazine-ISDN in AA patients with HF Ziaeian B et al JACC HF 2017 5,168 AA veterans affairs patients with HF admission between 2007 and 2013. 15% treated with Hyd-ISDN before the admission. Mortality at 18 months was 22% vs 25% (p=0.009) HR 0.85.
Nitrate Therapy for Heart Failure Gupta et al JACC Heart Failure 2013;1:183 In practice, patients receive lower doses than those proved beneficial in clinical trial. It is unknown weather lower doses provide either meaningful vasodilation, protection against tolerance or clinical benefit.
Change in BP during therapy Anand et al JACC 2007;49:32-9
Change in BP in relation to baseline BP Anand et al JACC 207;49:32-9
Hydralazine / ISDN What is the Dose? Daily Dose for Bidil 37.5 mg / 20mg 75 mg / 40 mg
Hydralazine / ISDN What is the Dose? Daily Dose for Bidil Mean dose in A-HeFT: Hydralazine 142 mg/d ISDN 76 mg/d
Why Use Hydralazine?
ISDN in HF Elkayam U et al, circulation 1991;84:2040
1. Increased endothelial and VSM mitochondrial superoxide formation. 2. Direct inhibition of NOS activation. 3. Uncoupling of NOS caused by peroxynitrite 4. Vasoconstrictor super sensitivity Due to activation of protein kinase C (PKG) 5 bioactivation of GTN. Munzel et al Pseudo tolerance 6. Inhibition of sgc by superoxide and peroxynitrite. 7.Inactivation of cgmp 8.Inhibition of PGI-S Endothelial dysfunction Smooth muscle dysfunction NADPH - Nicotinamide Adenine Dinucleotide Phosphate. ALDH-2-Aldehyde Dehydrogenase. PKC - Protein Kinase C. GTP-CH( cyclohydrolase), A cofactor of NO Synthase. B4 - tetrahydrobiopterin, A cofactor of NOS, ONOO - : Peroxynitrite,sags = Soluble Guanylyl Cyclase
Consequences of Nitric Oxide and Super Oxide Balance Disruption in Heart Failure Patients Isosorbide dinitrate Hydralazine Stimulation Nitric oxide synthase Citrulline Oxidase Inhibition L-Arginine NO O 2 O 2 O 2 Physiologic pathway Pathologic pathway Formation of cyclic guanosine monophosphate Hare JM. N Engl J Med. 2004;351:2112-2114. S-nitrosylation: post-translational modification of effector molecules Inhibition Peroxynitrite (ONOO ) DNA damage Cell damage Nitrates tolerance Endothelial dysfuncion Oxidized proteins
Potential Mechanisms of Hydralazine Induced Prevention of Nitrate Tolerance Marked reduction of vascular superoxide levels by inhibition of NADH oxidase (Munzel, JCI 1996). Direct free radical scavenger due to alteration in vascular inducible NOS/COX-2 gene expression (Leiro, Int Immunopharmacol 2004). Inhibition of peroxynitrite formation (Daiber, BBRC 2005) Scavenging of superoxide and quenching of peroxynitrite-derived free radicals. (Munzel, Circ Res 2005).
Oxidative Stress Concept of Nitrate Tolerance and the Antioxidant Properties of Hydralazine (Munzel et al,j Clin Invest 1996;98:1465-1470)
Prevention of tolerance to NTG with Hydralazine Bauer JA Circulation 1991;84:35 LVSP (mm Hg) 140 115 90 H * H* * * 0 2 4 6 8 10 * * Hemodynamic effects in rats with HF Hydralazine prevents tolerance to NTG in rat HF model LVEDP (mm Hg) 25 20 15 10 5 0 * * * * * * H H* * * * 0 2 4 6 8 10 * * NTG 10 µg/ml NTG 10 µg/ml + HYD Hours Bauer and Fung. Circulation. 1991;85:35.
Prevention of Nitrate Tolerance with Hydralazine in Patients with Heart Failure Gogia H, Elkayam U. JACC 1995;26:575 Percent Change from Baseline 0 10 20 30 40 50 * NTG NTG + HYD (75 mg qid) * * BL 0 1 2 4 8 12 16 20 24 Hours * * * *P<0.05 vs 0 hours.
Why Use Hydralazine?
Adverse Effects
Should Hyd/Nitrare therapy be used in non AA patients?
Use of Hyd-N in non AA Patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency. (Level of Evidence: B) Pregnant women with symptomatic HF due to HFrEF.
AHA/ACC HF Guidelines 2013 A combination of hydralazine and ISDN can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency. (Level of Evidence: B)
Change in EF and maximum oxygen consumption higher with nitrates Ejection Fraction P < 0.05 Oxygen Consumption P < 0.01
Hyd/ISDN in Patients D/C from Hospital Mullens W et al. Am J Cardiol 2009;103;1113 80% Caucasians SBP 108±16 mmhg Mean PWP 24±8 mmhg Freedom from all cause mortality Freedom from mortality and hospitalizations
Nitrates in patients with HFrEF in the CHAMPION study Increased furosemide dose by 51 mg/d Increased nitrates dose by 18 mg/d.
Hemodynamic Effects of Hydralazine/Nitrate Combination Roth, Elkayam AHJ 1993;125:155
Nitrate Resistance in Chronic HF Kulic D, Elkayam U JACC 1988;12:1023
Summary Hyd/ISDN combination (Bidil) is one of the most effective and underutilized interventions for the treatment of AA patients with symptomatic HFrEF. Use of Hyd/ISDN is recommended to all patients not tolerating angiotensin blocking therapy regardless of race.
Summary Hydralazine improves hemodynamic effect and also prevents attenuation of nitrates effect due to tolerance. Hyd/ISDN should be considered in non AA patients with severe HF for improvement of hemodynamics and possible outcome.
Summary When used for hemodynamic improvement, nitrates should be up titrated to achieve the desirable effect.
The Role of Organic Nitrates in the Treatment of Heart Failure Uri Elkayam, MD Professor of Medicine University of Southern California School of Medicine Los Angeles, California elkayam@usc.edu