Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction

NCT01516346 | Completed Phase 2 Results

• 2 other identifiers: 013405R21AG043802-02
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Wave Reflection Magnitude

  The dimensionless ratio of backward (reflected) to forward wave amplitude. Higher values imply more wave reflection.

  24 weeks

Secondary Outcomes (4)

• LV Mass

  24 weeks

• Quality of Life (Kansas City Cardiomyopathy Questionnaire Score)

  24 weeks

• Early Diastolic Mitral Annular Velocity

  24 weeks

• Myocardial Extracellular Volume Fraction

  24 weeks

Study Arms (3)

Isosorbide dinitrate

ACTIVE COMPARATOR

Research pharmacy-formulated capsules will be given to the subjects in two bottles. For this interventional arm, one of the bottles will contain the active ingredient Isosorbide Dinitrate and the other will contain placebo capsules. Dosage of Isosorbide Dinitrate will be 20mg (if Stage 1) OR 40mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.

Drug: Isosorbide Dinitrate

Isosorbide dinitrate + Hydralazine

ACTIVE COMPARATOR

Research pharmacy-formulated capsules will be given to the subjects in two bottles. For this interventional arm, one of the bottles will contain the active ingredient Isosorbide Dinitrate and the other will contain the active ingredient Hydralazine. Dosage of Isosorbide Dinitrate will be 20mg (if Stage 1) OR 40mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks. Dosage of Hydralazine will be 37.5mg (if Stage 1) OR 75mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily, to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.

Drug: Isosorbide Dinitrate + Hydralazine

Placebo

PLACEBO COMPARATOR

Research pharmacy-formulated capsules will be given to subjects in two bottles. For this interventional arm, both the bottles will contain placebo capsules. Dosage will be same regardless of up-titration from Stage 1 dosing to Stage 2 dosing. Frequency is three times daily, to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.

Drug: Placebo

Interventions

Isosorbide Dinitrate DRUG

Enrolled subjects will be randomized in a blinded fashion to 1 isosorbide dinitrate capsule TID + 1 placebo capsule TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs. Subjects receiving isosorbide dinitrate will be given 20mg PO q8am, 2pm, and 8pm and will be titrated up to 40mg PO q8am, 2pm, and 8pm.

Isosorbide dinitrate

Isosorbide Dinitrate + Hydralazine DRUG

Enrolled subjects will be randomized in a blinded fashion to 1 isosorbide dinitrate capsule TID + 1 hydralazine capsule TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs. Subjects receiving isosorbide dinitrate will be given 20mg PO q8am, 2pm, and 8pm and will be titrated up to 40mg PO q8am, 2pm, and 8pm. Subjects receiving hydralazine will be given 37.5mg PO q8am, 2pm, and 8pm and will be titrated up to 75mg PO q8am, 2pm, and 8pm.

Isosorbide dinitrate + Hydralazine

Placebo DRUG

Enrolled subjects will be randomized in a blinded fashion to 2 placebo capsules TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Previous clinical diagnosis of heart failure with current New York Heart Association Class II-IV symptoms.
• 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.
• Must have had at least one of the following within the 12 months prior to consent
• Hospitalization for decompensated HF
• Acute treatment for HF with intravenous loop diuretic or hemofiltration.
• Chronic treatment with a loop diuretic for control of HF symptoms.
• Chronic diastolic dysfunction on echocardiography as evidenced by left atrial enlargement or at least stage II diastolic dysfunction.
• 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.
• Stable medical therapy as defined by:
• No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days.
• No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days.
• No change in diuretic dose for 10 days.

You may not qualify if:

• Rhythm other than sinus rhythm (i.e., atrial fibrillation).
• Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from walking in a hallway.
• Non-cardiac condition limiting life expectancy to less than one year, per physician judgment.
• Current or anticipated future need for nitrate therapy.
• Valve disease (\> mild aortic or mitral stenosis; \> moderate aortic or mitral regurgitation).
• Hypertrophic cardiomyopathy.
• Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
• Pericardial disease.
• Primary pulmonary arteriopathy.
• 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.
• 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.
• Systolic blood pressure \< 110 mmHg or \> 180 mm Hg.
• Diastolic blood pressure \< 40 mmHg or \> 100 mmHg.
• Resting heart rate (HR) \> 100 bpm.
• A history of reduced ejection fraction (EF\<50%).

Sponsors & Collaborators

• Corporal Michael J. Crescenz VA Medical Center: lead
• University of Pennsylvania: collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Philadelphia VA Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (12)

• 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.

  PMID: 22081782 BACKGROUND

• 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.

  PMID: 20733089 BACKGROUND

• 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.

  PMID: 20733088 BACKGROUND

• 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.

  PMID: 8086327 BACKGROUND

• Greig LD, Leslie SJ, Gibb FW, Tan S, Newby DE, Webb DJ. Comparative effects of glyceryl trinitrate and amyl nitrite on pulse wave reflection and augmentation index. Br J Clin Pharmacol. 2005 Mar;59(3):265-70. doi: 10.1111/j.1365-2125.2004.02334.x.

  PMID: 15752371 BACKGROUND

• Lind L, Pettersson K, Johansson K. Analysis of endothelium-dependent vasodilation by use of the radial artery pulse wave obtained by applanation tonometry. Clin Physiol Funct Imaging. 2003 Jan;23(1):50-7. doi: 10.1046/j.1475-097x.2003.00469.x.

  PMID: 12558614 BACKGROUND

• Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003 Dec 15;68(12):2393-8.

  PMID: 14705758 BACKGROUND

• 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.

  PMID: 8310551 BACKGROUND

• 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.

  PMID: 16226934 BACKGROUND

• 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.

  PMID: 12714344 BACKGROUND

• 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.

  PMID: 30764699 DERIVED

• 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.

  PMID: 28219917 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Isosorbide Dinitrate; Hydralazine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Isosorbide; Sorbitol; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates; Phthalazines; Pyridazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Julio Chirinos, MD, PhD
• Organization: University of Pennsylvania

julio.chirinos@pennmedicine.upenn.edu

215-573-6606

Study Officials

• Julio A Chirinos, MD, PhD

  Philadelphia VA Medical Center & University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of non-invasive imaging and Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 19, 2012
• First Posted: January 24, 2012
• Study Start: January 1, 2012
• Primary Completion: February 5, 2016
• Study Completion: August 18, 2017
• Last Updated: June 21, 2022
• Results First Posted: June 21, 2022

Record last verified: 2022-06

Locations

US (1)