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Nitrates In Combination With Hydralazine in cardiorEnal Syndrome (NICHE) Study

Information source: National University Hospital, Singapore
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cardio-Renal Syndrome

Intervention: Hydralazine (Drug); Isosorbide Dinitrate (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National University Hospital, Singapore

Official(s) and/or principal investigator(s):
Su Ping Carolyn Lam, MBBS, MRCP, MS, Study Chair, Affiliation: National University Hospital, Singapore

Overall contact:
Su Ping Carolyn Lam, MBBS, MRCP, MS, Email: carolyn_lam@nuhs.edu.sg


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

Clinical Details

Official title: Nitrates In Combination With Hydralazine in cardiorEnal Syndrome (NICHE) Study

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Effort tolerance by assessing 6 Minute Walk Test (6MWT)

Secondary outcome:

Endothelial function as measured via a reactive hyperaemic index (RHI) by Peripheral Arterial Tonometry (PAT)

Renal function (eGFR, Cystatin C, markers of kidney injury (proteinuria as quantified by urine protein-creatinine ratio (uPCR), NGAL))

Cardiac structure and function by 2D and Doppler echocardiography

Quality of Life by self-reported 36-item Short Form Health Survey (SF-36)

Clinical outcomes by recording deaths and HF hospitalisations

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.


Minimum age: 21 Years. Maximum age: N/A. Gender(s): Both.


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

Locations and Contacts

Su Ping Carolyn Lam, MBBS, MRCP, MS, Email: carolyn_lam@nuhs.edu.sg

Changi General Hospital, Singapore 529889, Singapore; Not yet recruiting
Kui Toh Gerard Leong, MBBS, MRCP, MS, Email: gerard_leong@cgh.com.sg
Kui Toh Gerard Leong, MBBS, MRCP, MS, Principal Investigator

National Heart Centre Singapore, Singapore 169609, Singapore; Not yet recruiting
Kheng Leng David Sim, MBBS, MRCP, MS, Email: david_sim@nhcs.com.sg
Kheng Leng David Sim, MBBS, MRCP, MS, Principal Investigator

National University Hospital, Singapore, Singapore 119228, Singapore; Recruiting
Shir Lynn Lim, MBBS, MRCP, MMed, Email: shir_lynn_lim@nuhs.edu.sg
Shir Lynn Lim, MBBS, MRCP, MMed, Principal Investigator

Additional Information

Starting date: January 2015
Last updated: January 15, 2015

Page last updated: August 23, 2015

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