Neurology · Medical Literature
Cardiovascular-kidney-metabolic syndrome stage modifies the efficacy of intensive blood pressure control on cognitive outcomes: A post hoc analysis of SPRINT MIND.
Abstract
Whether cardiovascular-kidney-metabolic (CKM) syndrome stage modifies cognitive benefits of intensive blood pressure (BP) control remains unclear. This post hoc analysis of Systolic Blood Pressure Intervention Trial - Memory and Cognition in Decreased Hypertension (SPRINT MIND) classified participants into non-advanced CKM (Stage 2, n = 5,632) and advanced CKM (Stages 3-4, n = 2,931). The primary outcome was probable dementia; secondary outcomes included mild cognitive impairment (MCI) and probable dementia or MCI composite. Treatment effects were evaluated using Cox models and generalized linear models. In non-advanced CKM, intensive BP control reduced risks of probable dementia (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.46-0.85) and composite outcome (HR 0.74, 95% CI 0.62-0.89). No benefit was observed in advanced CKM (probable dementia: HR 1.15; composite: HR 0.97). Significant interactions between treatment and CKM stage were observed for probable dementia (p = 0.009). Among patients with hypertension and non-advanced CKM syndrome, intensive BP control was associated with lower risk of probable dementia, whereas no such benefit was observed in advanced CKM (see Graphical Abstract).
Clinical relevance
Does cardiovascular-kidney-metabolic (CKM) syndrome stage modify the cognitive benefit of intensive versus standard blood pressure control in adults with hypertension enrolled in SPRINT MIND? __SNAPSHOT__ {"studyDesign":"Post hoc subgroup analysis of a randomized controlled trial (SPRINT MIND)","setting":"Multicenter; >100 clinic sites across the United States and Puerto Rico (inherited from the parent SPRINT trial)","sampleSize":"n=8,563 total (non-advanced CKM Stage 2: n=5,632; advanced CKM Stages 3–4: n=2,931)","population":"Adults aged ≥50 years with hypertension and elevated cardiovascular risk, without prior stroke or dementia at enrollment, stratified post hoc by AHA CKM syndrome stage. CKM Stage 2 denotes metabolic risk factors (hypertension, dyslipidemia, type 2 diabetes, or metabolic syndrome) and/or moderate- to high-risk CKD without clinical or subclinical CVD. Stages 3–4 denote subclinical or clinical CVD, very-high-risk CKD, or established cardiovascular disease overlapping with CKM risk factors.","intervention":"Intensive systolic blood pressure (SBP) control targeting <120 mmHg","comparator":"Standard SBP control targeting <140 mmHg","primaryOutcome":"Probable dementia (adjudicated)","followUp":"Median approximately 3.3 years of active intervention in the parent trial; cognitive follow-up extended beyond trial closure (exact duration in this post hoc analysis not reported in the abstract)","fundingSource":"Not reported in the abstract; the parent SPRINT MIND trial was supported by the National Institutes of Health (NHLBI, NIA, NIDDK, NINDS) and the Alzheimer's Association"}
Key findings
In participants with non-advanced CKM (Stage 2, n=5,632), intensive BP control was associated with a statistically significant reduction in the risk of probable dementia (HR 0.62, 95% CI 0.46–0.85) and the composite of probable dementia or MCI (HR 0.74, 95% CI 0.62–0.89). The absolute risk reduction and NNT were not reported in the abstract. In participants with advanced CKM (Stages 3–4, n=2,931), no benefit was observed for probable dementia (HR 1.15; CI not reported in abstract) or the composite outcome (HR 0.97; CI not reported in abstract). A statistically significant interaction between treatment assignment and CKM stage was detected for the primary outcome of probable dementia (p=0.009), supporting effect modification rather than chance subgroup heterogeneity. P-values for secondary outcomes and confidence intervals for the advanced CKM subgroup were not reported in the abstract. No adverse event data were reported in the abstract.
Practice implications
This post hoc analysis provides clinically important hypothesis-generating evidence that the cognitive benefit of intensive BP control in SPRINT MIND is concentrated in patients with non-advanced CKM syndrome (Stage 2) and is absent—or possibly attenuated—in those with advanced disease (Stages 3–4). The statistically significant interaction term for probable dementia (p=0.009) strengthens the biological plausibility of this differential effect, suggesting that established cardiovascular or very-high-risk kidney disease may blunt the cerebrovascular benefit of aggressive BP lowering, possibly due to impaired cerebral autoregulation or fixed structural injury. The findings apply specifically to older adults (≥50 years) with hypertension and moderate-to-high cardiovascular risk; they cannot be generalized to younger patients, those with prior stroke, or those already on dementia treatment. Patients with advanced CKM syndrome (subclinical CVD, clinical CVD, or very-high-risk CKD) were not adequately represented in cognitive benefit analyses in the parent trial and appear to derive no dementia protection from intensive BP lowering in this analysis. Clinicians should note that this is a post hoc analysis subject to all inherent limitations of subgroup analyses; CKM staging was applied retrospectively using the 2023 AHA framework to a trial not designed around this construct. Practice should not change based on this analysis alone, but these findings meaningfully inform patient selection for intensive BP targets when cognitive outcomes are a priority. IMPORTANT LIMITATION: Only the abstract was available for review; full data tables, confidence intervals for the advanced CKM subgroup, safety outcomes, and covariate adjustment details were not accessible. __LIMITATIONS__ Post hoc subgroup analysis: CKM staging was applied retrospectively to SPRINT MIND data using the 2023 AHA framework, which was not available at the time of trial design, introducing the possibility of data-driven subgroup construction.,The parent trial was terminated early for cardiovascular benefit, limiting cumulative cognitive event rates and statistical power for dementia endpoints—a limitation that propagates into this subgroup analysis.,Confidence intervals and p-values for secondary outcomes in the advanced CKM subgroup were not reported in the abstract, precluding full evaluation of the precision of null findings.,CKM staging criteria require variables (e.g., subclinical CVD imaging, coronary artery calcium scores, cardiac biomarkers) that may have been incompletely captured in SPRINT; retrospective staging accuracy is uncertain.,No information on adverse events (e.g., hypotension, syncope, AKI, electrolyte disturbances) stratified by CKM stage is provided in the abstract, which is critical for assessing the benefit-harm balance in patients with advanced disease.,Single-blind design of the parent trial (participants unblinded to treatment assignment) could introduce differential reporting or health behavior bias.,The study population was restricted to adults ≥50 years with elevated CVD risk at U.S. and Puerto Rico sites; generalizability to younger patients, non-U.S. populations, or those with prior stroke is limited.,As a post hoc analysis, multiple comparisons inflate the risk of type I error despite the reported interaction p-value of 0.009.,Only the abstract was available; full methodological details, including how CKM staging variables were operationalized and imputed, could not be assessed. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In this post hoc analysis of SPRINT MIND, intensive BP control (target <120 mmHg) was associated with a 38% relative risk reduction in probable dementia among hypertensive adults with non-advanced CKM syndrome (Stage 2; HR 0.62, 95% CI 0.46–0.85), but no cognitive benefit was observed in those with advanced CKM (Stages 3–4; HR 1.15 for probable dementia), with a significant interaction by CKM stage (p=0.009). These findings suggest that CKM disease burden may identify patients most likely to derive cognitive benefit from intensive BP control, but the post hoc design prevents practice-changing conclusions. Clinicians should incorporate CKM staging into shared decision-making around intensive BP targets while awaiting prospective confirmation.