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Clinical Value of Predicting Individual Treatment Effects for Intensive Blood Pressure Therapy.

ABSTRACT: BACKGROUND:The absolute risk reduction (ARR) in cardiovascular events from therapy is generally assumed to be proportional to baseline risk-such that high-risk patients benefit most. Yet newer analyses have proposed using randomized trial data to develop models that estimate individual treatment effects. We tested 2 hypotheses: first, that models of individual treatment effects would reveal that benefit from intensive blood pressure therapy is proportional to baseline risk; and second, that a machine learning approach designed to predict heterogeneous treatment effects-the X-learner meta-algorithm-is equivalent to a conventional logistic regression approach. METHODS AND RESULTS:We compared conventional logistic regression to the X-learner approach for prediction of 3-year cardiovascular disease event risk reduction from intensive (target systolic blood pressure <120 mm?Hg) versus standard (target <140 mm?Hg) blood pressure treatment, using individual participant data from the SPRINT (Systolic Blood Pressure Intervention Trial; N=9361) and ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure; N=4733) trials. Each model incorporated 17 covariates, an indicator for treatment arm, and interaction terms between covariates and treatment. Logistic regression had lower C statistic for benefit than the X-learner (0.51 [95% CI, 0.49-0.53] versus 0.60 [95% CI, 0.58-0.63], respectively). Following the logistic regression's recommendation for individualized therapy produced restricted mean time until cardiovascular disease event of 1065.47 days (95% CI, 1061.04-1069.35), while following the X-learner's recommendation improved mean time until cardiovascular disease event to 1068.71 days (95% CI, 1065.42-1072.08). Calibration was worse for logistic regression; it over-estimated ARR attributable to intensive treatment (slope between predicted and observed ARR of 0.73 [95% CI, 0.30-1.14] versus 1.06 [95% CI, 0.74-1.32] for the X-learner, compared with the ideal of 1). Predicted ARRs using logistic regression were generally proportional to baseline pretreatment cardiovascular risk, whereas the X-learner observed-correctly-that individual treatment effects were often not proportional to baseline risk. CONCLUSIONS:Predictions for individual treatment effects from trial data reveal that patients may experience ARRs not simply proportional to baseline cardiovascular disease risk. Machine learning methods may improve discrimination and calibration of individualized treatment effect estimates from clinical trial data. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01206062; NCT00000620.

SUBMITTER: Duan T

PROVIDER: S-EPMC6756170 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Clinical Value of Predicting Individual Treatment Effects for Intensive Blood Pressure Therapy.

Duan Tony T Rajpurkar Pranav P Laird Dillon D Ng Andrew Y AY Basu Sanjay S

Circulation. Cardiovascular quality and outcomes 20190301 3

<h4>Background</h4>The absolute risk reduction (ARR) in cardiovascular events from therapy is generally assumed to be proportional to baseline risk-such that high-risk patients benefit most. Yet newer analyses have proposed using randomized trial data to develop models that estimate individual treatment effects. We tested 2 hypotheses: first, that models of individual treatment effects would reveal that benefit from intensive blood pressure therapy is proportional to baseline risk; and second, t ...[more]

PMID: 30857410

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Project description:BackgroundAlthough intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH).PurposeTo examine the effects of intensive BP-lowering treatment on OH in hypertensive adults.Data sourcesMEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions.Study selectionRandomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing.Data extraction2 investigators independently abstracted articles and rated risk of bias.Data synthesis5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH (P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged.LimitationsAssessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available.ConclusionIntensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension.Primary funding sourceNational Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).

Project description:BackgroundFew studies have answered the guiding significance of individual components of the Framingham risk score (FRS) to the risk of cardiovascular disease (CVD) after antihypertensive treatment. This study on the systolic blood pressure intervention trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) aimed to reveal previously undetected association patterns between individual components of the FRS and heterogeneity of treatment effects (HTEs) of intensive blood pressure control.MethodsA self-organizing map (SOM) methodology was applied to identify CVD-risk-specific subgroups in the SPRINT (n = 8,773), and the trained SOM was utilized directly in 4,495 patients from the ACCORD. The primary endpoints were myocardial infarction (MI), non-myocardial infarction acute coronary syndrome (non-MI ACS), stroke, heart failure (HF), death from CVD causes, and a primary composite cardiovascular outcome. Cox proportional hazards models were then used to explore the potential heterogeneous response to intensive SBP control.ResultsWe identified four SOM-based subgroups with distinct individual components of FRS profiles and the CVD risk. For individuals with type 2 diabetes mellitus (T2DM) in the ACCORD or without diabetes in the SPRINT, subgroup I characterized by male with the lowest concentrations for total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol measures, experienced the highest risk for major CVD. Conversely, subgroup III characterized by a female with the highest values for these measures represented as the lowest CVD risk. Furthermore, subgroup II, with the highest systolic blood pressure (SBP) and no antihypertensive agent use at baseline, had a significantly greater frequency of non-MI ACS under intensive BP control, the number needed to harm (NNH) was 84.24 to cause 1 non-MI ACS [absolute risk reduction (ARR) = -1.19%; 95% CI: -2.08, -0.29%] in the SPRINT [hazard ratio (HR) = 3.62; 95% CI: 1.33, 9.81; P = 0.012], and the NNH of was 43.19 to cause 1 non-MI ACS (ARR = -2.32%; 95% CI: -4.63, 0.00%) in the ACCORD (HR = 1.81; 95% CI: 1.01-3.25; P = 0.046). Finally, subgroup IV characterized by mostly younger patients with antihypertensive medication use and smoking history represented the lowest risk for stroke, HF, and relatively low risk for death from CVD causes and primary composite CVD outcome in SPRINT, however, except stroke, a low risk for others were not observed in ACCORD.ConclusionSimilar findings in patients with hypertensive with T2DM or without diabetes by multivariate subgrouping suggested that the individual components of the FRS could enrich or improve CVD risk assessment. Further research was required to clarify the potential mechanism.

Project description:BACKGROUND:Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN:Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS:9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease. INTERVENTIONS:Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm). OUTCOMES & MEASUREMENTS:Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event. RESULTS:There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively. LIMITATIONS:Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease. CONCLUSIONS:More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function. TRIAL REGISTRATION:Registered at ClinicalTrials.gov with study number NCT01206062.

Project description:BACKGROUND:The previously published results of the Systolic Blood Pressure Intervention Trial showed that among participants with hypertension and an increased cardiovascular risk, but without diabetes, the rates of cardiovascular events were lower among those who were assigned to a target systolic blood pressure of less than 120 mm Hg (intensive treatment) than among those who were assigned to a target of less than 140 mm Hg (standard treatment). Whether such intensive treatment affected patient-reported outcomes was uncertain; those results from the trial are reported here. METHODS:We randomly assigned 9361 participants with hypertension to a systolic blood-pressure target of less than 120 mm Hg or a target of less than 140 mm Hg. Patient-reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9), patient-reported satisfaction with their blood-pressure care and blood-pressure medications, and adherence to blood-pressure medications. We compared the scores in the intensive-treatment group with those in the standard-treatment group among all participants and among participants stratified according to physical and cognitive function. RESULTS:Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow-up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications. CONCLUSIONS:Patient-reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062 .).

Project description:BackgroundThere is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.MethodsA total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.ResultsAfter 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).ConclusionsIn patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

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Clinical Value of Predicting Individual Treatment Effects for Intensive Blood Pressure Therapy.

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Clinical Value of Predicting Individual Treatment Effects for Intensive Blood Pressure Therapy.

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