Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension

Abstract

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007–2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50–1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78–5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69–15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34–1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension

“…Finally, and most importantly, outcome RCTs in resistant hypertension are lacking. A recent real-world-evidence study in the United States included a total of 80 598 patients with resistant hypertension and compared the effectiveness of newly prescribed MRA treatment (6626 patients, 98% of whom were spironolactone users) with newly prescribed BB treatment (73 972 patients) as fourth line drugs [750]. In propensity score matched analysis, a 23% nonsignificant (95% CI 0.50– 1.19) reduction in favor of spironolactone for the combined primary outcome of stroke and myocardial infarction was found.…”

Efficacy of pharmacological and interventional treatment for resistant hypertension-a network meta-analysis

“…One major safety concern in MRA therapy is hyperkalemia, especially in patients with impaired renal function and/or with concomitant RAAS blockade. A recent published retrospective cohort study indicated that initiation of an MRA for resistant hypertension substantially increased the risk of hyperkalemia (57). Especially in CKD patients, hyperkalemia may restrict the access to MRA therapy, while co-treatment with diuretics may limit hyperkalemia.…”

The Global Burden of Resistant Hypertension and Potential Treatment Options

“…96 Real-world evidence from the US comprising more than 80,000 patients with RH found a non-significant reduction in the rates of stroke and MI in patients taking spironolactone compared to β-blockers as fourth-line treatment, though the risk of hyperkalaemia and kidney function worsening was significantly higher with the former. 97 The risk of hyperkalaemia with spironolactone is a cause for concern, particularly in patients with CKD taking RAAS blockers. According to current guidelines, spironolactone should be used with caution in patients with an eGFR <45 ml/min/1.73 m 2 when plasma potassium concentration is >4.5 mmol/l, as these were exclusion criteria in the PATHWAY-2 trial.…”