Treatment with Hydralazine and Nitrates Uri Elkayam, MD Professor of Medicine University of Southern California School of Medicine Los Angeles, California [email protected]
Treatment with Hydralazine and Nitrates
Uri Elkayam, MDProfessor of Medicine
University of Southern California School of Medicine
Los Angeles, [email protected]
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.
LVSP
(m
m H
g)LV
EDP
(mm
Hg)
140
115
90
H
H
25
20
15
10
5
0H
H
*
* * * **
*NTG 10 µg/mL
NTG 10 µg/mL + HYD***** *
*** *
*
0 2 4 86 10
0 2 4 86 10
Hours
Prevention of Nitrate Tolerance with Hydralazine in Patients with Heart Failure
Gogia H, Elkayam U. JACC 1995;26:575
0
−20
−30
−40
−50
−10
BL 0 1 2 4 8 12 16 20 24Hours
Perc
ent C
hang
e fro
m B
asel
ine
*P<0.05 vs 0 hours.
*
* *
**
*
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, [email protected]