Low-dose Spironolactone Combined with ACEIs/ARBs May Reduce Cardiovascular Events in Patients with CKD Stages 3b-5: A Nationwide Population-Based Cohort Study in Taiwan

Background: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly prescribed for hypertension and chronic kidney disease (CKD) management, but they can increase the risk of renal function deterioration and hyperkalaemia. Spironolactone, known for reducing cardiovascular events in CKD patients, faces limited use due to the risk of hyperkalaemia. This study evaluates the potential efficacy and complications of low-dose spironolactone as an adjunct therapy in patients with CKD stages 3b to 5 who are maintained on ACEIs or ARBs. Materials and methods: Hypertensive CKD patients (stages 3b-5) from Taiwan's National Health Insurance Research Database (2012-2016) were selected. Inverse probability treatment weighting (IPTW) was applied to balance baseline characteristics between patients treated with and without spironolactone. In this study, adherence to low-dose spironolactone (25 mg/day) was assessed using the medication possession ratio (MPR) over a continuous 3-month period within the first 12 months after initiation. Multivariate Cox regression models were used to compare clinical outcomes between two groups with MPR ≥80% and MPR <80%. The subgroup including poor adherence (MPR ≥40% and MPR <40%) was also evaluated. Results: Of the 2,623 advanced CKD patients on ACEIs/ARBs and spironolactone, 55.5% (n=1,456) had an MPR ≥80% over a median follow-up of 3.9 years. Post-IPTW, both groups were balanced. Patients with MPR ≥80% showed a lower risk of major adverse cardiovascular events (MACEs; aHR = 0.71, 95% CI = 0.57–0.89), nonfatal myocardial infarction (aHR = 0.54, 95% CI = 0.39–0.75), and heart failure hospitalization (aHR = 0.84, 95% CI = 0.72–0.98). No significant risk was observed for acute renal failure (aHR = 0.87, 95% CI = 0.75–1.02), chronic renal failure (aHR = 0.84, 95% CI = 0.71–1.00), or hyperkalaemia (aHR = 0.86, 95% CI = 0.69–1.07) in the MPR ≥80% group. Patients with MPR ≥40% also showed a lower risk of MACEs (aHR =0.78, 95% CI = 0.62-0.99) and nonfatal MI (aHR = 0.66, CI = 0.47– 0.93). Conclusion: In Taiwan, higher adherence to low-dose spironolactone (25 mg/day) in ACEI/ARB-treated patients with CKD stages 3b-5 may reduce cardiovascular disease risk without increasing the risk of renal failure or hyperkalaemia.