Abstract
BackgroundPatients 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.MethodsUK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 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 was 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.ResultsBetween 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 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol.ConclusionsUK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.
Highlights
Chronic kidney disease (CKD) affects between 2 and 17% of the general population [1, 2] and is associated with increased risks of progression to end-stage renal disease (ESRD) and morbidity and mortality from cardiovascular disease (CVD) [3, 4]
Renin–angiotensin system (RAS) inhibitors [angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs)] have been shown to reduce the risk of ESRD in patients with proteinuric chronic kidney disease (CKD) [5,6,7,8], but despite such treatments, patients remain at significant risk of progression to ESRD and CVD
Irbesartan 300 mg was selected as the comparator, as it has been shown to reduce the risk of ESRD among patients with diabetic kidney disease and is licensed for the treatment of proteinuric CKD [6, 21]
Summary
Chronic kidney disease (CKD) affects between 2 and 17% of the general population (depending on the country) [1, 2] and is associated with increased risks of progression to end-stage renal disease (ESRD) and morbidity and mortality from cardiovascular disease (CVD) [3, 4]. Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups.
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