CompletedNCT01516346Updated Jun 21, 2022Results posted

Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction

A Phase 2 interventional study of Isosorbide Dinitrate and Isosorbide Dinitrate + Hydralazine in Heart Failure and Congestive Heart Failure, sponsored by Corporal Michael J. Crescenz VA Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-06-21.

Sponsored by Corporal Michael J. Crescenz VA Medical Center · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 44
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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 studied

Heart Failure
Congestive Heart Failure

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Heart Failure 5,701

Keywords

Heart Failure
Heart failure with preserved ejection fraction (HFpEF)
Vasodilators
Isosorbide dinitrate
Hydralazine
wave reflections
arterial stiffness
hemodynamics

In context

Heart Failure

5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.

This study's enrollment of 44 is below the median of 72 across 3,736 interventional studies indexed under Heart Failure.

Browse Heart Failure studies →

Lead sponsor

Corporal Michael J. Crescenz VA Medical Center is the lead sponsor of 18 studies on the registry; 2 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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
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.
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

Exclusion Criteria:

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%).
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.
Hemoglobin \<10 g/dL.
Patients with known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal).
Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
Listed for cardiac transplantation.
Allergy to isosorbide dinitrate or hydralazine.
Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension.
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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 44 participants (actual)

Study arms

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
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
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

Interventions

DrugIsosorbide 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.
DrugIsosorbide 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.
DrugPlacebo
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.

What researchers measure

Primary outcomes

Wave Reflection Magnitude
The dimensionless ratio of backward (reflected) to forward wave amplitude. Higher values imply more wave reflection.
Time frame: 24 weeks

Secondary outcomes

LV Mass
LV mass measured by MRI, in grams normalized to height in meters raised to the 1.7 power (m\^1.7)
Time frame: 24 weeks
Quality of Life (Kansas City Cardiomyopathy Questionnaire Score)
Quality of life, assessed with the Kansas City cardiomyopathy questionnaire (overall summary score, which ranges from 0 to 100). Higher values imply better quality of life.
Time frame: 24 weeks
Early Diastolic Mitral Annular Velocity
Diastolic mitral annular velocity measured at the basal septal mitral annulus
Time frame: 24 weeks
Myocardial Extracellular Volume Fraction
Myocardial extracellular volume, expressed as percent of total tissue volume, measured by MRI (T1 mapping pre and post-gadolinium administration)
Time frame: 24 weeks

Results

Posted Jun 21, 2022

Participant flow

Participant flow — Overall Study
Milestone	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Started	13	15	16
Completed	7	9	11
Not completed	6	6	5

Outcome measures

PrimaryWave Reflection Magnitude

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

Time frame:: 24 weeks
Reported as:: Mean · dimensionless ratio

Wave Reflection Magnitude
dimensionless ratio	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Wave Reflection Magnitude	0.38 (0.33 to 0.43)	0.44 (0.37 to 0.51)	0.37 (0.31 to 0.43)

SecondaryLV Mass

LV mass measured by MRI, in grams normalized to height in meters raised to the 1.7 power (m\^1.7)

Time frame:: 24 weeks
Reported as:: Mean · grams / meters ^1.7

LV Mass
grams / meters ^1.7	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
LV Mass	68.2 (60 to 76.3)	66.2 (61.4 to 71.1)	67.2 (62.8 to 71.5)

SecondaryQuality of Life (Kansas City Cardiomyopathy Questionnaire Score)

Quality of life, assessed with the Kansas City cardiomyopathy questionnaire (overall summary score, which ranges from 0 to 100). Higher values imply better quality of life.

Time frame:: 24 weeks
Reported as:: Mean · Points on a scale

Quality of Life (Kansas City Cardiomyopathy Questionnaire Score)
Points on a scale	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Quality of Life (Kansas City Cardiomyopathy Questionnaire Score)	62.1 (51.1 to 73.1)	44.9 (37.1 to 62.7)	62.1 (50.8 to 73.1)

SecondaryEarly Diastolic Mitral Annular Velocity

Diastolic mitral annular velocity measured at the basal septal mitral annulus

Time frame:: 24 weeks
Reported as:: Mean · cm/s

Early Diastolic Mitral Annular Velocity
cm/s	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Early Diastolic Mitral Annular Velocity	6.8 (5.5 to 8.0)	7.3 (6.1 to 8.6)	6.5 (5.4 to 7.6)

SecondaryMyocardial Extracellular Volume Fraction

Myocardial extracellular volume, expressed as percent of total tissue volume, measured by MRI (T1 mapping pre and post-gadolinium administration)

Time frame:: 24 weeks
Reported as:: Mean · Percentage

Myocardial Extracellular Volume Fraction
Percentage	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Myocardial Extracellular Volume Fraction	29.0 (25.0 to 33.0)	31.3 (29.2 to 33.4)	29.5 (26.4 to 32.6)

Adverse events

Collected over 24 weeks. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Isosorbide Dinitrate	0/13 (0%)	3/13 (23.1%)	8/13 (61.5%)
Isosorbide Dinitrate + Hydralazine	0/15 (0%)	3/15 (20%)	9/15 (60%)
Placebo	0/16 (0%)	1/16 (6.3%)	1/16 (6.3%)

Most frequent serious events

Most frequent serious events
Event	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
Hospital AdmissionInvestigations	3/13	3/15	1/16

Most frequent other events

Most frequent other events
Event	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo
HeadacheGeneral disorders	4/13	2/15	1/16
HypotensionGeneral disorders	1/13	3/15	0/16
Dizziness/LightheadednessGeneral disorders	2/13	2/15	0/16
OrthostasisGeneral disorders	1/13	2/15	0/16
GI SymptomsGastrointestinal disorders	0/13	1/15	0/16
FatigueGeneral disorders	0/13	1/15	0/16

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo	Total
Median	61 (56 to 65)	60 (55 to 66)	66.5 (59.5 to 72)	62 (59 to 68)

Sex: Female, Male
Sex: Female, Male(Participants)	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo	Total
Female	5	4	4	13
Male	8	11	12	31

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo	Total
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	8	10	9	27
White	4	5	7	16
More than one race	0	0	0	0
Unknown or Not Reported	1	0	0	1

Region of Enrollment
Region of Enrollment(participants)	Isosorbide Dinitrate	Isosorbide Dinitrate + Hydralazine	Placebo	Total
United States	13	15	16	44

Study locations

1 site

Philadelphia VA Medical Center
Philadelphia, Pennsylvania 19104, United States

References and documents

Publications

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. PubMed 22081782 ↗
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. PubMed 20733089 ↗
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. PubMed 20733088 ↗
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. PubMed 8086327 ↗
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. PubMed 15752371 ↗
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. PubMed 12558614 ↗
Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003 Dec 15;68(12):2393-8. PubMed 14705758 ↗
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. PubMed 8310551 ↗
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. PubMed 16226934 ↗
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. PubMed 12714344 ↗
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. PubMed 30764699 ↗
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. PubMed 28219917 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jun 21, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01516346
Lead sponsor: Corporal Michael J. Crescenz VA Medical Center
Collaborators: University of Pennsylvania, National Institute on Aging (NIA)
Responsible party: Julio A.Chirinos (Director of non-invasive imaging and Assistant Professor of Medicine, Corporal Michael J. Crescenz VA Medical Center) — Principal investigator
First posted: Jan 24, 2012
Start date: Jan 2012
Primary completion: Feb 5, 2016
Completion: Aug 18, 2017
Results posted: Jun 21, 2022
Last update: Jun 21, 2022

Study contacts

Julio A Chirinos, MD, PhD

principal investigator · Philadelphia VA Medical Center & University of Pennsylvania

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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