Treatment with Hydralazine and Nitrates

Uri Elkayam, MDProfessor of Medicine

University of Southern California School of Medicine

Los Angeles, Californiaelkayam@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 CurveEffect of Hyd-N on LV FunctionMassie B Am J Cardiol 1977

The V-HeFT I Trial642 men with chronic HF.

Mean EF 30%, mean max VO2 14.5On 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 StudyEffect on all cause mortality

Dose: Average Dose:Hydralazine 270 mg/dISDN 136 mg/d

Mean F/U 2.3 mortality reduction at 2 years 25% (P<0.028)

V-HeFT I StudyEffect 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 Trial804 men receiving digoxin and

diuretics for HF. Randomized to enalapril 20 mg/d

or Hyd/ISDN 300 /160 mgAverage dose 199/100 mg/d

Identical survival curves on Hyd/N in V-HeFT I and II

Change in EF and maximum oxygen consumption higher with nitrates

Ejection FractionP < 0.05

Oxygen ConsumptionP < 0.01

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 overallMortality difference due to decreased sudden death

Mortality reductionMore prominent in class I-II patients

V–HeFT StudiesRacial 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

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 Trial

A-HeFTFirst Hospitalization for HF

A-HeFTHospitalizations

A-HeFTQuality of Life

A-HeFTEffect on Mortality

Effect on Mortality of Various HF Medications

Hyd/ISDNMagnitude of Benefit

HYD+ISDN or ICD?12% reduction in death and hospitalizationP=0.0024.5 mg/d Vs 33 mg/d

43% improvementIn survival in 10 monthsP=0.0123% survival benefit

with ICD in 45 monthsP<0.001

SCD - HeFT A - HeFT

Hydralazine and Oral NitratesWhen To Use It?

§ A combination of hydralazine and isosorbide dinitrate is recommendedto 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 FailureGupta 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=43,143GWTG-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 FailureGupta 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 therapyAnand et al JACC 2007;49:32-9

Change in BP in relation to baseline BP

Anand et al JACC 207;49:32-9

Hydralazine / ISDNWhat is the Dose?Daily Dose for Bidil

37.5 mg / 20mg

75 mg / 40 mg

Hydralazine / ISDNWhat 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 HFElkayam U et al, circulation 1991;84:2040

Munzel et al

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

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.

6. Inhibition of sGC by superoxide and peroxynitrite.

7.Inactivation of cGMP8 .Inhibition of PGI-S

Pseudo tolerance

Endothelial dysfunction

Smooth muscle dysfunction

Consequences of Nitric Oxide and Super Oxide Balance Disruption in Heart Failure Patients

Hare JM. N Engl J Med. 2004;351:2112-2114.

Nitric oxide

synthaseOxidase

Pathologic pathway

InhibitionOxidized proteins

Cell damageNitrates tolerance

Endothelial dysfuncion

Peroxynitrite (ONOO–)DNA damage

Citrulline

L-ArginineNO

Isosorbide dinitrate

Stimulation

Hydralazine

Inhibition

O2

Physiologic pathway

Formation of cyclic guanosine monophosphate

S-nitrosylation: post-translational

modification of effector molecules

O2−O2

−

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§ Hemodynamic effects in rats

with HF§ Hydralazine prevents

tolerance to NTG in rat HF model

Bauer and Fung. Circulation. 1991;85:35.

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NTG 10 µg/mL + HYD***** *

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0 2 4 86 10

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Prevention of Nitrate Tolerance with Hydralazine in Patients with Heart Failure

Gogia H, Elkayam U. JACC 1995;26:575

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NTGNTG + HYD (75 mg qid)

Why Use Hydralazine?

Adverse Effects

Should Hyd/Nitraretherapy 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 FractionP < 0.05

Oxygen ConsumptionP < 0.01

Hyd/ISDN in Patients D/C from HospitalMullens W et al . Am J Cardiol 2009;103;1113

80% CaucasiansSBP 108±16

mmHgMean PWP 24±8

mmHgFreedom 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 HFKulic 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, MDProfessor of Medicine

University of Southern California School of Medicine

Los Angeles, Californiaelkayam@usc.edu