Clinical trial NCT01516346: Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction
Official title: Effect of Organic Nitrates and Hydralazine on Wave Reflections and Left Ventricular Structure and Function in Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Congestive Heart Failure
Keywords: Heart Failure
Heart failure with preserved ejection fraction (HFpEF)
Vasodilators
Isosorbide dinitrate
Hydralazine
wave reflections
arterial stiffness
hemodynamics
Lead sponsor: Corporal Michael J. Crescenz VA Medical Center
Sponsor class: FED
Collaborators: name: University of Pennsylvania
name: National Institute on Aging (NIA)
First posted: 2012-01-24
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective is to test the effect of prolonged therapy (24 weeks) with isosorbide dinitrate ± hydralazine on arterial wave reflections (primary endpoint). Secondary endpoints include left ventricular (LV) mass, fibrosis and diastolic function) and exercise capacity (assessed via the 6-minute walk test) in patients with Heart Failure and Preserved Ejection Fraction (HFPEF). We will also test the hypothesis that the reduction in arterial wave reflections induced by vasoactive therapy will correlate with the improvement in exercise capacity, LV mass, fibrosis and diastolic function. Finally, we will assess whether the hemodynamic response to an acute dose of sublingual nitroglycerin (NTG) can predict the sustained changes in the reflected wave and other hemodynamic parameters in response to chronic vasodilator therapy.


Eligibility criteria: Inclusion Criteria:

1. Previous clinical diagnosis of heart failure with current New York Heart Association Class II-IV symptoms.
2. LV ejection fraction \>50% on a clinically indicated echocardiogram or ventriculogram within 12 months prior to consent, in the absence of a change in cardiovascular status, as assessed by the principal investigators.
3. Must have had at least one of the following within the 12 months prior to consent

   1. Hospitalization for decompensated HF
   2. Acute treatment for HF with intravenous loop diuretic or hemofiltration.
   3. Chronic treatment with a loop diuretic for control of HF symptoms.
   4. Chronic diastolic dysfunction on echocardiography as evidenced by left atrial enlargement or at least stage II diastolic dysfunction.
   5. Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.
4. Stable medical therapy as defined by:

   1. No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days.
   2. No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days.
   3. No change in diuretic dose for 10 days.

Exclusion Criteria:

1. Rhythm other than sinus rhythm (i.e., atrial fibrillation).
2. Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from walking in a hallway.
3. Non-cardiac condition limiting life expectancy to less than one year, per physician judgment.
4. Current or anticipated future need for nitrate therapy.
5. Valve disease (\> mild aortic or mitral stenosis; \> moderate aortic or mitral regurgitation).
6. Hypertrophic cardiomyopathy.
7. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
8. Pericardial disease.
9. Primary pulmonary arteriopathy.
10. Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent.
11. Other clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease.
12. Systolic blood pressure \< 110 mmHg or \> 180 mm Hg.
13. Diastolic blood pressure \< 40 mmHg or \> 100 mmHg.
14. Resting heart rate (HR) \> 100 bpm.
15. A history of reduced ejection fraction (EF\<50%).
16. Severe renal dysfunction (estimated GFR \<30 ml/min/1.73m2 by modified MDRD equation) GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units), which would impede the safe administration of gadolinium for MRI studies contrast.
17. Hemoglobin \<10 g/dL.
18. Patients with known severe liver disease (AST \> 3x normal, alkaline phosphatase or bilirubin \> 2x normal).
19. Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
20. Listed for cardiac transplantation.
21. Allergy to isosorbide dinitrate or hydralazine.
22. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension.
23. We will also exclude patients who are not suitable candidates for a cardiac MRI by virtue of having the following absolute or relative contraindications: (i) Central nervous system aneurysm clips; (ii) Implanted neural stimulators; (iii) Implanted cardiac pacemaker or defibrillator; (iv) Cochlear implant; (v) Ocular foreign body (e.g. metal shavings); (vi) Other implanted medical devices: (e.g. drug infusion ports); (vii) Insulin pump; (viii) Metal shrapnel or bullet; (ix) Claustrophobia; (x) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (xi) Unwillingness of the patient to undergo a cardiac MRI. All patients with metallic implants will be individually evaluated prior to MRI.

Primary outcomes:
measure: Wave Reflection Magnitude
timeFrame: 24 weeks
Secondary outcomes:
measure: LV Mass
timeFrame: 24 weeks
measure: Quality of Life (Kansas City Cardiomyopathy Questionnaire Score)
timeFrame: 24 weeks
measure: Early Diastolic Mitral Annular Velocity
timeFrame: 24 weeks
measure: Myocardial Extracellular Volume Fraction
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Philadelphia VA Medical Center
state: Pennsylvania
Study officials:
affiliation: Philadelphia VA Medical Center & University of Pennsylvania
name: Julio A Chirinos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bhuiyan T, Maurer MS. Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma. Curr Cardiovasc Risk Rep. 2011 Oct;5(5):440-449. doi: 10.1007/s12170-011-0184-2.
citation: Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 1: pressure and flow measurements and basic principles of wave conduction and reflection. Hypertension. 2010 Oct;56(4):555-62. doi: 10.1161/HYPERTENSIONAHA.110.157321. Epub 2010 Aug 23.
citation: Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 2: arterial pressure-flow and pressure-volume relations in humans. Hypertension. 2010 Oct;56(4):563-70. doi: 10.1161/HYPERTENSIONAHA.110.157339. Epub 2010 Aug 23.
citation: Endo H, Shiraishi H, Yanagisawa M. Afterload reduction by hydralazine in children with a ventricular septal defect as determined by aortic input impedance. Cardiovasc Drugs Ther. 1994 Feb;8(1):161-6. doi: 10.1007/BF00877105.
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citation: Downing GJ, Maulik D, Phillips C, Kadado TR. In vivo correlation of Doppler waveform analysis with arterial input impedance parameters. Ultrasound Med Biol. 1993;19(7):549-59. doi: 10.1016/0301-5629(93)90078-3.
citation: Elkayam U, Bitar F. Effects of nitrates and hydralazine in heart failure: clinical evidence before the african american heart failure trial. Am J Cardiol. 2005 Oct 10;96(7B):37i-43i. doi: 10.1016/j.amjcard.2005.07.031. Epub 2005 Aug 9.
citation: Brooks D, Solway S, Gibbons WJ. ATS statement on six-minute walk test. Am J Respir Crit Care Med. 2003 May 1;167(9):1287. doi: 10.1164/ajrccm.167.9.950. No abstract available.
citation: Chirinos JA, Bhattacharya P, Kumar A, Proto E, Konda P, Segers P, Akers SR, Townsend RR, Zamani P. Impact of Diabetes Mellitus on Ventricular Structure, Arterial Stiffness, and Pulsatile Hemodynamics in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2019 Feb 19;8(4):e011457. doi: 10.1161/JAHA.118.011457.
citation: Zamani P, Akers S, Soto-Calderon H, Beraun M, Koppula MR, Varakantam S, Rawat D, Shiva-Kumar P, Haines PG, Chittams J, Townsend RR, Witschey WR, Segers P, Chirinos JA. Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2017 Feb 20;6(2):e004262. doi: 10.1161/JAHA.116.004262.