Rajiv Agarwal1, Patrick Rossignol2, Alain Romero3, Dahlia Garza4, Martha R Mayo4, Suzette Warren4, Jia Ma5, William B White6, Bryan Williams7. 1. Department of Medicine, Division of Nephrology, Indiana University and Richard L Roudebush VA Medical Center, Indianapolis, IN, USA. Electronic address: ragarwal@iu.edu. 2. University of Lorraine, Institut National de la Santé et de la Recherche Médicale (Inserm) 1433 CIC-P CHRU de Nancy, Inserm U1116 and French Clinical Research Infrastructure Network INI-CRCT, Nancy, France. 3. Medical Affairs, Relypsa, a Vifor Pharma Group Company, Redwood City, CA, USA. 4. Clinical Development, Relypsa, a Vifor Pharma Group Company, Redwood City, CA, USA. 5. Biometrics, Relypsa, a Vifor Pharma Group Company, Redwood City, CA, USA. 6. Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT, USA. 7. Institute of Cardiovascular Sciences University College London (UCL) and National Institute for Health Research UCL/UCL Hospitals Biomedical Research Centre, London, UK.
Abstract
BACKGROUND: Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. METHODS: In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. FINDINGS: Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. INTERPRETATION: In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. FUNDING: Relypsa, a Vifor Pharma Group Company.
BACKGROUND: Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. METHODS: In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. FINDINGS: Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. INTERPRETATION: In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. FUNDING: Relypsa, a Vifor Pharma Group Company.
Authors: Anand Vaidya; Jenifer M Brown; Robert M Carey; Mohammed Siddiqui; Gordon H Williams Journal: Ann Intern Med Date: 2020-10-20 Impact factor: 25.391
Authors: Ahmed M Shaman; Brendan Smyth; Clare Arnott; Suetonia C Palmer; Anastasia S Mihailidou; Meg J Jardine; Martin P Gallagher; Vlado Perkovic; Min Jun Journal: Clin J Am Soc Nephrol Date: 2020-07-16 Impact factor: 8.237