SPIRONOLACTONE USE IN THE TREATMENT OF UNCONTROLLED AND TREATMENT-RESISTANT HYPERTENSION: A SYSTEMATIC LITERATURE REVIEW

Objectives: Spironolactone is recommended as a fourth-line treatment but is sometimes used off-label at earlier stages of hypertension management. This systematic literature review (SLR) aimed to understand the uptake, therapeutic effect and safety outcomes associated with spironolactone among uncontrolled hypertension (uHTN) and treatment-resistant hypertension (rHTN) cohorts, within real-world evidence (RWE) studies and randomised controlled trials (RCTs). Design and Methods: MEDLINE, Embase, CENTRAL, CDSR and DARE were searched in March 2024, supplemented by grey literature searches. Eligible articles reported incidence/prevalence, treatment, comorbidity, efficacy and safety data among patients with uHTN (systolic blood pressure >=130 mmHg with >=2 prior antihypertensives) or rHTN (systolic blood pressure >=130 mmHg with >=3 prior antihypertensives/achieved target blood pressure with >=4 prior antihypertensives) taking spironolactone. Methodological Standards for Epidemiological Research and Risk of Bias 2.0 tools were used to assess the quality of included studies. Results: This SLR included 12 RCTs and 25 RWE studies. RCTs showed a greater mean reduction in systolic blood pressure (SBP) with spironolactone compared with placebo (office SBP between-group difference range: 5.83–15.8 mmHg [p<0.001, n=1; p=0.011, n=1; p-value not reported, n=1]; 24-hour ambulatory SBP between-group difference range: 6.6–12.5 mmHg [p<0.05; n=3]). Blood pressure control was not widely reported in RWE studies. In RCTs, despite some overlap in values reported, hyperkalaemia may have occurred more frequently with spironolactone (0–26.7%) compared with comparators (0–8%; placebo, doxazosin, ramipril, bisoprolol or clonidine), while other adverse events (AEs; including dizziness and nausea/vomiting) were similar between arms (spironolactone, placebo, doxazosin, bisoprolol or clonidine). AEs were not well reported in RWE studies. Spironolactone treatment periods in RCTs ranged from 4 weeks–12 months, with dosage between 12.5–50 mg. Spironolactone use in RWE studies ranged from 1.7–49.3% among uHTN or rHTN patients (n=10) and 17.1–77.5% among rHTN hypertension who used >=5 antihypertensives (n=2). Conclusions: The use of spironolactone reported in RWE studies was lower than might be expected based on its blood pressure lowering effects seen in RCTs, suggesting a discrepancy between guidelines and clinical practice, potentially due to specific adverse events that can occur with spironolactone use, which require further real-world exploration.