Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Philadelphia Veterans Affairs Medical Center
Sponsor:
Collaborators:
University of Pennsylvania
Information provided by (Responsible Party):
Julio A.Chirinos, Philadelphia Veterans Affairs Medical Center
ClinicalTrials.gov Identifier:
NCT01516346
First received: January 19, 2012
Last updated: September 9, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Heart Failure
Congestive Heart Failure
Drug: Isosorbide Dinitrate
Drug: Isosorbide Dinitrate + Hydralazine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Organic Nitrates and Hydralazine on Wave Reflections and Left Ventricular Structure and Function in Heart Failure With Preserved Ejection Fraction

Resource links provided by NLM:


Further study details as provided by Philadelphia Veterans Affairs Medical Center:

Primary Outcome Measures:
  • The change in late systolic load from wave reflections between baseline and after 24 weeks of randomized therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The change in LV mass & collagen volume fraction measured by MRI; early mitral annular velocity, myocardial strain, 6-minute walk distance and NT-pro-BNP levels between baseline and after 24 weeks of randomized therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Change in quality of life [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 54
Study Start Date: January 2012
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Isosorbide dinitrate

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
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.
Active Comparator: Isosorbide dinitrate + Hydralazine

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
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.
Placebo Comparator: Placebo

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
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01516346

Contacts
Contact: Julio A Chirinos, MD, PhD 215-200-7779 julio.chirinos@uphs.upenn.edu

Locations
United States, Pennsylvania
Philadelphia VA Medical Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Julio A Chirinos, MD, PhD    215-823-5800 ext 6791    julio.chirinos@uphs.upenn.edu   
Principal Investigator: Julio A Chirinos, MD, PhD         
Sponsors and Collaborators
Philadelphia Veterans Affairs Medical Center
University of Pennsylvania
Investigators
Principal Investigator: Julio A Chirinos, MD, PhD Philadelphia VA Medical Center & University of Pennsylvania
  More Information

Publications:

Responsible Party: Julio A.Chirinos, Director of non-invasive imaging and Assistant Professor of Medicine, Philadelphia Veterans Affairs Medical Center
ClinicalTrials.gov Identifier: NCT01516346     History of Changes
Other Study ID Numbers: 01340
Study First Received: January 19, 2012
Last Updated: September 9, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by Philadelphia Veterans Affairs Medical Center:
Heart Failure
Heart failure with preserved ejection fraction (HFpEF)
Vasodilators
Isosorbide dinitrate
Hydralazine
wave reflections
arterial stiffness
hemodynamics

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Hydralazine
Isosorbide-5-mononitrate
Isosorbide Dinitrate
Vasodilator Agents
Isosorbide
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 26, 2014