Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD (HIDE)

Mass General Brigham

Status and phase: Completed; Phase 4

Conditions: Chronic Hemodialysis (ESRD)

Treatments: Drug: Hydralazine/Isorsorbide Dinitrate; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02228408

DK100772-01

Details and patient eligibility

About

This study is a pilot study designed to compare the safety and cardiovascular effects of 26 weeks of combination hydralazine/isorsorbide dinitrate therapy with placebo therapy in patients receiving chronic hemodialysis.

The investigators hypothesize that treatment of chronic hemodialysis (ESRD) patients with a combination of hydralazine/isosorbide dinitrate compared with placebo is safe and that it will improve heart function as well blood flow/blood vessel supply.

Full description

Sixteen patients receiving maintenance hemodialysis will be randomized to 26 weeks of therapy with combination hydralazine/isosorbide dinitrate or placebo. Study medications will be titrated to goal dose during the first 4 weeks and maintained at goal dose (as tolerated) between weeks 4-26. A final study visit to assess symptoms after drug discontinuation will occur 4 weeks after drug discontinuation.

Study duration-Maximum of 32 weeks with 26 weeks of active therapy.

Efficacy Measures -Tissue Doppler echocardiography and myocardial perfusion scanning using radioactive NH3 PET will be assessed at weeks 0 and 26.

Safety Measures-Adverse events rates including inter- and intra-dialytic hypotension, ,cardiovascular death and gastrointestinal symptoms will be assessed throughout the duration of the study.

Enrollment: 17 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

1. Maintenance hemodialysis therapy for end-stage renal disease
2. Age 18-85 years
3. ≥ 90 days since dialysis initiation
4. Ability to provide informed consent
5. Pre-dialysis seated systolic blood pressure measurements must be ≥ 120 mm Hg in the 2 weeks before enrollment and on the day of randomization.

Exclusion Criteria

1. Serum potassium ≥6.5 mEq/L within 2 months prior to screening

2. Unscheduled dialysis for hyperkalemia within the 3 months prior to screening

3. Hypotension defined as pre-dialysis SBP <100 mm Hg (seated measurement) within 4 weeks prior to enrollment

4. Recurrent intra-dialytic hypotension, defined as systolic blood pressure <80 mm Hg during ≥3 dialysis sessions per 30-day rolling period or treatment for either hypotension or symptoms of hypotension if systolic blood pressure is < 100 mm Hg during ≥3 dialysis sessions per 30-day rolling period.

5. Mitral valve repair or replacement

6. Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging

7. Prior coronary artery bypass graft

8. Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 6 months

9. Expected survival < 6 months

10. Allergy to study medications (ISD, HY, adenosine/diprimidole)

11. Active use of sildenafil, vardenafil or tadalafil

12. History of severe aortic stenosis or other cause of LV outflow obstruction

13. Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test on the day of PET scan

14. Incarceration

15. Participation in another intervention study

16. Use of monoamine oxidase inhibitors

17. Contraindication to adenosine including

    • 2nd or 3rd degree heart block, sick sinus syndrome or symptomatic bradycardia (without a functioning pacemaker)
    • moderate or severe asthma
    • chronic obstructive pulmonary disease

18. Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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17 participants in 2 patient groups

Hydralazine/Isorsorbide Dinitrate

Experimental group

Description:

Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events. Allowable Dosage Forms: ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day

Treatment:

Drug: Hydralazine/Isorsorbide Dinitrate

Placebo

Active Comparator group

Description:

Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.

Treatment:

Drug: Placebo