Comparative Effectiveness of Spironolactone Versus Beta-Blockers as Fourth-Line Therapy in Resistant Hypertension: Impact on Albuminuria in a Real-World Setting

Objective: Spironolactone is recommended as the preferred fourth-line agent for resistant hypertension; however, evidence demonstrating reductions in hard cardiovascular outcomes with fourth-line antihypertensive strategies remains limited. Albuminuria is a key marker of hypertensive target-organ damage and an established predictor of cardiovascular and renal outcomes. We compared spironolactone with beta-blockers (atenolol or metoprolol) as fourth-line antihypertensive treatment with respect to microalbuminuria in patients with resistant hypertension. Design and method: We analyzed 3,478 hypertensive adults from a real-world clinical registry at a tertiary cardiology center with available albuminuria data. Patients treated with more than three antihypertensive drug classes were included. Those receiving spironolactone or a beta-blocker as the fourth antihypertensive agent constituted the analytic groups. The primary outcome was microalbuminuria. Multivariable logistic regression models were adjusted for age, sex, body mass index, systolic blood pressure, diabetes mellitus, number of antihypertensive drug classes, and renin–angiotensin system blockade. Prespecified subgroup analyses, renal safety models, and propensity score matching were performed. Results: Among 3,478 patients receiving more than three antihypertensive drug classes, 1,962 were treated with spironolactone and 1,516 with a beta-blocker as fourth-line therapy. Microalbuminuria was less frequent with spironolactone than with beta-blockers (25.5% vs 37.0%; p<0.001). Spironolactone was associated with lower adjusted odds of microalbuminuria (OR 0.61, 95% CI 0.44–0.83), independent of renin–angiotensin system blockade. Findings were consistent across subgroups, in propensity score–matched analyses (n=122 per group), and after exclusion of patients with eGFR <30 mL/min/1.73 m2. Conclusions: In this real-world registry-based sample, spironolactone used as fourth-line therapy was associated with a lower prevalence of microalbuminuria compared with beta-blockers. In the absence of cardiovascular outcome data for fourth-line antihypertensive strategies, these findings are consistent with current guideline recommendations and suggest potential renal benefits beyond blood pressure reduction.