Highlights
- Intensive blood pressure (BP) control (target <130/80 mmHg) significantly reduced the risk of major adverse cardiovascular events (MACE) by 29% to 39% across Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 2, 3, and 4.
- All-cause mortality was significantly lower in participants with CKM stage 2 (HR 0.73) and stage 3 (HR 0.82) under intensive intervention, though the benefit was not statistically significant in stage 4.
- A quantitative benefit-harm analysis confirmed a positive net clinical benefit across all CKM stages, suggesting that the cardiovascular protection offered by intensive BP control outweighs the risks of treatment-related adverse events like hypotension.
- The study highlights the efficacy of a nonphysician-led, scalable BP intervention strategy in high-risk rural populations with multimorbid conditions.
The Convergence of Risk: Understanding CKM Syndrome
The concept of Cardiovascular-Kidney-Metabolic (CKM) syndrome, as recently defined by the American Heart Association (AHA), reflects the clinical reality that cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders such as type 2 diabetes and obesity do not exist in isolation. Instead, they form a pathological continuum. Hypertension serves as a primary driver within this continuum, accelerating the transition from early metabolic dysfunction to end-stage renal and cardiovascular disease.
Despite the known benefits of blood pressure reduction, clinical questions have persisted regarding whether intensive targets (systolic <130 mmHg) are equally effective and safe across the entire spectrum of CKM syndrome, particularly in patients with advanced disease (Stage 4) or those with complex metabolic profiles. This post hoc analysis of the China Rural Hypertension Control Project (CRHCP) provides much-needed evidence to guide management in this high-risk, multimorbid population.
Study Design and Methodology
The China Rural Hypertension Control Project (CRHCP) was a large-scale, cluster-randomized clinical trial conducted across 326 villages in rural China. This specific analysis included 33,736 participants aged 40 years or older with hypertension. The study sought to evaluate the impact of a comprehensive intensive BP intervention versus usual care across different CKM stages.
The Intervention: A Community-Based Approach
Participants in the intervention group were managed by trained nonphysician practitioners (village doctors) who followed a standardized protocol to achieve a target BP of less than 130/80 mmHg. The strategy included medication initiation, titration, and lifestyle counseling. The control group received usual care as provided by local healthcare providers. The median follow-up period was 3.02 years, allowing for a robust assessment of both efficacy and safety.
Defining the CKM Stages
The researchers categorized participants into three stages based on standard AHA criteria:
- Stage 2: Presence of metabolic risk factors (e.g., obesity, glucose intolerance, or early kidney disease markers) without subclinical or clinical CVD. This group comprised 55.3% of the cohort.
- Stage 3: Evidence of subclinical cardiovascular disease or a high predicted 10-year CVD risk (≥20%), accounting for 23.7% of participants.
- Stage 4: Established clinical cardiovascular disease, including histories of stroke or myocardial infarction, making up 21.0% of the cohort.
Efficacy Results Across the CKM Spectrum
The primary finding of the analysis was that intensive BP control provided consistent protection against major adverse cardiovascular events (MACE), which included stroke, myocardial infarction, heart failure, and cardiovascular death, regardless of the CKM stage.
Major Adverse Cardiovascular Events (MACE)
The risk reduction for MACE was statistically significant in all three analyzed stages:
- Stage 2: Hazard Ratio (HR) 0.61 (95% CI, 0.50-0.73).
- Stage 3: HR 0.71 (95% CI, 0.58-0.84).
- Stage 4: HR 0.67 (95% CI, 0.58-0.76).
These results demonstrate that the relative benefit of intensive BP control is preserved even as the complexity of the patient’s metabolic and renal profile increases. The consistency of these hazard ratios suggests that the underlying mechanisms of hypertensive damage remain susceptible to BP-lowering interventions across the entire CKM continuum.
All-Cause Mortality Findings
The study also examined all-cause mortality, revealing interesting nuances. In CKM Stage 2, intensive control was associated with a 27% reduction in death (HR 0.73; 95% CI, 0.57-0.90). In Stage 3, the reduction was 18% (HR 0.82; 95% CI, 0.68-0.96). However, in Stage 4, while the point estimate for MACE reduction remained strong, the mortality benefit was not statistically significant (HR 1.02; 95% CI, 0.84-1.20). This may suggest that in patients with established clinical CVD, non-cardiovascular causes of death or advanced disease state competing risks may dilute the survival benefit of BP lowering, despite the reduction in cardiovascular events.
Safety and the Quantitative Benefit-Harm Analysis
Intensive BP control is often scrutinized for its potential to increase adverse events, particularly in elderly or multimorbid populations. In this analysis, the risk of symptomatic hypotension was higher in the intervention group across all stages (relative risk ranging from 1.79 to 2.34). However, other serious safety concerns, such as syncope, injurious falls, and acute kidney adverse events, did not show a significant increase compared to the usual care group.
To provide a clearer picture for clinicians, the researchers conducted a quantitative benefit-harm analysis. This analysis weighed the reduction in MACE against the increase in adverse events. The net benefit scores were positive across all stages:
- Stage 2: 1.58
- Stage 3: 2.53
- Stage 4: 2.15
The higher net benefit in Stages 3 and 4 reflects the higher absolute risk of cardiovascular events in these populations; thus, the absolute number of events prevented by intensive control is greater in more advanced stages, even if the relative risk reduction is similar.
Clinical Implications and Expert Perspectives
These findings have significant implications for the management of hypertension in the context of CKM syndrome. They reinforce the concept that the "lower is better" approach for blood pressure (systolic <130 mmHg) is not only effective for the general hypertensive population but also for those with high metabolic and renal complexity.
Addressing the Rural Healthcare Gap
Perhaps the most impactful aspect of this study is the setting. By demonstrating that intensive BP targets can be successfully met and managed by nonphysician practitioners in rural areas, the CRHCP provides a blueprint for addressing healthcare disparities. In many low- and middle-income regions, access to specialists is limited. A protocolized, community-led intervention for CKM syndrome could significantly reduce the global burden of CVD.
Mechanistic Insights
The benefits observed in Stage 2—the early metabolic stage—are particularly noteworthy. By controlling BP early in the CKM continuum, clinicians may be able to slow the progression of renal decline and subclinical vascular damage, effectively "bending the curve" of the syndrome’s progression. This supports a shift toward more aggressive primary prevention in patients with metabolic risk factors.
Conclusion
The post hoc analysis of the CRHCP trial provides robust evidence that targeting a blood pressure of <130/80 mmHg is a beneficial strategy across CKM syndrome stages 2, 3, and 4. While clinicians must remain vigilant regarding the risk of hypotension, the overall reduction in cardiovascular events and the positive net clinical benefit support the implementation of intensive BP control. This study validates the use of scalable, community-based intervention models to manage the complex, overlapping risks of cardiovascular, kidney, and metabolic disease.
Funding and Clinical Trial Information
The China Rural Hypertension Control Project was supported by the Ministry of Science and Technology of China and other regional funding bodies. The trial is registered at ClinicalTrials.gov (NCT03527719).
References
- Guo X, Zhou S, Mu J, et al. Intensive Blood Pressure Control and Cardiovascular Outcomes Across Cardiovascular-Kidney-Metabolic Syndrome Stages: A Post Hoc Analysis of the China Rural Hypertension Control Project. JAMA Netw Open. 2026;9(2):e2557180.
- Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-Kidney-Metabolic Health: A Scientific Advisory From the American Heart Association. Circulation. 2023;148(20):1606-1635.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 2018;71(6):e13-e115.
