Systolic Blood Pressure Intervention Trial Participants Research Articles

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.

Antihypertensive Medication Regimens Used in the Systolic Blood Pressure Intervention Trial.

Describing the antihypertensive medication regimens used in the SPRINT (Systolic Blood Pressure Intervention Trial) would contextualize the standard and intensive systolic blood pressure (SBP) interventions and may inform future implementation efforts to achieve population-wide intensive SBP goals. We included SPRINT participants with complete medication data at the prerandomization and 12-month visits. Regimens were categorized by antihypertensive medication class. Analyses were stratified by treatment group (standard goal SBP <140 mm Hg versus intensive goal SBP <120 mm Hg). Among 7860 participants (83.7% of 9361 randomized), the median number of classes used at the prerandomization visit was 2.0 and 2.0 in the standard and intensive groups (P=0.559). At 12-months, the median number of classes used was 3.0 and 2.0 in the intensive and standard groups (P<0.001). Prerandomization, angiotensin-converting enzyme inhibitor (ACE), or angiotensin-II receptor blocker (ARB) monotherapy was the most common regimen in the intensive and standard groups (12.6% versus 12.2%). At 12-months, ACE/ARB monotherapy was still the most common regimen among standard group participants (14.7%) and was used by 5.3% of intensive group participants. Multidrug regimens used by the intensive and standard participants at 12 months were as follows: an ACE/ARB with thiazide (12.2% and 7.9%); an ACE/ARB with calcium channel blocker (6.2% and 6.8%); an ACE/ARB, thiazide, and calcium channel blocker (11.4% and 4.3%); and an ACE/ARB, thiazide, calcium channel blocker, and beta-blocker (6.5% and 1.2%). SPRINT investigators favored combining ACEs or ARBs, thiazide diuretics, and calcium channel blockers to target SBP <120 mm Hg, compared to ACE/ARB monotherapy to target SBP <140 mm Hg. URL: https://clinicaltrials.gov; Unique identifier: NCT01206062.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Intensive Blood Pressure Lowering in Patients With Malignant Left Ventricular Hypertrophy

BackgroundLeft ventricular hypertrophy (LVH) combined with elevations in cardiac biomarkers reflecting myocardial injury and neurohormonal stress (malignant LVH) is associated with a high risk for heart failure and death. ObjectivesThe aim of this study was to determine the impact of intensive systolic blood pressure (SBP) control on the prevention of malignant LVH and its consequences. MethodsA total of 8,820 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were classified into groups based on the presence or absence of LVH assessed by 12-lead ECG, and elevations in biomarker levels (high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro–B-type natriuretic peptide ≥125 pg/mL) at baseline. The effects of intensive vs standard SBP lowering on rates of acute decompensated heart failure (ADHF) events and death and on the incidence and regression of malignant LVH were determined. ResultsRandomization to intensive SBP lowering led to similar relative reductions in ADHF events and death across the combined LVH/biomarker groups (P for interaction = 0.68). The absolute risk reduction over 4 years in ADHF events and death was 4.4% (95% CI: −5.2% to 13.9%) among participants with baseline malignant LVH (n = 449) and 1.2% (95% CI: 0.0%-2.5%) for those without LVH and nonelevated biomarkers (n = 4,361). Intensive SBP lowering also reduced the incidence of malignant LVH over 2 years (2.5% vs 1.1%; OR: 0.44; 95% CI: 0.30-0.63). ConclusionsIntensive SBP lowering prevented malignant LVH and may provide substantial absolute risk reduction in the composite of ADHF events and death among SPRINT participants with baseline malignant LVH.

MO094: Intensive Blood Pressure Lowering and Myocardial Fibrosis Biomarkers in Individuals With and Without CKD: Results From the Systolic Blood Pressure Intervention Trial (Sprint)

Abstract BACKGROUND AND AIMS Circulating cardiac biomarkers implicated in the pathogenesis of heart disease may provide a non-invasive, more precise assessment of cardiovascular risk. In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive blood pressure lowering was associated with a 25% reduction in cardiovascular events and a 27% reduction in all-cause mortality. We sought to assess whether the beneficial effect of lowering systolic blood pressure on clinical outcomes was accompanied by a reduction in serum biomarkers of myocardial fibrosis. METHOD SPRINT, a multicenter randomized controlled trial conducted in the United States, enrolled participants aged ≥ 50 years, at increased risk for cardiovascular disease and randomized them to intensive systolic blood pressure lowering (target &amp;lt; 120 mmHg) or standard blood pressure lowering (target &amp;lt; 140 mmHg). In a randomly selected subgroup of SPRINT participants, myocardial fibrosis was assessed by two collagen-derived serum peptides, C-terminal propeptide of procollagen type I (CICP) and N-terminal propeptide of procollagen type 3 (P3NP) and Galectin 3 measured at study baseline and at 24 months follow-up. Chronic kidney disease was defined as eGFR &amp;lt; 60 mL/min/1.73 m2. Analyses were based on linear mixed models including clinic site as a random effect, with adjustments for treatment group and baseline level of each respective biomarker. RESULTS A total of 742 SPRINT participants with and without CKD with available measurements of myocardial fibrosis biomarkers at study baseline and 24 months were included in the study. The median (IQR) Galectin 3, CICP and P3NP levels at study baseline and 24 months follow-up in the intensive versus standard group are presented in the Table 1. Intensive blood pressure lowering was not associated with longitudinal changes in CICP or P3NP (Table 1 and Figure 1). Intensive blood pressure lowering was associated with a statistically significant increase in Galectin 3 level [between group mean difference 0.47 (IQR: 0.03–0.92) ng/mL, P = 0.04]. All of the findings were generally consistent across participants with and without CKD (Table 1). CONCLUSION In a random sample of SPRINT participants, intensive versus standard blood pressure lowering was not associated with a reduction in circulating myocardial fibrosis biomarkers overtime in hypertensive individuals with and without CKD.

Association of Intensive Blood Pressure Control and Living Arrangement on Cardiovascular Outcomes by Race

Living alone, a key proxy of social isolation, is a risk factor for cardiovascular disease. In addition, Black race is associated with less optimal blood pressure (BP) control than in other racial or ethnic groups. However, it is not clear whether living arrangement status modifies the beneficial effects of intensive BP control on reduction in cardiovascular events among Black individuals. To examine whether the association of intensive BP control with cardiovascular events differs by living arrangement among Black individuals and non-Black individuals (eg, individuals who identified as Alaskan Native, American Indian, Asian, Native Hawaiian, Pacific Islander, White, or other) in the Systolic Blood Pressure Intervention Trial (SPRINT). This secondary analysis incorporated data from SPRINT, a multicenter study of individuals with increased risk for cardiovascular disease and free of diabetes, enrolled at 102 clinical sites in the United States between November 2010 and March 2013. Race and living arrangement (ie, living alone or living with others) were self-reported. Data were collected between November 2010 and March 2013 and analyzed from January 2021 to October 2021. The SPRINT participants were randomized to a systolic BP target of either less than 120 mm Hg (intensive treatment group) or less than 140 mm Hg (standard treatment group). Antihypertensive medications were adjusted to achieve the targets in each group. Cox proportional hazards model was used to investigate the association of intensive treatment with the incident composite cardiovascular outcome (by August 20, 2015) according to living arrangement among Black individuals and other individuals. Transportability formula was applied to generalize the SPRINT findings to hypothetical external populations by varying the proportion of Black race and living arrangement status. Among the 9342 total participants, the mean (SD) age was 67.9 (9.4) years; 2793 participants [30%] were Black, 2714 [29%] lived alone, and 3320 participants (35.5%) were female. Over a median (IQR) follow-up of 3.22 (2.74-3.76) years, the primary composite cardiovascular outcome was observed in 67 of 1001 Black individuals living alone (6.7%), 76 of 1792 Black individuals living with others (4.2%), 108 of 1713 non-Black individuals living alone (6.3%), and 311 of 4836 non-Black individuals living with others (6.4%). The intensive treatment group showed a significantly lower rate of the composite cardiovascular outcome than the standard treatment group among Black individuals living with others (hazard ratio [HR], 0.53 [95% CI, 0.33-0.85]) but not among those living alone (HR, 1.07 [95% CI, 0.66-1.73]; P for interaction = .04). The association was observed among individuals who were not Black regardless of living arrangement status. Using transportability, we found a smaller or null association between intensive control and cardiovascular outcomes among hypothetical populations of 60% Black individuals or more and 60% or more of individuals living alone. Intensive BP control was associated with a lower rate of cardiovascular events among Black individuals living with others and individuals who were not Black but not among Black individuals living alone. ClinicalTrials.gov Identifier: NCT01206062.

Increased mortality with intensive control in patients with higher baseline SBP and lower Framingham risk.

In the Systolic Blood Pressure Intervention Trial (SPRINT), the relative reduction in primary outcome with intensive blood pressure (BP) control was numerically smallest in the highest baseline SBP tertile. In this post hoc analysis of SPRINT, the goal was to explore whether the effects of intensive BP treatment varied among patients with different baseline SBP and cardiovascular risks. Patient-level data from 9361 randomized participants in SPRINT were used. Heterogeneity between treatment and patient characteristics were examined stratified by different baseline SBP levels. Cumulative incidences of primary outcome and all-cause death were compared between treatment groups for patients with baseline SBP at least 160 mmHg and lower Framingham risk. For participants with a baseline SBP of at least 160 mmHg, intensive treatment was associated with a higher rate of all-cause death as compared with standard treatment (1.86 vs. 1.62% per year). After adjustment for age and sex, intensive treatment was associated with significantly increased all-cause death compared with standard treatment [hazard ratio (95% CI) for intensive group: 3.12 (1.00-9.69); P = 0.049] in participants with an SBP of at least 160 mmHg and a Framingham risk score of 31.3% or less (average of median and geometric mean). Patient outcomes were otherwise similar regarding age, use of antihypertensive therapy, cardiovascular disease or chronic kidney disease. Among the SPRINT participants with a baseline SBP of at least 160 mmHg and a lower Framingham risk score, targeting an SBP of less than 120mmHg compared with less than 140mmHg resulted in a significantly higher rate of all-cause death.

Genetic European Ancestry and Incident Diabetes in Black Individuals: Insights From the SPRINT Trial.

Black individuals have high incident diabetes risk, despite having paradoxically lower triglyceride and higher HDL (high-density lipoprotein) cholesterol levels. The basis of this is poorly understood. We evaluated the participants of SPRINT (Systolic Blood Pressure Intervention Trial) to assess the association of estimated European genetic ancestry with the risk of incident diabetes in self-identified Black individuals. Self-identified non-Hispanic Black SPRINT participants free of diabetes at baseline were included. Black participants were stratified into tertiles (T1-T3) of European ancestry proportions estimated using 106 biallelic ancestry informative genetic markers. The multivariable-adjusted association of European ancestry proportion with indices of baseline metabolic syndrome (ie, fasting plasma glucose, triglycerides, HDL cholesterol, body mass index, and blood pressure) was assessed. Multivariable-adjusted Cox regression determined the risk of incident diabetes (fasting plasma glucose ≥126 mg/dL or self-reported diabetes treatment) across tertiles of European ancestry proportion. Among 2466 Black SPRINT participants, a higher European ancestry proportion was independently associated with higher baseline triglyceride and lower HDL cholesterol levels (P<0.001 for both). European ancestry proportion was not associated with baseline fasting plasma glucose, body mass index, and blood pressure (P>0.05). Compared with the first tertile, those in the second (hazard ratio, 0.64 [95% CI, 0.45-0.90]) and third tertiles (hazard ratio, 0.61 [95% CI, 0.44-0.89]) of the European ancestry proportion had a lower risk of incident diabetes. A 5% point higher European ancestry was associated with a 29% lower risk of incident diabetes (hazard ratio, 0.71 [95% CI, 0.55-0.93]). There was no evidence of a differential association between the European ancestry proportion tertiles and incident diabetes between those randomized to intensive versus standard blood pressure treatment. The higher risk of incident diabetes in Black individuals may have genetic determinants in addition to adverse social factors. Further research may help understand the interplay between biological and social determinants of cardiometabolic health in Black individuals. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Analysis of Therapeutic Inertia and Race and Ethnicity in the Systolic Blood Pressure Intervention Trial: A Secondary Analysis of a Randomized Clinical Trial

Therapeutic inertia may contribute to racial and ethnic differences in blood pressure (BP) control. To determine the association between race and ethnicity and therapeutic inertia in the Systolic Blood Pressure Intervention Trial (SPRINT). This cross-sectional study was a secondary analysis of data from SPRINT, a randomized clinical trial comparing intensive (<120 mm Hg) vs standard (<140 mm Hg) systolic BP treatment goals. Participants were enrolled between November 8, 2010, and March 15, 2013, with a median follow-up 3.26 years. Participants included adults aged 50 years or older at high risk for cardiovascular disease but without diabetes, previous stroke, or heart failure. The present analysis was restricted to participant visits with measured BP above the target goal. Analyses for the present study were performed in from October 2020 through March 2021. Self-reported race and ethnicity, mutually exclusively categorized into groups of Hispanic, non-Hispanic Black, or non-Hispanic White participants. Therapeutic inertia, defined as no antihypertensive medication intensification at each study visit where the BP was above target goal. The association between self-reported race and ethnicity and therapeutic inertia was estimated using generalized estimating equations and stratified by treatment group. Antihypertensive medication use was assessed with pill bottle inventories at each visit. Blood pressure was measured using an automated device. A total of 8556 participants, including 4141 in the standard group (22 844 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1467 women [35.4%]) and 4415 in the intensive group (35 453 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1584 women [35.9%]) with at least 1 eligible study visit were included in the present analysis. Among non-Hispanic White, non-Hispanic Black, and Hispanic participants, the overall prevalence of therapeutic inertia in the standard vs intensive groups was 59.8% (95% CI, 58.9%-60.7%) vs 56.0% (95% CI, 55.2%-56.7%), 56.8% (95% CI, 54.4%-59.2%) vs 54.5% (95% CI, 52.4%-56.6%), and 59.7% (95% CI, 56.5%-63.0%) vs 51.0% (95% CI, 47.4%-54.5%), respectively. The adjusted odds ratios in the standard and intensive groups for therapeutic inertia associated with non-Hispanic Black vs non-Hispanic White participants were 0.85 (95% CI, 0.79-0.92) and 0.94 (95% CI, 0.88-1.01), respectively. The adjusted odds ratios for therapeutic inertia comparing Hispanic vs non-Hispanic White participants were 1.00 (95% CI, 0.90-1.13) and 0.89 (95% CI, 0.79-1.00) in the standard and intensive groups, respectively. Among SPRINT participants above BP target goal, this cross-sectional study found that therapeutic inertia prevalence was similar or lower for non-Hispanic Black and Hispanic participants compared with non-Hispanic White participants. These findings suggest that a standardized approach to BP management, as used in SPRINT, may help ensure equitable care and could reduce the contribution of therapeutic inertia to disparities in hypertension. ClinicalTrials.gov identifier: NCT01206062.

Association of chronic liver disease with cognition and brain volumes in two randomized controlled trial populations

Background and purposeWe examined the association of chronic liver disease with cognition and brain imaging markers of cognitive impairment using data from two large randomized controlled trials that included participants based on diabetes and hypertension, two common systemic risk factors for cognitive impairment and dementia. MethodsWe performed post hoc analyses using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Systolic Blood Pressure Intervention Trial (SPRINT) studies, which included participants with diabetes and hypertension, respectively. Data were from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. In ACCORD, our measure of chronic liver disease was the Dallas Steatosis Index (DSI). In SPRINT, we used self-reported chronic liver disease. We used linear regression to evaluate the association between the measure of chronic liver disease and both baseline and longitudinal cognitive test performance and brain magnetic resonance imaging volume measurements. ResultsAmong 2969 diabetic participants in ACCORD, the mean age of participants was 62 years, 47% were women. The median DSI was 1.0 (IQR, 0.2–1.8); a DSI of 1.0 corresponds to approximately a > 70% probability of having NAFLD. Among 2890 hypertensive participants in SPRINT, the mean age was 68 years, and 37% were women, and 60 (2.1%) had chronic liver disease. There were no consistent associations between liver disease and cognitive performance or brain volumes at baseline or longitudinally after adjustment. ConclusionMarkers of chronic liver disease were not associated with cognitive impairment or related brain imaging markers among individuals with diabetes and hypertension.

Self-Reported Race as a Social Determinant of Stroke Risk in Observational Versus Clinical Trial Datasets

ObjectivesSelf-reported Black (SRB) Americans are approximately twice as likely to have a stroke as self-reported White (SRW) Americans. While social determinants of health and vascular risk factors account for some of the disparity, half the increased risk remains unexplained and may be related to unmeasured real-world factors of the racialized experience. Materialsand Methods In this cohort study, we compared SRB and SRW participants in the Systolic Blood Pressure Intervention Trial (SPRINT) to the same groups in the observational Atherosclerosis Risk in Communities (ARIC) study to evaluate if clinical trial participation mitigates disparities in stroke risk. We set the ARIC baseline at visit 4 and excluded participants with prior stroke to create an ARIC cohort similar in age to SPRINT participants. The study outcome was incident primary stroke. We report hazard ratios from Cox models and inverse-probability weighted Cox models with propensity score matching on participant age, sex, diabetes, atrial fibrillation, and smoking. ResultsWe included 10,094 patients from ARIC and 8,869 from SPRINT, of which 26.1% were SRB. The risk of stroke between SRW participants in SPRINT versus ARIC was not significantly different (IPW-Weighted HR 0.78 [0.52–1.19]). SRB ARIC participants were twice as likely to have a stroke as SRW ARIC participants (IPW-Weighted HR = 1.96 [1.41–2.71]). However, SRB SPRINT participants did not have higher stroke risk compared to SRW SPRINT or ARIC participants (IPW-Weighted HR 0.99 [0.68–-1.77] and 0.95 [.57–1.59], respectively). SRB SPRINT participants in the intensive BP control group had a lower risk of stroke compared to SRB ARIC participants (IPW-Weighted HR = 0.39 [0.20–0.75]). ConclusionsSRB race, compared to SRW race, is associated with an increase in primary stroke risk in the ARIC study but not in the SPRINT trial. The absence of the racial disparity in stroke incidence in SPRINT indicates that aspects of the disparity are modifiable. Population-based interventions that test this hypothesis deserve further attention.

Abstract 13926: Air Pollution and Pulse Wave Velocity in Patients With Hypertension

Introduction: Ambient air pollution has been linked with increased cardiovascular risk, yet the mechanisms of this are incompletely understood. We sought to investigate the linkage between ambient particulate matter (PM 2.5 ) and pulse wave velocity (PWV), a marker of arterial stiffness, in the systolic blood pressure intervention trial (SPRINT). Methods: A subset of SPRINT participants underwent PWV measurements at baseline, and annually through 3 years using the Sphygmocor CPV® system and were linked with ambient PM 2.5 using participant address at study entry. Spearman’s correlations and linear regression analyses were performed to investigate the relationship between PM 2.5 , baseline PWV, and change in PWV through year 3. Results: A total of 517 participants were included (259 to standard BP, and 258 to intensive BP). Mean PM 2.5 was 9.5±1.8 μg/m 3 and mean baseline PWV was 10.7±2.7 m/s. Over 3 years, PWV increased by a mean of 0.27 m/sec from baseline (P&lt;0.001). There was no correlation between PM 2.5 and PWV at baseline (rho=0.01, P=0.84) or year 1 (rho=0.04, P=0.38). PM 2.5 , however, significantly correlated change in PWV between baseline and year 2 (rho=0.23, P&lt;0.001), and between baseline and year 3 [ΔPWV 0-3 ] (rho=0.26, P&lt;0.001). The association between PM 2.5 and ΔPWV 0-3 was similar in the intensive (rho=0.29, P&lt;0.001) and standard BP arms (rho=0.25, P&lt;0.001). After adjusting for age, sex, race, study randomization, Framingham risk score, smoking, prevalent cardiovascular disease, and eGFR, PM 2.5 remained associated with ΔPWV 0-3 (β 0.37 per 1 μg/m 3 of PM 2.5 , standard error 0.06, P&lt;0.001). Among participants living under the national air quality of 12 μg/m 3 , there was no change in PWV over 3 years (ΔPWV 0-3 0.13 m/s, P=0.26) while participants living above the NAAQS threshold experience significantly increased PWV over 3 years (ΔPWV 0-3 1.3 m/s, P&lt;0.001), P=0.001 between PM 2.5 &lt;12 vs ≥12 μg/m 3 . Conclusions: SPRINT participants who live in areas with higher ambient air pollution (PM 2.5 ) levels experienced larger increase in PWV over 3 years, without a significant impact of intensive BP lowering strategy. Arterial stiffness should be investigated as a mediator of air pollution-related cardiovascular risk.

Risk-Based Intensive Blood Pressure Lowering and Prevention of Heart Failure: A SPRINT Post Hoc Analysis.

[Figure: see text].

Abstract P021: Association Of Resting Heart Rate With All-cause And Cardiovascular Mortality: Sprint

Introduction: Elevated resting heart rate (RHR) has been shown to be associated with both all-cause and cardiovascular mortality. Prior studies have provided conflicting estimates of the strength of each association. To explore the relationship between RHR and competing mortality risks, we sought to compare the association between RHR and cardiovascular and non-cardiovascular mortality among participants in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods: Eligible SPRINT participants had baseline RHR, longitudinal follow-up, and were not using beta blockers or non-dihydropyridine calcium channel blockers. Mortality was classified by a treatment-blinded adjudication committee as cardiovascular if secondary to coronary heart disease, stroke, sudden cardiac death, or congestive heart failure. Multivariable Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CI) for cardiovascular and non-cardiovascular mortality, separately, associated with a 10 beats per minute increase in RHR. Results: Among 5,571 eligible SPRINT participants (67.1 ± 9.4 years, 33.8% female, 63.8% white, mean RHR 70.4±11.8 beats per minute) over a median 3.8 years of follow-up, there were 56 cardiovascular deaths and 176 non-cardiovascular deaths. In models adjusted for age, sex, race, prior cardiovascular disease, smoking, systolic blood pressure, creatinine, total cholesterol, high-density lipoprotein cholesterol, and trial treatment assignment, higher RHR (per ten beat-per-minute increase) was associated with both cardiovascular (HR 1.17, 95% CI 1.02-1.35) and non-cardiovascular mortality (HR 1.27, 95% CI 1.13-1.43). Conclusions: Elevated RHR was associated with both cardiovascular and non-cardiovascular mortality, suggesting that RHR may serve as a marker of both global health rather and cardiovascular health. Higher RHR may reflect imbalance in autonomic tone and further studies are needed to explore the mechanisms of these associations.4

Estimating Systolic Blood Pressure Intervention Trial Participant Posttrial Survival Using Pooled Epidemiologic Cohort Data.

BackgroundIntensive systolic blood pressure treatment (<120 mm Hg) in SPRINT (Systolic Blood Pressure Intervention Trial) improved survival compared with standard treatment (<140 mm Hg) over a median follow‐up of 3.3 years. We projected life expectancy after observed follow‐up in SPRINT using SPRINT‐eligible participants in the NHLBI‐PCS (National Heart, Lung, and Blood Institute Pooled Cohorts Study).Methods and ResultsWe used propensity scores to weight SPRINT‐eligible NHLBI‐PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in‐trial survival (<4 years) using a time‐based flexible parametric survival model. In SPRINT‐eligible NHLBI‐PCS participants, we estimated posttrial survival (≥4 years) using an age‐based flexible parametric survival model and applied the formula to SPRINT participants to predict posttrial survival. We projected overall life expectancy for each SPRINT participant and compared it to parametric regression (eg, Gompertz) projections based on SPRINT data alone. We included 8584 SPRINT and 10 593 SPRINT‐eligible NHLBI‐PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.2 (8.8) years, and 35.5% and 37.6% were women in SPRINT and NHLBI‐PCS, respectively. Using the NHLBI‐PCS–based method, projected mean life expectancy from randomization was 21.0 (7.4) years with intensive and 19.1 (7.2) years with standard treatment. Using the Gompertz regression, life expectancy was 11.2 (2.3) years with intensive and 10.5 (2.2) years with standard treatment.ConclusionsCombining SPRINT and NHLBI‐PCS observed data likely offers a more realistic estimate of life expectancy than parametrically extrapolating SPRINT data alone. These results offer insight into the potential long‐term effectiveness of intensive SBP goals.

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants

The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI). Observational cohort nested in a clinical trial. 2,351 SPRINT participants with eGFR< 60 mL/min/1.73 m2 at baseline. Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M) and β2-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH). Longitudinal changes in eGFR and risk of AKI. We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models toevaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression. From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively). The factors require validation in other settings. EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.

Patient Selection for Intensive Blood Pressure Management Based on Benefit and Adverse Events

BackgroundIntensive systolic blood pressure (SBP) treatment prevents cardiovascular disease (CVD) events in patients with high CVD risk on average, though benefits likely vary among patients. ObjectivesThe aim of this study was to predict the magnitude of benefit (reduced CVD and all-cause mortality risk) along with adverse event (AE) risk from intensive versus standard SBP treatment. MethodsThis was a secondary analysis of SPRINT (Systolic Blood Pressure Intervention Trial). Separate benefit outcomes were the first occurrence of: 1) a CVD composite of acute myocardial infarction or other acute coronary syndrome, stroke, heart failure, or CVD death; and 2) all-cause mortality. Treatment-related AEs of interest included hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, and acute kidney injury. Modified elastic net Cox regression was used to predict absolute risk for each outcome and absolute risk differences on the basis of 36 baseline variables available at the point of care with intensive versus standard treatment. ResultsAmong 8,828 SPRINT participants (mean age 67.9 years, 35% women), 600 CVD composite events, 363 all-cause deaths, and 481 treatment-related AEs occurred over a median follow-up period of 3.26 years. Individual participant risks were predicted for the CVD composite (C index = 0.71), all-cause mortality (C index = 0.75), and treatment-related AEs (C index = 0.69). Higher baseline CVD risk was associated with greater benefit (i.e., larger absolute CVD risk reduction). Predicted CVD benefit and predicted increased treatment-related AE risk were correlated (Spearman correlation coefficient = −0.72), and 95% of participants who fell into the highest tertile of predicted benefit also had high or moderate predicted increases in treatment-related AE risk. Few were predicted as high benefit with low AE risk (1.8%) or low benefit with high AE risk (1.5%). Similar results were obtained for all-cause mortality. ConclusionsSPRINT participants with higher baseline predicted CVD risk gained greater absolute benefit from intensive treatment. Participants with high predicted benefit were also most likely to experience treatment-related AEs, but AEs were generally mild and transient. Patients should be prioritized for intensive SBP treatment on the basis of higher predicted benefit. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062)

INFLUENCE OF RESTING HEART RATE ON BLOOD PRESSURE LOWERING EFFECT

Objective: Elevated resting heart rate (RHR) identifies hypertensive subjects at higher cardiovascular risk. The study was aimed to compare benefit of intensive blood pressure (BP) lowering in subjects with higher and lower RHR. Design and method: The analysis was performed using Systolic Blood Pressure Intervention Trial (SPRINT) data shared by National Heart, Lung and Blood Institute. SPRINT trial assessed intensive lowering of systolic BP to a target &lt; 120 mm Hg in comparison to standard goal (&lt; 140 mm Hg). Baseline RHR was estimated as a pulse rate obtained during automated office BP measurements at first study visit. RHR higher than 80 b.p.m. was defined as increased according to current European Society of Cardiology guidelines. Composite outcome event (CE) included myocardial infarction and other acute coronary syndrome, stroke, heart failure decompensation and cardiovascular death. Cox proportional model was used to assess impact of BP lowering in subjects with RHR higher and lower than 80 bpm. P-value for interaction between study BP intervention and baseline RHR. Results: Data of 9361 SPRINT participants, aged 67.9 ± 9.4 years, were analyzed. 3332 (35.6%) were female an 1877 (20.1%) were diagnosed with prior cardiovascular disease. Mean baseline RHR was 66.3 ± 11.6 b.p.m. Baseline HR in both treatment arms was similar (standard arm 66.3 ± 11.7 b.p.m. vs intensive arm 66.2 ± 11.5 b.p.m., p = 0.762) 1198 (12.8%) participants had baseline RHR higher than 80 b.p.m. and experienced 78 (6.8%) CE events. There were 484 (5.9%) events among subjects with RHR lower than 80 b.p.m. Intensive lowering of systolic BP was beneficial both in subjects with elevated RHR (hazard ratio 0.79 with 95% confidence interval 0.51–1.24, p = 0.311) and non-elevated RHR (hazard ratio 0.75 with 95% CI 0.62–0.89, p = 0.002). The intervention between study BP intervention and baseline RHR was not significant (p for interaction 0.819). Conclusions: Elevated RHR does not influence effect of BP reduction on cardiovascular events risk.

TARGET DIASTOLIC BLOOD PRESSURE RANGE ACCORDING TO THE AGE CATEGORY AND PRESENCE OF PRIOR CARDIOVASCULAR DISEASE DURING ANTIHYPERTENSIVE TREATMENT

Objective: The evidence supporting European Society of Cardiology (ESC) recommended target diastolic blood pressure (DBP) in range 70–79 mm Hg is scarce. The study was aimed to evaluate optimal DBP according to age category (&lt; 65 years, 65–80 years, &gt; 80 years) and presence of cardiovascular disease (CVD). Design and method: Analysis was performed using Systolic Blood Pressure Intervention Trial (SPRINT) data shared by National Heart, Lung and Blood Institute. On-treatment DBP was computed as a mean of DBP measurements made in period from 6th month of participation to the end of the study, when BP was stable. Composite outcome event (CE) included myocardial infarction and other acute coronary syndrome, stroke, heart failure decompensation and cardiovascular death. Adjusted Cox proportional models were used to establish association between DBP and hazard ratio according to age category and presence of CVD. Results: Data of 8890 SPRINT participants (aged 67.8 ± 9.4 years) with available data were analysed. 3139 (35.3%) were female and 1773 (19.9%) were diagnosed with prior CVD. There was 3049 (42.8%) participants younger than 65 years, 3288 (46.2%) in age 65–80 years and 780 (11%) older than 80 years in group without prior CVD. There was 583 (32.9%) participants younger than 65 years, 891 (50.3%) in age 65–80 years and 299 (16.9%) older than 80 years in group with prior CVD. There was 293 (4.1%) CE events in group without prior CVD and 168 (9.5%) CE events in participants with prior CVD. Figure 1 presents the relationship between DBP and hazard ratio according to age category and presence of CVD. Conclusions: Optimal DBP range for patients with hypertension and CVD younger than 80 years is similar to the recommended interval 70–79 mm Hg. Similar DBP target should be recommended for younger than 65 years adults with hypertension but without prior CVD. DBP range 70–79 mm Hg should be reconsidered as a treatment target in subjects without prior CVD older than 65 years and in subjects with prior CVD older than 80 years.

Modification of the effects of intensive systolic blood pressure control on kidney outcomes by baseline body mass index.

Obesity and intensive systolic blood pressure (SBP) control are independently associated with greater risk of acute kidney injury (AKI) and incident chronic kidney disease (CKD). We examined whether baseline body mass index (BMI) modifies the effects of intensive SBP lowering on AKI or incident CKD. The systolic blood pressure intervention trial (SPRINT) randomized 9361 participants with high blood pressure to an SBP target of either <120 mm Hg or < 140 mm Hg. In a secondary analysis of 9210 SPRINT participants with a baseline BMI of ≥18.5 and < 50 kg/m2 , we examined the interactions of baseline BMI and SPRINT SBP intervention on subsequent AKI and incident CKD. Each 5 kg/m2 increase in baseline BMI was associated with higher risk of AKI (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.01 to 1.25) and incident CKD (HR 1.17, 95% CI 1.01 to 1.32). Intensive SBP control increased the risk of AKI (HR 1.68, 95% CI 1.22-2.11) and incident CKD (HR 3.49, 95% CI 2.47-4.94). The increased risk of AKI with intensive SBP control was consistent across the baseline BMI spectrum (linear interaction p = 0.55); however, the risk of incident CKD with SPRINT intervention increased with higher BMI (linear interaction p = 0.043). The increased risk of adverse kidney events seen with intensive SBP control in the SPRINT persisted across the baseline BMI spectrum. A higher baseline BMI was associated with an augmented risk of incident CKD with intensive SBP control.