Clinical trial NCT02343393: Nitrates In Combination With Hydralazine in cardiorEnal Syndrome (NICHE) Study
Official title: Nitrates In Combination With Hydralazine in cardiorEnal Syndrome (NICHE) Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Cardio-Renal Syndrome
Keywords: Endothelial Dysfunction
Biomarkers
Hydralazine-Isosorbide Dinitrate
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: Singapore Clinical Research Institute
name: Changi General Hospital
name: National Heart Centre Singapore
First posted: 2015-01-22
Enrollment: 100
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a single-blind, randomised, clinical trial assessing the efficacy of Hydralazine and Isosorbidedinitrate combination (oral agents) in HF patients with renal dysfunction.

Detailed description: Cardiorenal syndrome (CRS), where renal failure and heart failure (HF) co-exist in a vicious cycle, is a very common problem of great morbidity and mortality. The management of CRS is challenging as therapeutic options are mutually contradictory and largely empirical.

Endothelial dysfunction from oxidative injury has recently emerged as a common link between the failing heart and kidneys in CRS. The endothelium plays an obligatory role in cardiovascular homeostasis, and impaired endothelium-mediated nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction. There is a high prevalence of endothelial dysfunction in our Asian HF patients, with a greater degree of dysfunction seen in those with CRS. We hypothesise that targeting endothelial dysfunction may improve clinical status among Asian patients with CRS.

Isosorbide dinitrate (ISDN) increases NO bioavailability. Concomitant hydralazine (H) therapy prevents nitrate tolerance and protects NO from oxidative stress-induced degradation. The synergistic combination of H-ISDN is thought to exert beneficial effects on the endothelium.

We aim to perform a prospective randomised controlled trial to assess the effect of H-ISDN therapy for 6 months on exercise capacity, endothelial function, renal function, clinical outcomes and quality of life (QOL) in Asian patients with CRS. Specifically, we hypothesise that H-ISDN therapy will lead to improvement in exercise capacity (6 minute walk test (6MWT)), endothelial dysfunction (assessed by non-invasive peripheral arterial tonometry(PAT)), renal function, cardiac structure and function, clinical outcomes (all-cause mortality, HF hospitalisations) and QOL in Asian patients with CRS.

Eligibility criteria: Inclusion Criteria:

1. At least 21 years of age
2. Asian patients with symptomatic HF (regardless of EF) and renal impairment (eGFR\<60ml/min/1.73m2)
3. At least one hospitalisation for HF during the preceeding year
4. On stable (at least 1 month) optimal medical therapy (maximum tolerated doses of ACE inhibitors or ARBs, beta blockers and aldosterone antagonists for HFREF, and optimally managed cardiovascular risk factors for HFPEF)
5. Able to complete 6 minute walk test (6MWT)
6. Able to maintain a systolic blood pressure ≥100mmHg
7. Able to provide written informed consent

Exclusion Criteria:

1. On chronic therapy with hydralazine and/or nitrates.
2. Known hypersensitivity to hydralazine and/or nitrates
3. Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors
4. Females who are pregnant, nursing, or of childbearing potential and not practising effective contraception
5. Have had acute myocardial infarction, unstable or stable angina pectoris, or a cerebrovascular accident within the last 3 months
6. Have had cardiac revascularisation within the last 3 months or are likely to require coronary revascularisation within the study period
7. Have had cardiac arrest or life-threatening ventricular arrhythmia requiring intervention within 3 months
8. Rapidly deteriorating HF (2 admissions for acute decompensated HF, not due to non-compliance, within 6 months)
9. eGFR\< 15ml/min/1.73m2, or on regular dialysis, or planned dialysis within the study period
10. Serious medical condition, emergency condition, uncontrolled systemic disease or any other medical condition that, in the judgement of the investigator, prohibits the patient from entering or potentially completing the study
11. Planned participation in any other interventional study or having received trial medication in the last 4 weeks within a clinical trial

Primary outcomes:
measure: Effort tolerance by assessing 6 Minute Walk Test (6MWT)
timeFrame: 24 weeks
Secondary outcomes:
measure: Endothelial function as measured via a reactive hyperaemic index (RHI) by Peripheral Arterial Tonometry (PAT)
timeFrame: 24 weeks
measure: Renal function (eGFR, Cystatin C, markers of kidney injury (proteinuria as quantified by urine protein-creatinine ratio (uPCR), NGAL))
timeFrame: 24 weeks
measure: Cardiac structure and function by 2D and Doppler echocardiography
timeFrame: 24 weeks
measure: Quality of Life by self-reported 36-item Short Form Health Survey (SF-36)
timeFrame: 24 weeks
measure: Clinical outcomes by recording deaths and HF hospitalisations
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital, Singapore
city: Singapore
country: Singapore
facility: National Heart Centre Singapore
city: Singapore
country: Singapore
facility: Changi General Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Su Ping Carolyn Lam, MBBS, MRCP, MS
role: STUDY_CHAIR
References: