Fourth-Line Treatment in Resistant Hypertension After QUADRO: Comparative Evidence, Single-Pill Strategies, and Clinical Selection

Background: Low-dose spironolactone is the preferred fourth-line treatment for resistant hypertension, but hyperkalemia, renal dysfunction, endocrine adverse effects, and monitoring requirements limit its use. The QUADRO trial provides new evidence for a bisoprolol-containing quadruple single-pill combination (SPC). Methods: This narrative review with an expert-viewpoint component is based on a focused PubMed/MEDLINE and Scopus search (January 2000–September 2026), earlier landmark studies, and current guidelines. Results: In PATHWAY-2, spironolactone lowered home systolic blood pressure (BP) by 8.70 mmHg versus placebo and by 4.48 mmHg versus bisoprolol. In QUADRO (n = 183), perindopril/indapamide/amlodipine/bisoprolol lowered office and 24-h systolic BP by a further 8.0 and 7.5 mmHg versus continued triple therapy at 8 weeks, with office BP control in 66% versus 43% of patients. QUADRO had no spironolactone comparator, matched tablet burden between groups, excluded patients already receiving beta-blockers, and did not test an adherence advantage or cardiovascular and renal outcomes. The proposed framework confirms true resistance, optimizes background therapy, weighs renal function, potassium, comorbidities, tolerability, and monitoring capacity, and separates drug-class selection from formulation choice. Conclusions: Spironolactone remains the preferred fourth-line agent for most eligible patients. The quadruple SPC is a complementary option when all components and fixed doses are appropriate, chiefly when spironolactone is unsuitable; its use in patients with established beta-blocker indications is an extrapolation. Head-to-head trials are needed.