Intensive Systolic Blood Pressure Control Research Articles

Association of intensive blood pressure management with cardiovascular outcomes in patients using multiple classes of antihypertensive medications: a post-hoc analysis of the STEP Trial

High medication burden is associated with poor treatment effect and high risk of cardiovascular outcomes. This study aimed to investigate the association between the antihypertensive medication burden and cardiovascular outcomes in the STEP trial. This post-hoc analysis of the STEP trial enrolled 8511 participants, including 8041 with low burden and 470 with high burden. High antihypertensive medication burden was defined as being treated with ≥3 different classes of prescribed antihypertensive medications. The primary outcome was a composite of cardiovascular outcomes. Fine-Gray model was used in this study. Among all participants, high antihypertensive medication burden was associated with a higher risk of the primary outcome compared with low medication burden (HR, 1.52; 95% CI, 1.03–2.24), which was consistent in the standard group (HR, 1.95; 95% CI, 1.20–3.18) and the intensive group (HR, 1.10; 95% CI, 0.57–2.13; Pinteraction = 0.18). The beneficial effects of intensive systolic blood pressure (SBP) control on the primary outcome remained significant in the high burden group (HR, 0.42; 95% CI, 0.19–0.95) and the low burden group (HR, 0.79; 95% CI, 0.63–0.98; Pinteraction = 0.18). At 24 months, the percentage of participants achieving the target SBP was lower in the high medication burden group (risk ratio, 0.93; 95% CI, 0.89–0.98). In both standard and intensive treatment groups, participants with a high medication burden were harder to achieve the target SBP (Pinteraction = 0.65). High antihypertensive medication burden was associated with worse SBP control and a greater risk of cardiovascular events. Intensive SBP control showed cardiovascular benefits in both medication burden groups. Trial registration: STEP ClinicalTrials.gov number, NCT03015311. Registered 2 January 2017.

Intensive Versus Standard Blood Pressure Management after Endovascular Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

Prospective clinical studies on blood pressure (BP) management targets after endovascular therapy (EVT) for acute ischemic stroke (AIS) have recently been published. Our objective was to assess the impact on clinical outcomes of BP management guided by established systolic BP (SBP) targets within the first 24 hours after successful EVT. Four randomized controlled trials (RCTs) including 1556 participants across 5 SBP target settings identified from 5 databases up to September 6, 2023 were included in this systematic review and meta-analysis. All the intensive SBP target groups in these RCTs were combined to facilitate head-to-head comparisons. Patients receiving intensive SBP management had lower risk of 90-day functional independence as assessed by the modified Rankin scale score (relative risk [RR], 0.81; 95% confidence interval [CI], 0.72 to 0.91; I2, 12%), excellent outcomes (RR,0.86; 95% CI, 0.75 to 0.99; I2, 7%), favorable outcomes (RR, 0.85; 95% CI, 0.78 to 0.92; I2, 0%), and quality of life (standardized mean difference, -0.22; 95% CI, -0.35 to -0.10; I2,0%). There were no differences in the probability of any intracerebral hemorrhage (RR, 1.04; 95% CI, 0.92 to 1.19; I2,0%), symptomatic intracerebral hemorrhage (RR, 1.10; 95% CI, 0.76 to 1.60; I2, 0%), stroke-related death (RR, 1.16; 95% CI, 0.80 to 1.68; I2, 0%), or parenchymal hematoma (RR, 1.71; 95% CI, 0.74 to 3.98; I2, 47%) between SBP targets. This meta-analysis provides evidence from RCTs suggesting that intensive SBP control (target<160mm Hg) may be detrimental to clinical outcomes in AIS patients with successful reperfusion after EVT.

Abstract WP210: Intensive vs. Conventional Blood Pressure Management After Thrombectomy for Acute Ischemic Stroke: Systemic Review and Meta-Analysis of Randomized Controlled Trials

Background: Optimal Blood pressure management after thrombectomy for acute ischemic stroke and its association with clinical outcomes remains unclear. We performed this study to compare clinical outcomes between intensive systolic blood pressure (SBP) control (&lt;120-140mmHg) and conventional SBP control (&lt; 180mmHg). Methods: In September 2023, this registered systematic review (CRD42023464176) was performed using multiple databases for the following keywords: stroke, thrombectomy, and Blood Pressure from 2010 to present. Randomized control studies were included if they had the reported the outcome for adults aged &gt;18 who underwent successful thrombectomy (defined as mTICI 2b or higher) for acute ischemic stroke. The primary outcome of interest was the rate of functional independence, defined as a modified Rankin scale of 0-2 at 90 days. The secondary outcomes of interest included rates of mortality, and symptomatic intracranial hemorrhage (sICH). For all outcome events, corresponding odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effects meta-analysis model. Results: Four studies comprising 1497 patients were included. Compared to conventional SBP control, intensive SBP control was associated with lower rates of functional independence (OR 0.67, 95% CI 0.51- 0.88 p=0.0). There were comparable rates of sICH (OR 1.12, 95% CI 0.75-1.67; p = 0.56) and mortality (OR 1.21, 95% CI 0.90-1.64; p = 0.19) between intensive and conventional SBP control groups. Conclusions: Our findings suggest that intensive blood pressure control does not improve clinical outcomes. More robust data is needed to draw definite conclusions.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (&lt;120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP ( = 132 mm Hg vs &lt;132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., &gt;65 years old, Table 1).ConclusionRestricting age to individuals to = 65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP&lt;120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation

AbstractBackgroundEpidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (&lt;120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.MethodWe used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP (≥132 mm Hg vs &lt;132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.ResultAs expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., &gt;65 years old, Table 1).ConclusionRestricting age to individuals to ≤65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP&lt;120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.

Abstract 15307: Sex-Specific Cognitive Effects of Intensive Systolic Blood Pressure Lowering in Patients With and Without Diabetes Mellitus

Background: The SPRINT trial demonstrated that intensive systolic blood pressure (SBP) lowering (&lt;120 mm Hg) reduced risk of mild cognitive impairment compared to standard SBP control (&lt;140 mm Hg). However, the ACCORD-BP trial did not show the same effect in patients with diabetes. Aims: This study aimed to 1) determine the impact of intensive SBP on cognitive impairment in patients with and without diabetes by analyzing individual patient data of ACCORD-BP and SPRINT, using three cognitive domains and the same follow-up durations, and 2) assess potential sex differences in the effect of intensive SBP lowering on cognitive function in patients with and without diabetes. Methods/Approach: We pooled individual patient data from the SPRINT and ACCORD-BP and standardized cognitive outcomes at baseline, 20-24 months, and 40-48 months post-randomization. Both studies randomized hypertensive patients to intensive SBP control or standard SBP control. Cognitive outcomes included general cognitive function, cognitive processing speed, and memory. Linear mixed models were employed, adjusting for covariates such as age, baseline BMI, SBP, eGFR and LDL. Analyses were repeated separately for patients with and without diabetes and for men and women. Results: The study cohort comprised of 10,800 patients (mean age 67.2 ±9.1 years; mean baseline SBP:139.6 ± 15.6 mmHg, with 14.7% having diabetes and 61.8% being women. Patients without diabetes in the intensive SBP control group had an accelerated decline in processing speed decline compared to the standard control group (P time*treatment interaction=0.02). Patients with diabetes exhibited similar rates of decline in all cognitive outcomes across treatment groups. Stratifying by sex, intensive SBP control was associated with improved memory in female patients (estimated sd=0.07 (0.03), p=0.06), and faster decline in processing speed in male patients. (p=0.03). Conclusions: The effects of intensive SBP control on general cognitive function were comparable between patients with and without diabetes and between men and women. While intensive SBP control was associated with accelerated decline in cognitive processing speed in patients without diabetes, it was linked to improved memory in female patients.

Association of baseline serum cholesterol with benefits of intensive blood pressure control.

Intensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether baseline serum lipid parameters influence the benefits of intensive SBP control is unclear. The STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to <130 mmHg) and standard (SBP target of 130 to <150 mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. A total of 8283 participants from the STEP study were included in this post hoc analysis to examine whether the effects of the SBP intervention differed by baseline low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) concentrations. Regardless of the randomized SBP intervention, baseline LDL-C and non-HDL-C concentrations had a J-shaped association with the hazard of the primary outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline LDL-C level ( P for interaction = 0.80) and non-HDL-C level ( P for interaction = 0.95). Adjusted subgroup analysis using tertiles in LDL-C1 (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.52-1.13; P = 0.18), LDL-C2 (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29), and LDL-C3 (HR, 0.68; 95% CI, 0.47-0.98; P = 0.04) was provided, with an interaction P value of 0.49. Similar results were showed in non-HDL-C1 (HR, 0.87; 95% CI, 0.59-1.29; P = 0.49), non-HDL-C2 (HR, 0.70; 95% CI, 0.48-1.04; P = 0.08), and non-HDL-C3 (HR, 0.67; 95% CI, 0.47-0.95; P = 0.03), with an interaction P -value of 0.47. High baseline serum LDL-C and non-HDL-C concentrations were associated with increased risk of primary cardiovascular disease outcome, but there was no evidence that the benefit of the intensive SBP control differed by baseline LDL-C and non-HDL-C concentrations. ClinicalTrials.gov, NCT03015311.

Associations of Hyponatremia with Cognition Function and All-Cause Mortality: Post Hoc Analysis of the Systolic BP Intervention Trial.

Acute neurological effects of severe hyponatremia are well known. However, the long-term association of hyponatremia with cognitive impairment are unclear. In this post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), we examined whether incident hyponatremia is a risk factor for mild cognitive impairment (MCI) or probable dementia (PD). In those with baseline serum sodium ≥ 130 mmol/L, we defined incident hyponatremia in the first 6 months as a SPRINT safety alert for serum sodium < 130 mmol/L from randomization to the 6-month visit. In multivariate, Cox regression models adjusted for baseline cognitive function and other variables, we related incident hyponatremia in the first 6 months with subsequent MCI or PD in 8,540 participants with cognitive outcomes data and with all-cause mortality (ACM) in 9,135 participants with mortality data. Incident hyponatremia in the first 6 months was noted in 116 (1.4%) participants. Older age, female sex, non-African American race, lower body mass index and randomization to intensive systolic blood pressure control were associated with incident hyponatremia. Compared to those without hyponatremia, those with incident hyponatremia had higher risk of PD (2.1 versus 0.9 events/ 100 person years, HR 3.08, 95% CI 1.48 to 6.41) but not MCI (3.1 versus 3.6 events/ 100 person years, HR 0.95, 95% CI 0.54 to 1.68) and the composite of MCI/ PD (5.0 versus 4.2 events/ 100 person years, HR 1.28, 95% CI 0.82 to 2.0). There were no significant differences in ACM (HR 1.84, 95% CI 0.90 to 3.73). Biological plausibility for the association of incident hyponatremia with PD but not MCI or death is unclear. The association of incident hyponatremia with PD could reflect a chance finding or non-causal biological association or causal relationship.

Study on the associations of meeting intensive systolic blood pressure control goals with risk for incident cardiovascular and cerebrovascular diseases among the adult hypertensive patients in China

Objective: To evaluate the associations of meeting intensive systolic blood pressure (SBP) control goals with risk for incident cardiovascular and cerebrovascular diseases among the adult hypertensive patients in China. Methods: We used data from adult hypertensive patients from the China Kadoorie Biobank. logistic regression models evaluated the influencing factors of meeting intensive and standard SBP control goals. Cox proportional hazard models evaluated the associations between meeting intensive vs. standard SBP control goals and risk for incident cardiovascular and cerebrovascular diseases. Results: A total of 3 628 hypertensive patients who reported continuous medication use were included in this study, of which 5.0% of the participants met the goals of intensive SBP control (≤130 mmHg). Participants with higher educational attainment (OR=2.36,95%CI: 1.32-4.04), healthier diet (OR=2.09,95%CI: 1.45-2.96), daily intake of fresh fruit (OR=1.67,95%CI: 1.17-2.36) and combination treatment (OR=1.82,95%CI: 1.03-3.09) were more likely to meet intensive SBP control goal after adjustment of age, sex and urban/rural areas. During an average follow-up of (10.0±3.7) years, 1 278 cases of composite cardiovascular outcome were recorded. This study did not find a statistical correlation between achieving the goal of enhanced SBP control and the occurrence of composite cardiovascular and cerebrovascular outcomes (HR=0.89, 95%CI: 0.63-1.25). For major adverse cardiovascular events (MACE), cerebrovascular diseases, stroke, and ischemic stroke, we observed a trend of decrease in risk of outcomes with more intensive SBP control (trend test P<0.05). Conclusions: We observed decreased risk for MACE and cerebrovascular diseases with more intensive SBP control. However, there was no significant risk reduction for cardiovascular and cerebrovascular diseases when meeting the intensive SBP control goal, compared to the standard SBP control goal.

Machine-learning-based high-benefit approach versus conventional high-risk approach in blood pressure management.

In medicine, clinicians treat individuals under an implicit assumption that high-risk patients would benefit most from the treatment ('high-risk approach'). However, treating individuals with the highest estimated benefit using a novel machine-learning method ('high-benefit approach') may improve population health outcomes. This study included 10 672 participants who were randomized to systolic blood pressure (SBP) target of either <120 mmHg (intensive treatment) or <140 mmHg (standard treatment) from two randomized controlled trials (Systolic Blood Pressure Intervention Trial, and Action to Control Cardiovascular Risk in Diabetes Blood Pressure). We applied the machine-learning causal forest to develop a prediction model of individualized treatment effect (ITE) of intensive SBP control on the reduction in cardiovascular outcomes at 3 years. We then compared the performance of high-benefit approach (treating individuals with ITE >0) versus the high-risk approach (treating individuals with SBP ≥130 mmHg). Using transportability formula, we also estimated the effect of these approaches among 14 575 US adults from National Health and Nutrition Examination Surveys (NHANES) 1999-2018. We found that 78.9% of individuals with SBP ≥130 mmHg benefited from the intensive SBP control. The high-benefit approach outperformed the high-risk approach [average treatment effect (95% CI), +9.36 (8.33-10.44) vs +1.65 (0.36-2.84) percentage point; difference between these two approaches, +7.71 (6.79-8.67) percentage points, P-value <0.001]. The results were consistent when we transported the results to the NHANES data. The machine-learning-based high-benefit approach outperformed the high-risk approach with a larger treatment effect. These findings indicate that the high-benefit approach has the potential to maximize the effectiveness of treatment rather than the conventional high-risk approach, which needs to be validated in future research.

Asociación del nivel de ácido úrico en suero con los beneficios del control intensivo de la presión arterial

Introduction and objectivesIntensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether the serum uric acid concentration at baseline alters the benefits of intensive SBP control is unknown. MethodsThe STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to<130mmHg) and standard (SBP target of 130 to <150mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. This post hoc analysis was performed to examine whether the effects of intensive SBP intervention differed by the baseline uric acid concentration using 2 models: restricted cubic spline curves and subgroup analyses, both based on the Fine-Gray subdistribution hazard model in the analysis of the primary outcome and secondary outcomes (excluding all-cause death). In the analysis of all-cause death, the Cox regression model was used. We also examined the change in the follow-up uric acid concentrations. ResultsOverall, the risk of the primary outcome rose as the cumulative uric acid concentration increased in both the intensive and standard treatment groups. Patients with intensive treatment had a lower multivariable-adjusted subdistribution hazard ratio for the primary outcome, but with a wide overlap of 95%CI. Next, we stratified patients according to their baseline uric acid concentration (tertile 1 [T1], <303.0μmol/L; tertile 2 [T2], 303.0 to <375.8μmol/L; and tertile 3 [T3], ≥375.8μmol/L). Subgroup analyses using tertiles provided HRs and 95%CI in T1 (HR, 0.55; 95%CI, 0.36–0.86; P=.008), T2 (HR, 0.80; 95%CI, 0.56–1.14; P=.22) and T3 (HR, 0.86; 95%CI, 0.60–1.21; P=.39), with an interaction P value of .29. The results for most of the secondary outcomes followed the same trends. ConclusionsThere was no evidence that the benefit of the intensive SBP control differed by baseline uric acid concentrations. This trial was registered at ClinicalTrial.gov (Identifier: NCT03015311).

Cost-effectiveness of Intensive vs Standard Blood Pressure Control Among Older Patients With Hypertension

Older patients with hypertension receiving intensive systolic blood pressure control (110-130 mm Hg) have lower incidences of cardiovascular events than those receiving standard control (130-150 mm Hg). Nevertheless, the mortality reduction is insignificant, and intensive blood pressure management results in more medical costs from treatments and subsequent adverse events. To examine the incremental lifetime outcomes, costs, and cost-effectiveness of intensive vs standard blood pressure control in older patients with hypertension from the health care payer's perspective. This economic analysis was conducted with a Markov model to examine the cost-effectiveness of intensive blood pressure management among patients aged 60 to 80 years with hypertension. Treatment outcome data from the Trial of Intensive Blood-Pressure Control in Older Patients With Hypertension (STEP trial) and different cardiovascular risk assessment models for a hypothetical cohort of STEP-eligible patients were used. Costs and utilities were obtained from published sources. The incremental cost-effectiveness ratio (ICER) against the willingness-to-pay threshold was used to evaluate whether the management was cost-effective. Extensive sensitivity, subgroup, and scenario analyses were performed to address uncertainty. The US and UK population using race-specific cardiovascular risk models were conducted in the generalizability analysis. Data for the STEP trial were collected from February 10 to March 10, 2022, and were analyzed for the present study from March 10 to May 15, 2022. Hypertension treatments with a systolic blood pressure target of 110 to 130 mm Hg or 130 to 150 mm Hg. Incremental lifetime quality-adjusted life-years (QALYs), costs, and ICER are discounted at the given rates annually. After simulating 10 000 STEP-eligible patients assumed to be 66 years of age (4650 men [46.5%] and 5350 women [53.5%]) in the model, the ICER values were ¥51 675 ($12 362) per QALY gained in China, $25 417 per QALY gained in the US, and £4679 ($7004) per QALY gained in the UK. Simulations projected that the intensive management in China being cost-effective were 94.3% and 100% below the willingness-to-pay thresholds of 1 time (¥89 300 [$21 364]/QALY) and 3 times (¥267 900 [$64 090]/QALY) the gross domestic product per capita, respectively. The US had 86.9% and 95.6% probabilities of cost-effectiveness at $50 000/QALY and $100 000/QALY, respectively, and the UK had 99.1% and 100% of probabilities of cost-effectiveness at £20 000 ($29 940)/QALY and £30 000 ($44 910)/QALY, respectively. In this economic evaluation, the intensive systolic blood pressure control in older patients produced fewer cardiovascular events and had acceptable costs per QALY gained, well below the typical willingness-to-pay thresholds. The cost-effective advantages of intensive blood pressure management in older patients were consistent over various clinical scenarios across different countries.

Association of serum uric acid with benefits of intensive blood pressure control

Introduction and objectivesIntensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether the serum uric acid concentration at baseline alters the benefits of intensive SBP control is unknown. MethodsThe STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to<130mmHg) and standard (SBP target of 130 to <150mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. This post hoc analysis was performed to examine whether the effects of intensive SBP intervention differed by the baseline uric acid concentration using 2 models: restricted cubic spline curves and subgroup analyses, both based on the Fine-Gray subdistribution hazard model in the analysis of the primary outcome and secondary outcomes (excluding all-cause death). In the analysis of all-cause death, the Cox regression model was used. We also examined the change in the follow-up uric acid concentrations. ResultsOverall, the risk of the primary outcome rose as the cumulative uric acid concentration increased in both the intensive and standard treatment groups. Patients with intensive treatment had a lower multivariable-adjusted subdistribution hazard ratio for the primary outcome, but with a wide overlap of 95%CI. Next, we stratified patients according to their baseline uric acid concentration (tertile 1 [T1], <303.0μmol/L; tertile 2 [T2], 303.0 to <375.8μmol/L; and tertile 3 [T3], ≥375.8μmol/L). Subgroup analyses using tertiles provided HRs and 95%CI in T1 (HR, 0.55; 95%CI, 0.36–0.86; P=.008), T2 (HR, 0.80; 95%CI, 0.56–1.14; P=.22) and T3 (HR, 0.86; 95%CI, 0.60–1.21; P=.39), with an interaction P value of .29. The results for most of the secondary outcomes followed the same trends. ConclusionsThere was no evidence that the benefit of the intensive SBP control differed by baseline uric acid concentrations. This trial was registered at ClinicalTrial.gov (Identifier: NCT03015311).

Impact of Blood Pressure Control on Graft Survival in Kidney Transplant Recipients

Cardiovascular disease is the primary driver of morbidity and mortality in kidney transplant recipients. Hypertension is an important risk factor for development of cardiovascular disease in this population. Despite its important role in post-transplant outcomes, the blood pressure goals for kidney transplant recipients remain elusive. Current guidelines are based on observational data or data extrapolated from the chronic kidney disease population. We followed 5-year blood pressure control of 378 kidney-alone transplant recipients at a single center and evaluated patient survival, graft survival, proteinuria, and rate of decline of kidney graft function. We found that a mean systolic blood pressure (BP) of 121 to 130 mm Hg was associated with better graft survival, slower decline of kidney allograft function, and lower degree of proteinuria when compared with a mean systolic BP ≤120 or >130 mm Hg. This study provides evidence for strict blood pressure control, systolic BP between 121 and 130 mm Hg, and also cautions against intensive control of systolic BP <120 mm Hg in kidney transplant recipients.

Abstract 9705: Diastolic Blood Pressure and Intensive Blood Pressure Control on Cognitive Outcomes: Insights From the SPRINT Trial

Introduction: The potential benefits or harms of intensive systolic blood pressure (SBP) lowering on cognitive function in individuals with low diastolic blood pressure (DBP) remain unclear. Hypothesis: The effects of intensive SBP lowering on cognitive outcomes were consistent across baseline DBP levels. Methods: In this post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), 8563 participants with at least one follow-up cognitive assessment were included. Cognitive outcomes were the occurrence of probable dementia, mild cognitive impairment (MCI), and a composite of probable dementia or MCI. Cox regression models and likelihood ratio tests were used to assess the interaction between DBP quartiles and intensive SBP control on cognitive outcomes. Results: The incidence rates of cognitive outcomes among participants in the lowest DBP quartile were higher than those in the other three DBP quartiles (Figure 1). However, participants in the intensive group had a lower incidence rate of probable dementia or MCI than those in the standard group, regardless of DBP quartiles. There were no significant interactions between SBP intervention and DBP quartiles for probable dementia ( P for interaction =0.06), MCI ( P for interaction =0.80), or a composite of probable dementia or MCI ( P for interaction =0.24) (Figure 2). Conclusions: In this post hoc analysis of the SPRINT study, patients with lower DBP had a higher incidence of cognitive impairment. However, the effects of intensive SBP lowering on cognitive outcomes were consistent across different DBP groups.

Individualising intensive systolic blood pressure reduction in hypertension using computational trial phenomaps and machine learning: a post-hoc analysis of randomised clinical trials

The cardiovascular benefits of intensive systolic blood pressure control vary across clinical populations tested in large randomised clinical trials. We aimed to evaluate the application of machine learning to clinical trials of patients without and with type 2 diabetes to define the personalised cardiovascular benefit of intensive control of systolic blood pressure. In SPRINT, a trial of intensive (systolic blood pressure <120 mm Hg) versus standard (systolic blood pressure <140 mm Hg) systolic blood pressure control in patients without type 2 diabetes, we defined a phenotypic representation of the study population using 59 baseline variables. We extracted personalised treatment effect estimates for the primary outcome, time-to-first major adverse cardiovascular event (MACE; cardiovascular death, myocardial infarction or acute coronary syndrome, stroke, and acute decompensated heart failure), through iterative Cox regression analyses providing average hazard ratio (HR) estimates weighted for the phenotypic distance of each participant from the index patient of each iteration. Next, we trained an extreme gradient boosting algorithm (known as XGBoost) to predict the personalised effect of intensive systolic blood pressure control using features most consistently linked to increased personalised benefit, before evaluating its performance in the ACCORD BP trial of patients with type 2 diabetes randomly assigned to receive intensive versus standard systolic blood pressure control. We stratified patients based on their predicted treatment effect, and key demographic groups (age, sex, cardiovascular disease, and smoking). We assessed the presence of heterogeneity with an interaction test, and assessed the performance of the algorithm in a simulation analysis of SPRINT in the presence or absence of an artificially introduced heterogeneous treatment effect. From SPRINT, we included all 9361 study participants (mean age 67·9 years [SD 9·4], 3332 [35·6%] female) who underwent randomisation to either intensive (n=4678) or standard (n=4683) treatment. The median individualised HR for MACE was 0·63 (IQR 0·53-0·78). An eight-feature tool built for this analysis to predict personalised benefit in SPRINT was externally tested in ACCORD BP (4733 participants (mean age 62·7 years [SD 6·7], 2258 [47·7%] female), wherein it successfully identified individuals with differential benefit from intensive versus standard systolic blood pressure control (adjusted HR for MACE of 0·70 [95% CI 0·55-0·90] in individuals with above-median MACE benefit versus 1·05 [95% CI 0·84-1·32] for below-median predicted benefit; pinteraction=0·0184). Subgroup analysis based on age (<65 years: HR 0·89 [95% CI 0·71-1·12]; ≥65 years: 0·85 [0·67-1·09]), sex (male: 0·89 [0·72-1·10]; female: 0·85 [0·65-1·10]), established cardiovascular disease (no: 0·89 [0·70-1·14]; yes: 0·84 [0·67-1·06]), or active smoking (no: 0·85 [0·71-1·02]; yes: 1·01 [0·64-1·60]) did not identify groups with heterogeneity of treatment effect. In a simulation analysis of SPRINT, the proposed algorithm detected groups with heterogeneous treatment effects in the presence, but not absence, of simulated subgroup differences. By use of machine learning to define an individual's personalised benefit through phenotypic representations of clinical trials, we created a practical tool for individualising the selection of intensive versus standard systolic blood pressure control in patients without and with type 2 diabetes. National Heart, Lung, and Blood Institute of the US National Institutes of Health.

Influence of Baseline Diastolic Blood Pressure on the Effects of Systolic Blood Pressure Lowering on Cognitive Function in Type 2 Diabetes Mellitus.

Lowering of systolic blood pressure (SBP) in patients with low diastolic blood pressure (DBP), can further lower DBP. This can potentially decrease cerebral perfusion and cognition. We examined the influence of baseline DBP on the effect of lowering SBP on cognition. This is a post hoc analysis of the Memory in Diabetes (MIND) substudy (N = 1,430) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (NCT00000620). Standard neuropsychological tests (Digit Symbol Substitution Test [DSST], Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Test [RAVLT], and Stroop test) were performed at baseline and months 20 and 40. We compared the effects of intensive (goal SBP <120 mm Hg) vs. standard (goal SBP <140 mm Hg) SBP control on the changes in the 4 test scores from baseline to the averages of months 20 and 40 across the range of baseline DBP using cubic spline terms. Mean age was 63 ± 6 years, 55% were women and 66% White. Participates with lower baseline DBP were older, had more cardiovascular events and a longer duration of diabetes. There was no difference in the change in DSST (-0.22; 95% CI -0.97, 0.52), MMSE (-0.14; 95% CI -0.34, 0.06), RAVLT (-0.12; 95% CI -0.29, 0.06), and Stroop interference (-0.47; 95% CI -1.76, 0.82) in the intensive vs. standard SBP intervention. There was no interaction between baseline DBP and change in scores with the SBP intervention. Intensive SBP reduction does not adversely affect cognition, even in those with low baseline DBP.

A machine learning approach identifies modulators of heart failure hospitalization prevention among patients with type 2 diabetes: A revisit to the ACCORD trial

BackgroundTo examine patient characteristics that may modulate the heterogeneous treatment effect of intensive systolic blood pressure control (SBP) and intensive glycemic control on incident heart failure (HF) risk in people with type 2 diabetes. MethodsWe analyzed 10,251 participants from the ACCORD glucose trial, and 4733 from the SBP sub-trial separately. We applied a robust machine-learning (ML) algorithm, namely the causal forest/causal tree analysis, to each trial to identify participants' characteristics that modulate the effectiveness of each trial intervention. ResultsDiastolic blood pressure (DBP) was found to interact with intensive glycemic control and impact outcomes. An increased HF risk associated with intensive glycemic control (absolute risk change (ARC): 2.28 %, 95 % confidence interval (CI): 0.69 % to 3.90 %; relative risk (RR):1.57, 95 % CI: 1.15 to 2.20; P < 0.05) was observed in individuals with baseline DBP at the lowest tertile (45–69 mmHg), while no changes in HF risk associated with intensive glycemic control were observed in individuals with baseline DBP at the middle (70–79 mmHg) and the highest tertiles (80–100 mmHg). Liver function was identified as a modulator of intensive BP control, and baseline Alanine transaminase (ALT) level was a sensitive marker for the modulating effect. Only individuals with baseline ALT at the lowest tertile (8–19 mg/dl) benefited from the intensive BP control for HF prevention (ARC: −1.95 %, 95 % CI: −4.06 % to 0.11 %; RR:0.62. 95 % CI: 0.27 to 0.94; P < 0.05). ConclusionsOur study is the first to observe and quantify the potential synergistic harmful effect when low DBP was combined with an intensive blood glucose intervention. Recognizing these may help clinicians develop a more precise approach to such treatments, thus increasing the efficiency and outcomes of diabetes treatments.

COST-EFFECTIVENESS OF INTENSIVE VERSUS STANDARD BLOOD-PRESSURE CONTROL IN OLDER PATIENTS WITH HYPERTENSION

Objective: In the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, Chinese patients aged 60 to 80 years who received intensive systolic blood-pressure control (target, 110 to 130 mmHg) had a significantly lower incidence rate of cardiovascular events than did those who received standard control (target 130 to 150 mmHg). Based on these data, we aimed to examine the lifetime cost-effectiveness of intensive versus standard blood-pressure control from the different healthcare providers’ perspectives. Design and method: A microsimulation model was employed to apply STEP treatment effects and medical costs and utility from national sources or published data to a hypothetical cohort of STEP-eligible patients in China. Incremental cost-effectiveness ratio (ICER) against willing-to-pay threshold was used to evaluate whether intensive versus standard blood-pressure control was a cost-effective option. A series of sensitivity, subgroup, and scenario analyses in other countries (the US and UK) were performed to account for the generalisability and uncertainties arising from study assumptions and parameters. Results: The ICER values of intensive versus standard blood-pressure control were approximate ¥ 48,000, $32,300, £10,055 per QALY gained from the perspective of healthcare providers in China, the US and the UK. Simulation results indicated that intensive treatment would be cost-effective (54.6% and 70.1% below the willing-to-pay thresholds of ¥ 80,000 and ¥240,000). The scenario analyses presented that intensive treatment would be cost-effective in the US and UK settings (63.9% and 80.4% below the willing-to-pay thresholds of $50,000 and $150,000 in the US; 75% and 82.1% below the willing-to-pay thresholds of £30,000 and £90,000 in the UK) Conclusions: In this simulation study, intensive blood-pressure control in the older Chinese population produced fewer cardiovascular events and acceptable costs per QALY gained, commonly below the willing-to-pay threshold. Given the STEP treatment effects in other populations, the cost-effectiveness of intensive blood-pressure control in older patients was likely consistent across different countries.

Association between blood pressure levels and cognitive impairment in older women: a prospective analysis of the Women's Health Initiative Memory Study

SummaryBackgroundWhether blood pressure (BP), and at what level of controlled BP, reduces risk of cognitive impairment remains uncertain. We investigated the association of BP and hypertension treatment status with mild cognitive impairment and dementia in older women.MethodsWe prospectively analysed a sample of 7207 community-dwelling women aged 65–79 years participating in the Women’s Health Initiative Memory Study (WHIMS). Participants were recruited between May 28, 1996, and Dec 13, 1999, at 39 US clinical centres, and they were followed up until Dec 31, 2019. Cognitive function was assessed annually. Mild cognitive impairment and probable dementia were defined through a centralised adjudication process. BP was measured by trained and certified staff at baseline. Pulse pressure (PP) was calculated as systolic BP (SBP) minus diastolic BP. Hypertension was defined using the American Heart Association 2017 Guideline for High BP in Adults. Outcomes were (1) mild cognitive impairment, (2) probable dementia, and (3) cognitive loss (the combined endpoint of either mild cognitive impairment or probable dementia, or both). We estimated hazard ratios (HRs) to assess the association between hypertension, SBP, and PP with the risk of study outcomes using Cox proportional hazards regression models, with adjustment for key covariates.FindingsDuring a median follow-up of 9 years (IQR 6–15), 1132 (15·7%) participants were classified as mild cognitive impairment, 739 (10·3%) as probable dementia, and 1533 (21·3%) as cognitive loss. The incidence rates per 1000 person-years were 15·3 cases (95% CI 14·4–16·2) for mild cognitive impairment, 9·7 cases (9·0–10·4) for probable dementia, and 20·3 (19·3–21·3) for cognitive loss. Elevated SBP and PP were significantly associated with increased risk of mild cognitive impairment and cognitive loss (test for trends across SBP and PP strata, p<0·01). Individuals with hypertension, but with controlled SBP of less than 120 mm Hg did not have a significantly increased risk of mild cognitive impairment (HR 1·33, 95% CI 0·98–1·82, p=0·071), and of cognitive loss (1·09, 0·82–1·44, p=0·57) compared with normotension. Individuals on anti-hypertensive treatment with PP of less than 50 mm Hg did not have a significantly higher risk of mild cognitive impairment (1·26, 0·98–1·62, p=0·07) and of cognitive loss (1·17, 0·94–1·46, p=0·16). There were no significant associations between hypertension, SBP, or PP and probable dementia.InterpretationResults of our study show significant associations of hypertension and elevated SBP and PP levels with risk of mild cognitive impairment and the combined endpoint of either mild cognitive impairment or probable dementia, suggesting that intensive control of hypertension, SBP, and PP can preserve cognitive health in older women.FundingNational Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services.