Clinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial
Authors: Deepak Bhatnagar
BiCARB study group
Petra Rauchhaus
Gwen Kennedy
Roberta Littleford
Peter T Donnan
Biswa Mishra
Gowrie Balasubramaniam
Paul McNamee
Margaret Band
Philip A Kalra
Kolitha Basnayake
Sandip Mitra
Deepa Sumukadas
Aimun Ahmed
Georgia Winnett
Deirdre Plews
Geeta Hampson
Wai Tse
Johann Nicholas
Neill Duncan
Stewart Lambie
Anthony Chan
Martin Wilkie
Graham Warwick
Adam Kirk
Michael K Almond
Edmund J Lamb
Huey Yi Chong
May Khei Hu
Alison Avenell
Miles D Witham
Roy L Soiza
Paul E Stevens
Journal: BMC Medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Acidosis; Randomised controlled trial; Renal insufficiency, chronic; Sodium bicarbonate.

Abstract:  Background: Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations &lt; 22 mmol/L. Methods: Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of &lt; 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration &lt; 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained. Results: We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect - 0.4 (95% CI - 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI - 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). Conclusions: Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. Trial registration: European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012. 

Retracted: No

PubPeer comments:
 ### BiCARB: No benefit from sodium bicarbonate in patients with advanced chronic kidney disease Metabolic acidosis occurs in more than 20% of all patients with chronic kidney disease (CKD) and is associated with a worse course of the disease according to observational studies. Its prevalence increases with increasing impairment of kidney function. Current guidelines for the therapy of CKD recommend treatment with oral sodium bicarbonate from serum bicarbonate levels 22 mmol L. The double-blind, multicenter, randomized controlled BiCARB study investigated the treatment with sodium bicarbonate vs. placebo in a total of 300 patients u226560 years with advanced CKD (eGFR 30 mL min 1.73m2). Patients on hemodialysis were excluded. The primary endpoint was physical function at 12 months, measured with the Short Physical Performance Battery (SPPB). Secondary endpoints included quality of life, renal function, biomarkers and therapy-associated adverse events. For sodium bicarbonate, none of these prespecified outcomes showed a benefit. In the intervention group, especially gastrointestinal and cardiovascular side effects were significantly more frequent (acute coronary syndrome myocardial infarction; 10 vs. 2). The quality of life deteriorated, costs of therapy were increased. The results remained stable even after subgroup analyses. There was a high dropout rate of 38% after 12 months, caused by death, disease progression or withdrawal of willingness to participate in the study after the start of haemodialysis. The increase in serum bicarbonate levels in the intervention group was moderate overall (+1.7 mmol L after 3 months; 95% CI 1.0-2.4; p 0.001; no further significant after 24 months). This may be due to the pragmatic study design, which should reflect the real dosage behaviour of British nephrologists: In the intervention group, only up to a maximum of 3 g sodium bicarbonate was dosed. The authors discussed that a  treat-to-target approach could only further increase the risk of side effects as well as the exposure to polypharmacy in older patients. ,