Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: UK Heart and Renal Protection (UK HARP)-III. Rationale, trial design and baseline data

Journal article

Background: Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis.

Methods: UK Heart And Renal Protection (HARP)-III is a multicentre double-blind randomized controlled trial comparing sacubitril/valsartan 97/103 mg twice daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg once daily among 414 patients with CKD. Patients aged ≥18 years with an estimated glomerular filtration rate (eGFR) ≥45 <60 mL/min/1.73m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 <45 mL/min/1.73m2 (regardless of uACR) were invited to be screened. Following a 4-7 week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim is to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD.

Results: Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age was 63 years; 72% male.) Mean eGFR was 34.0 mL/min/1.73m2 and median uACR was 58.5 mg/mmol.

Conclusions UK HARP-III will provide important information on the short-term effects on renal function, tolerability and safety of sacubitril/valsartan among patients with CKD.

Authors: Haynes, R; Judge, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Nephrology, Dialysis and Transplantation
• Volume: 32
• Issue: 12
• Pages: 2043-2051
• Publication date: 2016-09-17
• Acceptance date: 2016-07-14
• DOI: 10.1093/ndt/gfw321
• ISSN: 0931-0509 and 1460-2385
• Keywords: cardiovascular disease; chronic kidney disease; neprilysin; progression