Introduction: The optimal fourth-line drug therapy for resistant hypertension remains uncertain. We emulated a target trial of initiating spironolactone versus an alpha or beta blocker as an add-on therapy on blood pressure (BP) control in patients with resistant hypertension (RH). Methods: We emulated sequential trials for adults with resistant hypertension, defined as having a systolic BP > 130 mm Hg while concurrently on three classes of anti-hypertensive medication. We included patients in the Veterans Health Administration (VA) who met eligibility criteria between 2016 and 2022 who initiated one of three add-on medications for treatment of RH: spironolactone, an alpha-1 blocker, or a beta blocker. We applied inverse probability of treatment weights using >50 baseline covariates to approximate randomization. The outcome of interest was the difference in change in systolic BP from baseline to 6 months and baseline to 12 months between spironolactone and other drug classes, estimated through a weighted linear mixed effects model. Results: Among 918 adults who initiated spironolactone, 916 adults who initiated an alpha-1 blocker, and 3690 patients who initiated a beta blocker (mean age 67.6 years SD, 9.7, mean systolic BP 146.7 mm Hg SD, 13.1), the average duration of continuous treatment was 14.7 months (SD, 9.5), 11.7 months (SD, 9.8), and 15.8 (SD, 9.6) months respectively. The change in systolic BP from baseline to 6 and 12 months was 7 mm Hg (95% CI, 6, 8) and 9 mm Hg (8, 11) respectively for spironolactone; 6 mm Hg 5, 7 and 7 mm Hg 5, 8) for an alpha 1 blocker; and 5 mm Hg 4, 6 and 5 mm Hg 4, 6) for a beta blocker. The difference between change in systolic BP at 12 months between spironolactone versus an alpha-1 blocker or beta blockers was significantly larger for spironolactone at 12 months (vs alpha-1 blockers, 3 mm Hg 1, 5; vs beta blockers, 3 mm Hg 2, 5). Conclusions: Spironolactone was more effective add-on fourth-line therapy for systolic BP lowering in the treatment of RH, supporting findings from PATHWAY-2 in a larger population with more comorbidity.
Li et al. (Tue,) studied this question.