Systolic Blood Pressure Intervention Trial Participants Research Articles

Urine Ammonium Concentrations and Cardiovascular and Kidney Outcomes in SPRINT Participants with Chronic Kidney Disease.

Impaired urine ammonium excretion is common in chronic kidney disease (CKD) and may identify risk of metabolic acidosis earlier than reductions in serum bicarbonate or pH, and thus may have associations with cardiovascular disease (CVD) outcomes. We evaluated the association of urine ammonium with CVD and kidney outcomes among persons with hypertension and non-diabetic CKD enrolled in a trial of blood pressure reduction. We measured urine ammonium concentration in spot urine specimens collected at baseline among 2092 participants of the Systolic Blood Pressure Intervention Trial (SPRINT) with an eGFR <60 ml/min/1.73m2. We used multivariable-adjusted Cox models to evaluate associations of urine ammonium concentration with the SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death), all-cause mortality, the SPRINT kidney composite outcome (50% kidney function decline, end stage kidney disease, or transplant), and acute kidney injury (AKI). At baseline, the mean (SD) age was 73 (9) years; 40% were female; and 25% were Black participants. The mean (SD) serum bicarbonate was 25.6 (2.8) mmol/L, median (interquartile range, IQR) urine ammonium concentration was 14.4 (9.5, 23.1) mmol/L, and median (IQR) eGFR was 49 (39,55) ml/min/1.73m2. There were 255 CVD composite events, 143 deaths, 63 kidney composite events, and 146 AKI events during a median follow-up of 3.8 years. In multivariable models, each 2-fold higher urinary ammonium concentration was associated with a 26% (95% CI 1.05, 1.52) higher risk of the CVD composite, whereas there was no association with all-cause mortality, the SPRINT kidney composite outcome, or AKI. Among non-diabetic individuals with hypertension and CKD, higher urine ammonium concentration is associated with higher risk of CVD. Further studies are needed to evaluate this association in other cohorts.

#783 Individualized net benefit of intensive blood pressure lowering among older adults in SPRINT

Abstract Background and Aims The optimal blood pressure (BP) target for older adults remains controversial. This study aimed to determine whether results from the Systolic Blood Pressure Intervention Trial (SPRINT) could be tailored to individual trial participants using risk estimates and simulated preferences about the relative importance of multiple outcomes related to BP lowering. Method This analysis included 4,850 SPRINT participants age ≥65 years. Parsimonious Cox models were internally validated to predict the absolute difference in risk between intensive versus standard BP lowering in each SPRINT participant for all-cause death, cardiovascular outcomes, cognitive outcomes, and serious adverse events. Treatment effects were combined using simulated preference weights into an individualized net benefit, which represents the weighted sum of risk differences across outcomes. Individualized net benefits among older SPRINT participants were compared across categories of age (65-74 years vs. ≥ 75 years), frailty (fit, less fit, and frail), and polypharmacy status. Results When simulating preferences for older adults who view death, cardiovascular events, and cognitive impairment as much more important than the harms of BP lowering, the median (IQR) individualized net benefit was 5% (3%, 7%), and 100% had a net benefit that favoured intensive BP lowering. When simulating benefits and harms to have similar importance, the median (IQR) individualized net benefit was 2% (1%, 3%), and 95.4% had a positive net benefit. In subgroup analyses, the predicted net benefit of intensive BP lowering was significantly greater among those with advanced age, frailty, and polypharmacy compared with lower risk individuals (P&amp;lt;0.001 for all comparisons). Conclusion Almost all older participants in SPRINT had a predicted net benefit that favoured intensive BP control, but the degree of net benefit varied considerably. Personalizing BP targets for older adults according to each person's estimated risks and preferences may provide more refined BP target recommendations.

Chronic Kidney Disease Stage and Cardiovascular and Mortality Events Among Older Adults: The SPRINT Trial

Rationale & ObjectiveThe risk implications of the Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification in older adults are controversial. We evaluated the risk of adverse outcomes in this population across categories of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). Study DesignProspective cohort. Settings & Participants2509 participants aged ≥75 years in the Systolic Blood Pressure Intervention Trial (SPRINT). ExposuresKDIGO eGFR and UACR categories. We combined KDIGO categories G1 and G2, G3b and G4, as well as A2 and A3. OutcomesPrimary SPRINT outcome (composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), and all-cause death. Analytical ApproachMultivariable Cox proportional hazard models. ResultsMean age was 79.8 years, 37.4% were female, mean eGFR was 64.0 ml/min/1.73 m2, and median UACR 13.1 mg/g. In multivariable Cox proportional hazard analysis, compared with participants with eGFR ≥60 ml/min/1.73 m2 and UACR <30 mg/g, there was no statistically significant difference in the risk of the primary outcome among participants with eGFR 45-59 or 15-44 ml/min/1.73 m2 and UACR <30 mg/g. However, those with eGFR 45-59 or 15-44 ml/min/1.73 m2 and UACR ≥30 mg/g had higher risk of the primary outcome (HR [95% CI], 1.97 [1.27, 3.04] and 3.32 [2.23, 4.93], respectively). The risk for all-cause death was higher for each category of abnormal eGFR and UACR, with the highest risk observed among those with eGFR 15-44 ml/min/1.73 m2 and UACR ≥30 mg/g (3.34 [2.05, 5.44]). LimitationsIndividuals with diabetes and urine protein >1 g/day were excluded from SPRINT. ConclusionAmong older adults SPRINT participants, low eGFR without albuminuria was associated with higher mortality but not with increased risk of cardiovascular events. Additional studies are needed to evaluate an adapted CKD stage-based risk stratification for older adults.

Self-rated health and risk of incident cardiovascular events among individuals with hypertension

Background: The relationship between self-rated health (SRH) and cardiovascular events in individuals with hypertension, but without diabetes mellitus, is understudied. Methods: We performed a post hoc analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). SRH was categorized into excellent, very good, good and fair/poor. Using multivariable Cox regression, we estimated hazard ratios and 95% confidence intervals (CIs) for the association of SRH with both all-cause mortality and a composite of cardiovascular events (the primary outcome), which was defined to include myocardial infarction (MI), other acute coronary syndromes, stroke, acute decompensated heart failure, and cardiovascular death. Results: We included 9319 SPRINT participants (aged 67.9 ± 9 years, 35.6% women) with a median follow-up of 3.8 years. Compared with SRH of excellent, the risk [hazard ratio (95% CI)] of the primary outcome associated with very good, good, and fair/poor SRH was 1.11(0.78–1.56), 1.45 (1.03–2.05), and 1.87(1.28–2.75), respectively. Similarly, compared with SRH of excellent, the risk of all-cause mortality [hazard ratio (95% CI)] associated with very good, good, and fair/poor SRH was 1.13 (0.73–1.76), 1.72 (1.12–2.64), and 2.11 (1.32–3.38), respectively. Less favorable SRH (LF-SRH) was also associated with a higher risk of each component of the primary outcome and serious adverse events (SAE). Conclusion: Among individuals with hypertension, SRH is independently associated with the risk of incident cardiovascular events, all-cause mortality, and SAE. Our study suggest that guidelines should consider the potential significance of including SRH in the clinical history of patients with hypertension.

Abstract MP12: Educational Attainment and the Effect of Intensive Blood Pressure Reduction: A Post-Hoc Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT)

Introduction: Hypertension is a major risk factor for cardiovascular disease (CVD). The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that systolic blood pressure (SBP) &lt;120 mm Hg reduced CVD risk and all-cause mortality among those with elevated SBP and high CVD risk. Educational attainment (EA) is associated with CV health, but whether EA modifies the effect of intensive SBP reduction remains unclear. Hypothesis: We predicted that SPRINT participants with lower EA would have greater CVD risk reduction with intensive SBP lowering than those with higher EA. Methods: We included 9,361 individuals recruited as part of the SPRINT study and categorized them by EA (&lt;college, some college through college graduate, and &gt;college degree). We examined the effect of intensive SBP lowering across EA strata in relation to the composite endpoint defined by SPRINT (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or CV death) in multivariable proportional hazards models. Results: The cohort was age 67.9±9.4 years, 35.6% female, and 57.8% White race. Those with high EA were more likely to be older, male, and White race. Higher EA was associated in a dose-response manner with a larger reduction in the risk of developing the composite endpoint after intensive SBP lowering [highest to lowest EA: adjusted HR 0.48 (95% CI: 0.34, 0.70); 0.81 (0.63, 1.03); 0.90 (0.70, 1.15); P , interaction=0.01] ( Table ). The interaction between intensive SBP lowering and EA was limited to non-Black individuals; among Black participants, the association of SBP lowering with the endpoint did not differ significantly by EA. Conclusion: In the SPRINT cohort, higher EA was associated with a larger improvement in CV outcomes after intensive SBP reduction, with differences by race or ethnicity. This post-hoc SPRINT analysis suggests that the benefit of intensive SBP lowering varies by EA, and highlights a need for tailored approaches to optimize hypertension management for individuals with different social backgrounds.

Intensive Blood Pressure Lowering in Individuals With Low Diastolic Blood Pressure and Elevated Troponin Levels in SPRINT.

Among individuals with hypertension and low diastolic blood pressure (DBP), the optimal BP target remains controversial due to concerns that BP lowering may reduce coronary perfusion. We determined the impact of intensive BP control among individuals with elevated systolic BP who have low DBP and elevated hs-cTnT (high-sensitivity cardiac troponin T) levels. A total of 8828 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were stratified by baseline DBP. Those with low DBP (<70 mm Hg) were further stratified by elevated hs-cTnT (≥14 ng/L) at baseline. The effects of intensive versus standard BP lowering on a cardiovascular disease composite end point, all-cause death, and 1-year change in hs-cTnT were determined. The combination of low DBP/high hs-cTnT was independently associated with a higher risk for cardiovascular disease and all-cause death, as well as greater 1-year increases in hs-cTnT, compared with DBP ≥70 mm Hg. However, randomization to intensive versus standard BP lowering led to similar reductions in cardiovascular disease risk among individuals with low DBP/high hs-cTnT (hazard ratio [HR], 0.82 [95% CI, 0.57-1.19]), low DBP/low hs-cTnT (HR, 0.48 [95% CI, 0.29-0.79]), and DBP ≥70 mm Hg (HR, 0.73 [95% CI, 0.60-0.89]; P for interaction=0.20). Intensive BP lowering also led to a reduction in all-cause death that was similar across groups (P for interaction=0.57). In this nonprespecified subgroup analysis of SPRINT, individuals with low DBP and elevated hs-cTnT, low DBP and nonelevated hs-cTnT, and DBP ≥70 mm Hg derived similar cardiovascular disease and mortality benefits from intensive BP lowering. These findings warrant confirmation in other studies.

Medication Regimens against Hypertension Utilized in the Systolic Blood Pressure Intervention Stud

Context: Standard and intensive Systolic Blood Pressure (SBP) interventions would be contextualized by describing the antihypertensive medication regimens used in the SPRINT (Systolic Blood Pressure Intervention Trial). This information may also help future implementation efforts to meet population-wide intensive SBP goals. Methods: At the rerandomization and 12-month visits, we provided SPRINT participants with comprehensive medication data. The class of antihypertensive medications was used to categorize regimens. The analyses were divided into groups based on the kind of treatment (intensive target SBP &lt;120 mm Hg versus standard goal SBP &lt;140 mm Hg) Findings: The median number of classes used at the rerandomization visit was 2.0 for 7860 individuals (83.7% of 9361 randomized), and 2.0 for the standard and intensive groups (P=0.559). After a year, the intensive and conventional groups used a median of 3.0 and 2.0 classes, respectively (P&lt;0.001). In the intensive and standard groups, the most common regimens were rerandomization, Angiotensin-Converting Enzyme inhibitor (ACE), or Angiotensin-II Receptor Blocker (ARB) monotherapy (12.6% versus 12.2%). After a year, 5.3% of participants in the intense group and 14.7% of participants in the normal group still used ACE/ARB monotherapy. The following multidrug regimens were utilized at 12 months by both the intensive and regular participants: a calcium channel blocker and thiazide (12.2% and 7.9%) combined in an ACE/ARB thiazide, and calcium channel blocker (11.4% and 4.3%); an ACE/ARB, thiazide, calcium channel blocker, and beta-blocker (6.5% and 1.2%); and 6.2% and 6.8% of each category. Conclusions: Compared to ACE/ARB monotherapy, SPRINT investigators preferred combining ACEs or ARBs, thiazide diuretics, and calcium channel blockers to aim SBP &lt;120 mm Hg.

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND COGNITIVE IMPAIRMENT: IS DEPRESSION A MEDIATOR?

Abstract By 2040, over 9 million US adults will live with dementia. Understanding the relationship between risk factors and cognitive decline is critical to prevent disease and slow progression. Depression and cardiovascular disease (CVD) are independent risk factors for cognitive impairment (CI) which may interact, suggesting depression may play a mediating role in the relationship between CVD and CI, an hypothesis explored in this study. Data from the Systolic Blood Pressure Intervention Trial (SPRINT), a multi-center, randomized, controlled trial were used in this multivariate logistic regression analysis. CI was defined as adjudicated cases of mild CI and probable dementia. Depression was defined as a Patient Health Questionnaire-9 score ≥10 or current antidepressant therapy. We developed a CVD risk score using data from SPRINT participants and discretized the scores into tertiles. Of 9259 SPRINT participants, our analytic sample included 8456 who had adjudicated mild CI or dementia and had baseline depression scores. They were on average 68 years and 36% were female. After adjusting for age, sex, education, race, prior CVD, chronic kidney disease and treatment assignment, participants with high cardiovascular risk were more likely to have CI (OR: 1.55, 95% CI: 1.17-2.05). Participants with depression were more likely to have CI (OR: 1.29, 95% CI: 1.05-1.58) however, the interaction between cardiovascular risk and cognition was not significant. Findings from this study suggest that while depression and CVD are associated with CI, depression may not explain the CVD-CI relationship. More research is needed to understand the relationship between depression, CVD and CI.

Abstract 12741: Malignant Left Ventricular Hypertrophy and Risk of Cognitive Impairment or Probable Dementia: A Post Hoc Analysis of the SPRINT Trial

Background: Left ventricular hypertrophy (LVH) accompanied by biomarker of myocardial injury as measured by high sensitivity cardiac troponin (hs-cTnT) and neurohormonal activation, as measured by N-terminal pro-B-type natriuretic peptide (NT-proBNP), indicates a malignant form of LVH. While malignant LVH has been linked to poor CVD outcomes, its association with cognitive outcomes is unclear. Aim: To examine the association of malignant LVH with cognitive outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT). Hypothesis: Malignant LVH is associated with incident cognitive outcomes. Methods: We performed a post hoc analysis of 8,027 SPRINT participants with at least one cognitive assessment. Participants were classified into six groups based on the presence or absence of LVH assessed by 12-lead electrocardiogram (ECG), and elevations in levels of hs-cTnT ≥14 ng/L or NT-proBNP ≥125 pg/mL at baseline visit. The adjudicated outcome of incident probable dementia or mild cognitive impairment (MCI) or a composite outcome of probable dementia or mild cognitive impairment. Cox proportional hazard models were used to examine the association of baseline LVH/biomarker groups with incident cognitive outcomes. Results: During a median follow-up of 5 years, 597, 306, and 818 participants developed MCI, dementia, and composite outcome respectively. Compared with participants without LVH or elevated biomarkers, participants with LVH or elevated biomarkers, either in isolation or combined, had a higher risk of MCI and composite outcome. Highest risk for composite outcome was observed in those with concomitant LVH and elevated levels of both biomarkers. There was no significant association between LVH/biomarkers with incident probable dementia except for those with concomitant LVH and elevated levels of both biomarkers ( Table ). Conclusions: Among SPRINT participants, malignant LVH is associated with mild cognitive impairment and probable dementia.

Abstract 17590: Association of Intensive vs Standard Blood Pressure Lowering With 1-year and 2-year Changes in Cardiac Biomarker Levels: Findings From SPRINT

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive systolic blood pressure (SBP) lowering was associated with marked reductions in cardiovascular disease (CVD) endpoints. We recently reported that intensive SBP lowering was also associated with a small increase in high-sensitivity cardiac troponin T (hs-cTnT) and a large decrease in N-terminal pro-B-type natiuretic peptide (NT-proBNP) over 1-year. However, data on longer term biomarker changes with intensive versus standard SBP lowering have not been previously reported. Methods: hs-cTnT and NT-proBNP were measured at baseline, 1 year, and 2 years from stored specimens in SPRINT participants. Changes in biomarkers were evaluated continuously on the log scale with interval censoring of participants with CVD events. The effect of intensive SBP lowering on biomarker changes was assessed using linear regression models with treatment effects reported as geometric mean ratios. Results: Of 9,361 SPRINT participants, hs-cTnT and NT-proBNP were measured in 8,828 (baseline), 7,887 (Year 1), and 7,463 (Year 2) free of CVD events. Intensive SBP lowering led to a 3% increase in log-transformed hs-cTnT from baseline to Year 1, but there was no significant change observed from baseline to Year 2. In contrast, intensive SBP lowering led to a consistent 10% decrease in NT-proBNP from baseline to Year 1 and to Year 2. NT-proBNP levels increased slightly from Year 1 to Year 2 in both treatment arms such that the 1-Year treatment effect for intensive SBP lowering was maintained to Year 2 (see Table). Conclusions: Intensive SBP lowering was associated with a transient, modest increase in hscTnT at Year 1 that was no longer present at Year 2. In contrast, intensive SBP lowering was associated with a persistent reduction in NT-proBNP at both 1 and 2 years follow-up. These findings highlight the complex responses of cardiac biomarkers to intensive SBP lowering.

Abstract 14347: Albuminuria, N-Terminal Pro-Brain Natriuretic Peptide and Incident Congestive Heart Failure in High-Risk Adults With Hypertension: A Post Hoc Analysis of the Systolic Blood Pressure Intervention Trial

Introduction: Abnormal levels of urinary albumin concentration (UAC) and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) have each been independently associated with an increased risk of congestive heart failure (CHF). It remains unknown whether the concomitant presence of abnormal UAC and NT-proBNP increases an individual’s risk for future CHF beyond that contributed by each biomarker. Objective: To examine the joint association between abnormal UAC and NT-ProBNP with incident CHF in participants from the SPRINT (Systolic Blood Pressure Intervention Trial) study. Methods: This analysis included 8,176 participants from SPRINT with available data on baseline UAC and NT-proBNP. UAC was measured by urine albumin-creatinine ratio (UACR). Albuminuria was defined as UACR ≥30 mg/g. Abnormal NT-proBNP was defined as levels ≥125 pg/ml. Cox proportional hazard models were used to examine the association of UAC and NT-proBNP, as well as albuminuria and abnormal NT-proBNP, with incident CHF. Results: Over a median follow-up of 3.2 years, 179 incident cases of CHF were observed. In adjusted models, the risk of incident CHF (HR 95% CI) associated with each 1 (one) unit standard deviation increase in the levels of UAC and NT-proBNP was 1.10 (1.04-1.16; p &lt;0.001) and 1.13 (1.10-1.16; p &lt;0.0001), respectively. A statistically significant multiplicative interaction between UAC*NT-proBNP was observed in the fully adjusted model (p &lt;0.0001). The risk associated with the presence of abnormal UAC +/- abnormal NT-proBNP in the SPRINT cohort is depicted in the figure. Conclusions: Among SPRINT participants, we found a significant multiplicative interaction between UAC and NT-proBNP as predictors of incident CHF. Also, the risk of future CHF was over six times higher in individuals with abnormal UAC and NT-proBNP, compared with those with normal levels of both biomarkers. More studies are needed to further explore this interaction and the implications on CHF prevention.

Abstract 18264: Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Cognitive Outcomes in SPRINT

Background: Subclinical elevations in high sensitivity cardiac troponin T (hsc-TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) identifies a high-risk subgroup with reduction in cardiovascular disease in response to intensive systolic blood pressure (SBP) lowering. However, it remains unknown if these markers also identify subgroups with greater improvement in cognitive outcomes from intensive SBP lowering. Methods: We measured hs-cTnT and NT-proBNP at baseline in Systolic Blood Pressure Intervention Trial (SPRINT). Adjudicated cognitive outcomes were classified as probable dementia (PD) and mild cognitive impairment (MCI). Combined cardiac biomarker categories were defined as elevated, intermediate, and non-elevated. The association of combined biomarker categories with risk of cognitive outcomes was assessed using multivariable Cox proportional hazards models. Heterogeneity in the effect of intensive versus standard SBP lowering on the risk of cognitive outcomes across combined biomarker categories was determined. Results: Of 8,111 SPRINT participants with measured biomarkers and at least one follow-up cognitive assessment, 830 (10.2%) experienced the composite outcome of PD or MCI. After multivariable adjustment, elevated vs. non-elevated cardiac biomarker levels were independently associated with increased risk of composite outcome [HR 95% CI: 1.56 (1.26 - 1.92)]. The effect of intensive SBP lowering on the composite outcome was strongest among participants with non-elevated cardiac biomarkers (see Table). Conclusion: Elevated cardiac biomarkers were associated with higher risk for cognitive impairment. The effect of intensive SBP lowering on preventing cognitive impairment was strongest among patients with non-elevated cardiac biomarkers. This suggests that intensive SBP lowering may be more effective in preventing cognitive impairment in individuals with favorable cardiac biomarker profiles.

Abstract 12225: The Association of Intensive Blood Pressure Therapy to Mortality in Older Adults After an Injurious Fall. Geriatric Insights From SPRINT

Introduction: The primary finding of the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive (IT, &lt;120 mmHg) compared to standard (&lt;140 mmHg) blood pressure (BP) treatment on an index serious adverse event (SAE), injurious falls, was similar. However, mortality after the index fall has not been well studied. We hypothesized that the occurrence of falls may be associated with reduced mortality benefits. Methods: Using the publicly available SPRINT dataset we analyzed the association of IT on the primary outcome of all-cause mortality and the secondary outcome of non-cardiovascular (CV) mortality as a function of falls. Results: Among 9,361 SPRINT participants, 7.1% (n=666) had a fall. Falls were more likely in older adults (p&lt;0.0001), among women (45.9% vs 34.8%), and those with baseline cardiovascular disease (20.3% vs 16.4%). Among those who fell, 7.8% (52/666) died which was 14.2% of all deaths in SPRINT (52/365). In those who fell, mortality increased with age (p&lt;0.0001) and was highest in those ≥ 80 years (13.7%, Figure ). For all-cause mortality- Falls independently and significantly were associated with increased risk (HR 1.41,1.04-1.91, p=0.03 ) while IT significantly decreased the risk (HR 0.73, 0.60-0.91, p=0.004) . The joint effect (IT+Fall) demonstrated a non-significant increased risk (HR 1.03, 0.56-1.88, p int =0.92). For non-CV mortality- Falls independently and significantly were associated with increased risk (HR 1.63, 1.16-2.29, p=0.005) while IT did not significantly lower risk (HR 0.81, 0.63-1.03, p=0.09) . The joint effect (IT+Fall) demonstrated a non-significant increased risk (HR 1.21, 0.63-2.35, p int =0.56). Conclusions: Our findings suggest that current reporting of potential harm of the treatment effects of IT, measured by the index SAE, may underrepresent true risk and overstate treatment benefits.

Association between weight variability, weight change and clinical outcomes in hypertension

ObjectiveThe effect of body weight variability (BWV) and body weight change (BWC) in high-risk individuals with hypertension, but without diabetes mellitus (DM) remains unclear. We examined the effect of BWV and BWC on the primary outcome [the composite of myocardial infarction (MI), other acute coronary syndromes, stroke, acute decompensated heart failure (HF), or cardiovascular (CV) death] and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). MethodsIn this post-hoc analysis, we used multivariate Cox regression models to examine the risk associated with BWV and BWC for the primary outcome in SPRINT. BWV was defined as the intra-individual average successive variability (ASV). BWC was defined as baseline weight minus final weight. ResultsA total of 8714 SPRINT participants (mean age 67.8 ± 9.4 years, 35.1 % women, 58.9 % Whites) with available data on body weight were included. The median follow-up was about 3.9 years (IQR, 3.3–4.4). In multivariable-adjusted Cox models, each 1 unit standard deviation (SD) of BWV was significantly associated with a higher risk for the primary outcome, all-cause mortality, HF, MI, and stroke [HR(95 % CI)]: 1.13 (1.07–1.19; p < 0.0001), 1.22 (1.14–1.30; p < 0.0001), 1.16 (1.07–1.26; p < 0.001), 1.10 (1.00–1.20; p = 0.047), and 1.15 (1.05–1.27; p = 0.005), respectively. Similarly, each 1 unit SD of BWC was significantly associated with a higher risk of the primary outcome, all-cause mortality, MI, and HF: 1.11(1.02–1.21; p = 0.017), 1.44 (1.26–1.65; p < 0.0001), 1.16 (1.01–1.32; p = 0.041) and 1.19 (1.02–1.40; p = 0.031) respectively. However, there was no significant association with CV death (for both BWV and BWC) or stroke (BWC). ConclusionIn high-risk hypertension, BWV and BWC were both associated with higher risk of the primary outcome and all-cause mortality. These results further stress the clinical importance of sustained weight loss and minimizing fluctuations in weight in hypertension.

Association between physical activity and clinical outcomes in high-risk hypertension: Post-hoc analysis of SPRINT

ObjectiveEngaging in physical activity (PA) is recommended to reduce the risk of morbidity and mortality in patients with hypertension. However, the association between PA and clinical outcomes in individuals with high-risk hypertension is understudied. We examined the relationship between PA and clinical outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT investigated the benefit of intensive (vs. standard) blood pressure treatment in patients with high-risk hypertension. MethodsBaseline data on PA was self-reported. Vigorous-intensity PA (VPA) was categorized into 2 groups based on frequency of “Rarely or Never” and 1 or more sessions/month. Moderate-intensity PA (MPA) was also categorized into 2 groups based on average duration/day of <15 min and 15 or more minutes. Using multivariable Cox regression, we estimated the associations between PA the primary outcome which was a composite of cardiovascular events, and all-cause mortality. ResultsA total of 8,320 (age 67.8 ± 9.3, 34.9% women) of SPRINT participants with data on PA were included. During a median follow-up of 3.8 years, 619 primary outcome, and 419 all-cause mortality events occurred. Compared to not engaging in VPA, the risk of the primary outcome, myocardial infarction, and all-cause mortality (HR 95% CIs) associated with VPA of ≥1sessions/month was 0.79(0.65–0.94; p=0.009), 0.70(0.52–0.93; p=0.014) and 0.75(0.60–0.94; p=0.011), respectively. Similarly, the risk of the primary outcome and all-cause mortality (HR 95% CI) associated with engaging in MPA for ≥15 min/day, relative to <15 min/day was 0.76(0.63–0.93; p=0.008) and 0.80(0.62–1.02; p=0.066), respectively. ConclusionAmong individuals with hypertension from the SPRINT study, VPA and MPA at a threshold of ≥1sessions/month and MPA of ≥15 min/day respectively, were both associated with a lower risk for cardiovascular events, and VPA was also associated with a reduced risk for all-cause mortality. Further studies are required to identify the optimal volume and intensity of PA in high-risk hypertension.

Estimated Population Health Benefits of Intensive Systolic Blood Pressure Treatment Among SPRINT-Eligible US Adults.

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated an intensive (<120 mm Hg) vs. standard (<140 mm Hg) systolic blood pressure (SBP) goal lowered cardiovascular disease (CVD) risk. Estimating the effect of intensive SBP lowering among SPRINT-eligible adults most likely to benefit can guide implementation efforts. We studied SPRINT participants and SPRINT-eligible participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study and National Health and Nutrition Examination Surveys (NHANES). A published algorithm of predicted CVD benefit with intensive SBP treatment was used to categorize participants into low, medium, or high predicted benefit. CVD event rates were estimated with intensive and standard treatment. Median age was 67.0, 72.0, and 64.0 years in SPRINT, SPRINT-eligible REGARDS, and SPRINT-eligible NHANES participants, respectively. The proportion with high predicted benefit was 33.0% in SPRINT, 39.0% in SPRINT-eligible REGARDS, and 23.5% in SPRINT-eligible NHANES. The estimated difference in CVD event rate (standard minus intensive) was 7.0 (95% confidence interval [CI] 3.4-10.7), 8.4 (95% CI 8.2-8.5), and 6.1 (95% CI 5.9-6.3) per 1,000 person-years in SPRINT, SPRINT-eligible REGARDS participants, and SPRINT-eligible NHANES participants, respectively (median 3.2-year follow-up). Intensive SBP treatment could prevent 84,300 (95% CI 80,800-87,920) CVD events per year in 14.1 million SPRINT-eligible US adults; 29,400 and 28,600 would be in 7.0 million individuals with medium or high predicted benefit, respectively. Most of the population health benefit from intensive SBP goals could be achieved by treating those characterized by a previously published algorithm as having medium or high predicted benefit.

CARDIOVASCULAR RISK IN TREATED HYPERTENSIVE PATIENTS WITH ISOLATED DIASTOLIC HYPERTENSION AND ISOLATED LOW DIASTOLIC BLOOD PRESSURE

Objective: Antihypertensive therapy in the elderly often targets at systolic blood pressure (SBP) and excessive lowering of diastolic blood pressure (DBP) may occur. Evidence on the cardiovascular risk of isolated diastolic hypertension (IDH) is inconsistent. This study investigated whether IDH and isolated low diastolic blood pressure (ILDBP) were associated with major adverse cardiovascular events (MACE) in patients who were receiving antihypertensive therapy and had normalized SBP. Design and method: A total of 7582 hypertensive patients aged &gt; = 50 years and with on-treatment SBP &lt;130 mmHg from the Systolic Blood Pressure Intervention Trial (SPRINT) were analyzed. Average DBP of 60 mmHg during follow-up visits was determined as the lower boundary by a multivariate adaptive regression spline analysis for MACE. According to the on-treatment DBP, patients were divided into &lt;60 mmHg (ILDBP, n = 1031), 60–79 mmHg (n = 5432), and &gt; = 80 mmHg (IDH, n = 1119). Time-varying Cox proportional hazards model was used to estimate the MACE risk, comparing IDH or ILDBP with DBP 60–79 mmHg. External validation was carried out with a two-stage meta-analysis of individual participant data (IPD) for 3560 individuals from six cohorts. Results: The SPRINT participants had a median age of 68.2 years, and 64.9% of whom were men. During a median follow-up of 3.5 years, 512 patients had MACE. Incidence of MACE per 100 person-years was 3.9 case for ILDBP, 1.9 cases for DBP 60 – 79 mmHg, and 1.8 cases for IDH. Compared with DBP 60 – 79 mmHg, ILDBP was associated with a 1.32-fold increased MACE risk (95% CI: 1.05 – 1.66), but IDH was not (hazard ratio: 1.18, 95% CI: 0.87 – 1.59). Among the 50 – 64 years subgroup, IDH was associated with a 1.59-fold increased MACE risk (95% CI: 1.01 – 2.49), with effect modification by age (P for interaction 0.005). The IPD meta-analysis also suggested a significantly higher risk for MACE among patients with ILDBP (hazard ratio: 1.22, 95% CI: 1.03 – 1.46), compared to patients with DBP 60 – 79 mmHg. Conclusions: Among patients on antihypertensive medications with normalized SBP, excessively low DBP increased the MACE risk but IDH did not. More research is needed to develop appropriate treatment strategies for ILDBP.

Identifying Patients for Intensive Blood Pressure Treatment Based on Cognitive Benefit

Intensive vs standard treatment to lower systolic blood pressure (SBP) reduces risk of mild cognitive impairment (MCI) or dementia; however, the magnitude of cognitive benefit likely varies among patients. To estimate the magnitude of cognitive benefit of intensive vs standard systolic BP (SBP) treatment. In this ad hoc secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), 9361 randomized clinical trial participants 50 years or older with high cardiovascular risk but without a history of diabetes, stroke, or dementia were followed up. The SPRINT trial was conducted between November 1, 2010, and August 31, 2016, and the present analysis was completed on October 31, 2022. Systolic blood pressure treatment to an intensive (<120 mm Hg) vs standard (<140 mm Hg) target. The primary outcome was a composite of adjudicated probable dementia or amnestic MCI. A total of 7918 SPRINT participants were included in the analysis; 3989 were in the intensive treatment group (mean [SD] age, 67.9 [9.2] years; 2570 [64.4%] men; 1212 [30.4%] non-Hispanic Black) and 3929 were in the standard treatment group (mean [SD] age, 67.9 [9.4] years; 2570 [65.4%] men; 1249 [31.8%] non-Hispanic Black). Over a median follow-up of 4.13 (IQR, 3.50-5.88) years, there were 765 and 828 primary outcome events in the intensive treatment group and standard treatment group, respectively. Older age (hazard ratio [HR] per 1 SD, 1.87 [95% CI, 1.78-1.96]), Medicare enrollment (HR per 1 SD, 1.42 [95% CI, 1.35-1.49]), and higher baseline serum creatinine level (HR per 1 SD, 1.24 [95% CI, 1.19-1.29]) were associated with higher risk of the primary outcome, while better baseline cognitive functioning (HR per 1 SD, 0.43 [95% CI, 0.41-0.44]) and active employment status (HR per 1 SD, 0.44 [95% CI, 0.42-0.46]) were associated with lower risk of the primary outcome. Risk of the primary outcome by treatment goal was estimated accurately based on similar projected and observed absolute risk differences (C statistic = 0.79). Higher baseline risk for the primary outcome was associated with greater benefit (ie, larger absolute reduction of probable dementia or amnestic MCI) of intensive vs standard treatment across the full range of estimated baseline risk. In this secondary analysis of the SPRINT trial, participants with higher baseline projected risk of probable dementia or amnestic MCI gained greater absolute cognitive benefit from intensive vs standard SBP treatment in a monotonic fashion. ClinicalTrials.gov Identifier: NCT01206062.

Concordance between clinical outcomes in the Systolic Blood Pressure Intervention Trial and in the electronic health record

BackgroundRandomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. MethodsWe linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. Results2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. ConclusionsThese results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

Serum Magnesium Levels and Cardiovascular Outcomes in Systolic Blood Pressure Intervention Trial Participants

Serum magnesium levels have been inversely yet inconsistently associated with cardiovascular (CV) outcomes. In this study, we examined the association of serum magnesium levels with CV outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT) participants. Case-control post hoc analysis of SPRINT. A total of 2,040 SPRINT participants with available serum samples at baseline level were included in this study. Case participants (n=510) who experienced a CV event during the SPRINT observation period (median follow-up of 3.2 years) and control participants (n=1,530) without CV events were sampled in a 1:3 ratio for measurements of serum magnesium level at baseline and 2-year follow-up. Baseline serum magnesium levels and 2-year percentage change in serum magnesium levels (ΔSMg). SPRINT primary composite CV outcome. Multivariable conditional logistic regression analysis, accounting for matching factors, was used to evaluate the association of baseline and ΔSMg with CV outcomes. Individual matching of cases and controls was based on the SPRINT treatment arm allocation (standard vs intensive) and prevalence of chronic kidney disease (CKD). The median serum magnesium level at baseline was similar among the case and control groups. In a fully adjusted model, each standard deviation (SD) (0.18mg/dL) higher of the baseline serum magnesium level was independently associated with a lower risk for composite CV outcomes in all study participants (adjusted odds ratio 95% CI, 0.79 [0.70-0.89]). This association was similar when serum magnesium levels were analyzed in quartiles but dissipated in the standard (vs intensive) arm of SPRINT (0.88 [0.76-1.02] vs 0.65 [0.53-0.79], respectively; Pinteraction=0.06). The presence or absence of CKD at baseline did not modify this association. ΔSMg was not independently associated with CV outcomes occurring after 2 years. ΔSMg was small in magnitude, limiting effect size. Higher baseline serum magnesium levels were independently associated with reduced risk for CV outcomes in all study participants, but ΔSMg was not associated with CV outcomes.