Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Background Chronic kidney disease (CKD) is a long‐term condition that occurs as a result of damage to the kidneys. Early recognition of CKD is becoming increasingly common due to widespread laboratory estimated glomerular filtration rate (eGFR) reporting, raised clinical awareness, and international adoption of the Kidney Disease Improving Global Outcomes (KDIGO) classifications. Early recognition and management of CKD affords the opportunity to prepare for progressive kidney impairment and impending kidney replacement therapy and for intervention to reduce the risk of progression and cardiovascular disease. Angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are two classes of antihypertensive drugs that act on the renin‐angiotensin‐aldosterone system. Beneficial effects of ACEi and ARB on kidney outcomes and survival in people with a wide range of severity of kidney impairment have been reported; however, their effectiveness in the subgroup of people with early CKD (stage 1 to 3) is less certain. This is an update of a review that was last published in 2011. Objectives To evaluate the benefits and harms of ACEi and ARB or both in the management of people with early (stage 1 to 3) CKD who do not have diabetes mellitus (DM). Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 6 July 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and Embase, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) reporting the effect of ACEi or ARB in people with early (stage 1 to 3) CKD who did not have DM were selected for inclusion. Only studies of at least four weeks duration were selected. Authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria. Data collection and analysis Data extraction was carried out by two authors independently, using a standard data extraction form. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross‐checked by another. When more than one study reported similar outcomes, data were pooled using the random‐effects model. Heterogeneity was analysed using a Chi² test and the I² test. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach Main results Six studies randomising 9379 participants with CKD stages 1 to 3 (without DM) met our inclusion criteria. Participants were adults with hypertension; 79% were male from China, Europe, Japan, and the USA. Treatment periods ranged from 12 weeks to three years. Overall, studies were judged to be at unclear or high risk of bias across all domains, and the quality of the evidence was poor, with GRADE rated as low or very low certainty. In low certainty evidence, ACEi (benazepril 10 mg or trandolapril 2 mg) compared to placebo may make little or no difference to death (any cause) (2 studies, 8873 participants): RR 2.00, 95% CI 0.26 to 15.37; I² = 76%), total cardiovascular events (2 studies, 8873 participants): RR 0.97, 95% CI 0.90 to 1.05; I² = 0%), cardiovascular‐related death (2 studies, 8873 participants): RR 1.73, 95% CI 0.26 to 11.66; I² = 54%), stroke (2 studies, 8873 participants): RR 0.76, 95% CI 0.56 to 1.03; I² = 0%), myocardial infarction (2 studies, 8873 participants): RR 1.00, 95% CI 0.84 to 1.20; I² = 0%), and adverse events (2 studies, 8873 participants): RR 1.33, 95% CI 1.26 to 1.41; I² = 0%). It is uncertain whether ACEi (benazepril 10 mg or trandolapril 2 mg) compared to placebo reduces congestive heart failure (1 study, 8290 participants): RR 0.75, 95% CI 0.59 to 0.95) or transient ischaemic attack (1 study, 583 participants): RR 0.94, 95% CI 0.06 to 15.01; I² = 0%) because the certainty of the evidence is very low. It is uncertain whether ARB (losartan 50 mg) compared to placebo (1 study, 226 participants) reduces: death (any‐cause) (no events), adverse events (RR 19.34, 95% CI 1.14 to 328.30), eGFR rate of decline (MD 5.00 mL/min/1.73 m2, 95% CI 3.03 to 6.97), presence of proteinuria (MD ‐0.65 g/24 hours, 95% CI ‐0.78 to ‐0.52), systolic blood pressure (MD ‐0.80 mm Hg, 95% CI ‐3.89 to 2.29), or diastolic blood pressure (MD ‐1.10 mm Hg, 95% CI ‐3.29 to 1.09) because the certainty of the evidence is very low. It is uncertain whether ACEi (enalapril 20 mg, perindopril 2 mg or trandolapril 1 mg) compared to ARB (olmesartan 20 mg, losartan 25 mg or candesartan 4 mg) (1 study, 26 participants) reduces: proteinuria (MD ‐0.40, 95% CI ‐0.60 to ‐0.20), systolic blood pressure (MD ‐3.00 mm Hg, 95% CI ‐6.08 to 0.08) or diastolic blood pressure (MD ‐1.00 mm Hg, 95% CI ‐3.31 to 1.31) because the certainty of the evidence is very low. Authors' conclusions There is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have DM. The available evidence is overall of very low certainty and high risk of bias. We have identified an area of large uncertainty for a group of patients who account for most of those diagnosed as having CKD.