Renin-Guided Risk Stratification and Therapy in Hypertension to Reduce Major Adverse Cardiovascular Outcomes

Abstract Background Risk stratification in hypertension remains challenging. The prognostic value of plasma renin in guiding therapy for hypertension is not well established. Methods In this multicenter retrospective cohort of 16,600 people with hypertension, we evaluated the association between plasma renin activity and major adverse cardiovascular events (MACE) defined as stroke, myocardial infarction, and all-cause death. Plasma renin was analyzed as a continuous variable using restricted cubic splines. A 6-month landmark analysis assessed treatment effects of mineralocorticoid receptor antagonists (MRA) as opposed to baseline renin-angiotensin system inhibitors. Results Continuous renin level showed a U-shaped association with MACE, with the lowest risk at 1.17ng/mL/h. In categorical analyses, low renin (3.0ng/mL/h; HR=1.19, 95% CI 1.06-1.33) were both associated with higher MACE risk. Initiation of MRA therapy after renin measurement was associated with a graded reduction in MACE risk where patients with low renin had the lowest risk (HR=0.75, 95%CI 0.60-0.92), and patients with high-renin had the highest risk (HR=1.41, 95%CI 1.03-1.94). In contrast, baseline use of renin-angiotensin system inhibitors was associated with a graded reduction in MACE risk where patients with high-renin had the lowest risk (HR=0.76, 95%CI 0.63-0.92) but those with low renin did not benefit (HR=0.87, 95%CI 0.72-1.04). Conclusions Plasma renin is a prognostic biomarker for MACE and may serve as a guide for treatment selection. A renin-guided strategy that favors MRAs in patients with low renin may reduce MACE and support individualized hypertension care. Clinical Perspective What is News? In this large multicenter cohort of 16,600 patients with hypertension, plasma renin activity demonstrated a U-shaped association with major adverse cardiovascular events, with increased risk observed at both suppressed and elevated renin levels. Renin-defined hypertensive phenotypes were associated with differential treatment responses that mineralocorticoid receptor antagonist initiation was associated with lower cardiovascular risk in patients with low renin, whereas baseline renin-angiotensin system inhibitor use was associated with lower risk in patients with higher renin. These findings extend the clinical role of renin beyond screening for primary aldosteronism, suggesting that renin may serve as an accessible marker that links hypertension pathophysiology, cardiovascular risk, and treatment responsiveness. What Are the Clinical Implications? Plasma renin may help clinicians move beyond blood pressure levels alone and recognize biologically distinct forms of hypertension that may require different therapeutic strategies. Suppressed renin may identify a broader phenotype of renin-independent aldosteronism or mineralocorticoid receptor activation, in which earlier consideration of mineralocorticoid receptor antagonist therapy may be appropriate even without a formal diagnosis of primary aldosteronism. A renin-guided treatment strategy may provide a practical framework for mechanism-based hypertension care, while prospective studies are needed to determine whether this approach improves long-term cardiovascular outcomes.