Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction
Condition: Heart Failure; Congestive Heart Failure
MeSH terms: Heart Failure
Intervention: Isosorbide Dinitrate; Isosorbide Dinitrate + Hydralazine; Placebo
Intervention description: 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.; 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.; 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.
Intervention MeSH terms: Hydralazine; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 44.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Heart Failure; Heart failure with preserved ejection fraction (HFpEF); Vasodilators; Isosorbide dinitrate; Hydralazine; wave reflections; arterial stiffness; hemodynamics

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.