Intensive Blood Pressure Control and Cardiovascular Outcomes Across Cardiovascular-Kidney-Metabolic Syndrome Stages

Importance: Cardiovascular-kidney-metabolic (CKM) syndrome represents a syndromic continuum encompassing overlapping cardiovascular, kidney, and metabolic dysfunction. Hypertension is a central driver in the pathogenesis of CKM syndrome, promoting both kidney and metabolic deterioration, but little is known about the benefits of intensive blood pressure (BP) control across CKM syndrome stages. Objective: To evaluate CKM syndrome stage-specific outcomes, safety, and net clinical benefits associated with a comprehensive intensive BP intervention. Design, Setting, and Participants: This is a post hoc, secondary analysis of a cluster randomized clinical trial, the China Rural Hypertension Control Project (CRHCP), which was conducted between May 2018 and March 2023. Participants were adults aged 40 years or older with hypertension and CKM syndrome stages 2 to 4, which were defined using standard criteria. Stage 2 indicates that the patient has a metabolic risk factor; stage 3, subclinical cardiovascular disease or predicted 10-year risk of 20% or greater; and stage 4, clinical cardiovascular disease. In this analysis, participants had a median (IQR) follow-up of 3.02 (2.97-3.06) years. Data analysis was conducted from November 2024 to June 2025. Intervention: The comprehensive BP control strategy targeted a systolic BP less than 130 mm Hg and a diastolic BP less than 80 mm Hg. The intervention was delivered by trained nonphysician practitioners. Main Outcomes and Measures: The primary clinical outcome was a composite of major adverse cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death). Safety outcomes included hypotension, syncope, injurious falls, and kidney adverse events. A quantitative benefit-harm analysis was conducted to estimate net benefit associated with the intervention. Results: Among 33 736 participants (mean [SD] age, 63.0 [9.2] years; 20 677 [61.3%] women), 18 662 (55.3%) had stage 2 CKM syndrome (of whom 9526 [51.0%] received the intervention), 7984 (23.7%) had stage 3 (of whom 4032 [50.5%] received the intervention), and 7090 (21.0%) had stage 4 (of whom 3713 [52.4%] received the intervention). Treatment outcomes were generally consistent across CKM syndrome stages. Intensive BP control was associated with reduced cardiovascular events across all stages: in stage 2, the hazard ratio (HR) was 0.61 (95% CI, 0.50-0.73); in stage 3, the HR was 0.71 (95% CI, 0.58-0.84); and in stage 4, the HR was 0.67 (95% CI, 0.58-0.76). The risk of all-cause mortality was also lower in stage 2 (HR, 0.73; 95% CI, 0.57-0.90) and stage 3 (HR, 0.82; 95% CI, 0.68-0.96) but not in stage 4 (HR, 1.02; 95% CI, 0.84-1.20). Risk of hypotension increased across all stages (relative risk range, 1.79-2.34), while other adverse events, including kidney events, were similar between groups, despite some numerical variation across stages. Net benefits were favorable: stage 2, 1.58 (95% CI, 1.53-1.62); stage 3, 2.53 (95% CI, 2.42-2.64); and stage 4, 2.15 (95% CI, 2.04-2.26). Conclusions and Relevance: In this post hoc analysis of a cluster randomized clinical trial, a comprehensive intervention targeting BP less than 130/80 mm Hg demonstrated a favorable benefit-to-harm profile across CKM syndrome stages, with no clear heterogeneity across CKM syndrome stages. These findings provide the first trial-based evidence to guide CKM syndrome management and support scalable strategies for this high-risk, multimorbid population. Trial Registration: ClinicalTrials.gov Identifier: NCT03527719.