Intensive Blood Pressure Reduction Research Articles

Comparison of intensive treatment versus standard treatment in lowering blood pressure and its association with cognitive decline and dementia: a systematic review and meta-analysis

Abstract Background The ideal blood pressure target level for preventing cognitive decline or dementia in patients with systemic arterial hypertension (SAH) remains unclear. Purpose This study aims to investigate whether intensive blood pressure reduction compared to standard treatment is associated with a reduced risk of cognitive decline or dementia in adults with SAH. Methods PubMed, Scopus and Cochrane databases were searched for randomized clinical trials (RCTs) comparing intensive treatment versus standard treatment for blood pressure reduction in patients with SAH. A random-effects model was used for analyzing the results, which were presented as relative risk (RR) with a 95% confidence interval (CI). Heterogeneity was examined using the I² statistic. Statistical analysis was performed using R software version 4.2.3. Results A total of 5 RCTs and 46,658 patients were included, of whom 23,726 (50,85%) underwent intensive therapy for SAH treatment. The mean age of participants ranged from 62.8 to 80.9 years in the intensive treatment group while it ranged from 63.3 to 80.3 years in the standard treatment group. Occurrence of dementia or probable dementia was significantly lower in the intensive treatment group (3.8% vs. 4,3%; RR 0.88; 95% CI: 0.80 - 0.96; p= 0.0049; I²=0%). Dementia or Cognitive decline (16.4% vs. 18.8%; RR 0.87; 95% CI 0.83 - 0.90; p < 0.000001; I²=0%), and cognitive decline (13.2% vs. 15.2%; RR 0.88; 95% CI 0.80 - 0.98; p= 0.014; I²=53%) also tended towards the intensive treatment group. Additionally, no significant association was found in mortality (6.4% vs. 7.3%; RR 0.87; 95% CI 0.75 - 1.02; p= 0.09; I²=28%) and serious adverse effects (34.4% vs. 35.5%; RR 0.99; 95% CI 0.92 - 1.06; p=0.73; I²=63%). Conclusion Our study shows that intensive blood pressure treatment is associated with a fewer occurrence of dementia, probable dementia and cognitive decline in comparison to the standard blood pressure target.General Analysis

Process Evaluation of an Ambulance-Delivered Early Intensive Blood Pressure-Lowering Stroke Trial: Design, Rationale, and Reflection

Introduction: The fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4) is a large-scale, multicenter, prospective, randomized, open-label, blinded endpoint assessment trial, initiated in an ambulance in China, aiming at evaluating the effectiveness and safety of prehospital blood pressure (BP) lowering in patients with suspected acute stroke and elevated BP. A prespecified process evaluation is intended to explore the implementation of the trial intervention, provide support to interpret the trial outcomes and put forward suggestions to scale up the intervention in broader settings in the future. Methods: This process evaluation is a mixed-methods design, and follows the Normalization Process Theory (NPT) and the UK Medical Research Council (UK MRC) guidance. Fidelity, reach, acceptability, appropriateness, adoption, sustainability, and relevant contextual factors and mechanisms affecting the implementation of prehospital early intensive BP-lowering treatment will be analyzed. Semi-structured interviews with ambulance staff, ward and emergency department clinicians, and nurses are undertaken to explore perceptions of the intervention, contextual factors, and potential suggestions for future implementation in practice. Data from observational records, surveys, conventional monitoring data, on-site records, and case report forms will be analyzed to understand background care and context. Conclusion: The process evaluation of INTERACT4 will provide insights for the implementation of prehospital early intensive BP-lowering intervention in different health systems and help better explain the trial results for further scale up.

Statistical Analysis Plan for the INTEnsive Ambulance-Delivered Blood Pressure Reduction in Hyper-ACute Stroke Trial.

Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4), a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of prehospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. Patients were randomized (1:1) to intensive (target systolic BP 130-140 mm Hg within 30 min) or guideline-recommended BP management (BP lowering only considered if systolic BP >220 mm Hg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2,320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis and to avoid potential bias in the evaluation of the trial intervention.

Effects of Achieving Rapid, Intensive, and Sustained Blood Pressure Reduction in Intracerebral Hemorrhage Expansion and Functional Outcome.

The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes. Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension. We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10). Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion. This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

An interpretable framework to identify responsive subgroups from clinical trials regarding treatment effects: Application to treatment of intracerebral hemorrhage.

Randomized Clinical trials (RCT) suffer from a high failure rate which could be caused by heterogeneous responses to treatment. Despite many models being developed to estimate heterogeneous treatment effects (HTE), there remains a lack of interpretable methods to identify responsive subgroups. This work aims to develop a framework to identify subgroups based on treatment effects that prioritize model interpretability. The proposed framework leverages an ensemble uplift tree method to generate descriptive decision rules that separate samples given estimated responses to the treatment. Subsequently, we select a complementary set of these decision rules and rank them using a sparse linear model. To address the trial's limited sample size problem, we proposed a data augmentation strategy by borrowing control patients from external studies and generating synthetic data. We apply the proposed framework to a failed randomized clinical trial for investigating an intracerebral hemorrhage therapy plan. The Qini-scores show that the proposed data augmentation strategy plan can boost the model's performance and the framework achieves greater interpretability by selecting complementary descriptive rules without compromising estimation quality. Our model derives clinically meaningful subgroups. Specifically, we find those patients with Diastolic Blood Pressure≥70 mm hg and Systolic Blood Pressure<215 mm hg benefit more from intensive blood pressure reduction therapy. The proposed interpretable HTE analysis framework offers a promising potential for extracting meaningful insight from RCTs with neutral treatment effects. By identifying responsive subgroups, our framework can contribute to developing personalized treatment strategies for patients more efficiently.

Can propensity score matching replace randomized controlled trials?

Randomized controlled trials (RCTs) have long been recognized as the gold standard for establishing causal relationships in clinical research. Despite that, various limitations of RCTs prevent its widespread implementation, ranging from the ethicality of withholding potentially-lifesaving treatment from a group to relatively poor external validity due to stringent inclusion criteria, amongst others. However, with the introduction of propensity score matching (PSM) as a retrospective statistical tool, new frontiers in establishing causation in clinical research were opened up. PSM predicts treatment effects using observational data from existing sources such as registries or electronic health records, to create a matched sample of participants who received or did not receive the intervention based on their propensity scores, which takes into account characteristics such as age, gender and comorbidities. Given its retrospective nature and its use of observational data from existing sources, PSM circumvents the aforementioned ethical issues faced by RCTs. Majority of RCTs exclude elderly, pregnant women and young children; thus, evidence of therapy efficacy is rarely proven by robust clinical research for this population. On the other hand, by matching study patient characteristics to that of the population of interest, including the elderly, pregnant women and young children, PSM allows for generalization of results to the wider population and hence greatly increases the external validity. Instead of replacing RCTs with PSM, the synergistic integration of PSM into RCTs stands to provide better research outcomes with both methods complementing each other. For example, in an RCT investigating the impact of mannitol on outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, the baseline characteristics of comorbidities and current medications between treatment and control arms were significantly different despite the randomization protocol. Therefore, PSM was incorporated in its analysis to create samples from the treatment and control arms that were matched in terms of these baseline characteristics, thus providing a fairer comparison for the impact of mannitol. This literature review reports the applications, advantages, and considerations of using PSM with RCTs, illustrating its utility in refining randomization, improving external validity, and accounting for non-compliance to protocol. Future research should consider integrating the use of PSM in RCTs to better generalize outcomes to target populations for clinical practice and thereby benefit a wider range of patients, while maintaining the robustness of randomization offered by RCTs.

Intensive vs Conventional Blood Pressure Control After Thrombectomy in Acute Ischemic Stroke

Endovascular thrombectomy (EVT) is standard treatment for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), but optimal post-EVT blood pressure (BP) control remains debated. To assess the association of different systolic BP targets following EVT with functional outcomes, mortality, and complications in patients with AIS due to LVO. Systematic review and meta-analysis of databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library) to September 8, 2023. Inclusion criteria consisted of randomized clinical trials examining post-EVT management of systolic BP in patients with AIS and LVO comparing intensive vs conventional targets. Nonrandomized studies, observational studies, noninterventional trials, meeting abstracts, duplicate studies, studies with overlapping data, and non-English language studies were excluded. Two authors independently applied these criteria through a blinded review, with discrepancies resolved through consensus. The risk of bias in the included studies was assessed using the revised tool for assessing risk of bias in randomized trials. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Three authors extracted data regarding study characteristics, baseline patient data, and outcomes of interest. The pooled data were analyzed using a random-effects meta-analysis. Rates of functional independence, 90-day mortality, symptomatic intracranial hemorrhage, and hypotensive events. A total of 4 randomized clinical trials with 1571 initially enrolled patients were included in the analysis. Lower functional independence rates were observed in the intensive control group (relative risk [RR], 0.81 [95% CI, 0.67-0.98]). No significant differences were found in 90-day mortality (RR, 1.18 [95% CI, 0.92-1.52]), symptomatic intracranial hemorrhage (RR, 1.12 [95% CI, 0.75-1.67]), or hypotensive events (RR, 1.80 [95% CI, 0.37-8.76]). There was minimal heterogeneity among the studies included in the functional independence outcome (I2 = 13% and τ2 = 0.003), which was absent among other outcomes (I2 = 0 and τ2 = 0). These findings suggest that intensive post-EVT BP reduction does not yield benefits and may carry risks. While awaiting the results of additional ongoing trials, a conservative BP management strategy after endovascular recanalization is favored in daily practice.

Enhancing blood pressure management protocol implementation in patients with acute intracerebral haemorrhage through a nursing-led approach: A retrospective cohort study.

To evaluate the impact of nurse care changes in implementing a blood pressure management protocol on achieving rapid, intensive and sustained blood pressure reduction in acute intracerebral haemorrhage patients. Retrospective cohort study of prospectively collected data over 6 years. Intracerebral haemorrhage patients within 6 h and systolic blood pressure ≥ 150 mmHg followed a rapid (starting treatment at computed tomography suite with a target achievement goal of ≤60 min), intensive (target systolic blood pressure < 140 mmHg) and sustained (maintaining target stability for 24 h) blood pressure management plan. We differentiated six periods: P1, stroke nurse at computed tomography suite (baseline period); P2, antihypertensive titration by stroke nurse; P3, retraining by neurologists; P4, integration of a stroke advanced practice nurse; P5, after COVID-19 impact; and P6, retraining by stroke advanced practice nurse. Outcomes included first-hour target achievement (primary outcome), tomography-to-treatment and treatment-to-target times, first-hour maximum dose of antihypertensive treatment and 6-h and 24-h systolic blood pressure variability. Compared to P1, antihypertensive titration by stroke nurses (P2) reduced treatment-to-target time and increased the rate of first-hour target achievement, retraining of stroke nurses by neurologists (P3) maintained a higher rate of first-hour target achievement and the integration of a stroke advanced practice nurse (P4) reduced both 6-h and 24-h systolic blood pressure variability. However, 6-h systolic blood pressure variability increased from P4 to P5 following the impact of the COVID-19 pandemic. Finally, compared to P1, retraining of stroke nurses by stroke advanced practice nurse (P6) reduced tomography-to-treatment time and increased the first-hour maximum dose of antihypertensive treatment. Changes in nursing care and continuous education can significantly enhance the time metrics and blood pressure outcomes in acute intracerebral haemorrhage patients. STROBE guidelines. No Patient or Public Contribution.

Abstract 149: Different Response to Blood Pressure Reduction in Lobar and Deep Intracerebral Hemorrhage

Background: Blood pressure (BP) reduction is associated with better neuroimaging and clinical outcomes in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). Because this evidence comes from studies that overwhelmingly enrolled deep hemorrhages, the impact of BP reduction in patients with lobar ICH remains understudied. Methods: We re-analyzed data from the pivotal Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) study. We included all patients with available neuroimaging data. Participants were randomized to either intensive (systolic BP target 110-139 mmHg) or standard (systolic BP target 140-179 mmHg) acute BP lowering. The main outcome measures were hematoma expansion &gt; 6 mL in the first 24 hours (HE), poor functional outcome (3-month mRS 4-6) and renal adverse events (RAE) until day 7 or hospital discharge. We fitted multivariable logistic regression models to test for association between the intervention and our outcomes of interest. Covariates included sex, age, race and ethnicity, and baseline ICH volume. Results: Among 1,000 patients enrolled in ATACH-2, 875 (87.5%) with complete data were included (88.9% deep hemorrhages and 11.1% lobar hemorrhages). The baseline characteristics of the intensive and standard treatment groups remained balanced as in the original study (all comparisons p &gt;0.05). Multivariable logistic regression showed that intensive BP reduction decreased the risk of HE (OR 0.60, 95%CI 0.39-0.90; p=0.02) and increased the risk of RAE (OR 2.53, 95%CI 1.40-4.77; p=0.003) in patients with deep, but not lobar ICH (HE, OR: 0.89; 95% CI= 0.31 - 2.52; p=0.83 and RAE, OR: 0.46; 95% CI= 0.04 - 5.10; p=0.53). Intensive BP reduction was not associated with improved mRS in either deep (OR: 0.96; 95 % CI= 0.68 - 1.37; p= 0.82) nor lobar (OR: 0.66; 95% CI= 0.16 - 2.42; p= 0.54) ICH. Conclusion: The impact of intensive blood pressure lowering differs in deep and lobar ICH. These results emphasize the need for a better understanding about biologic differences in ICH, which may have therapeutic implications.

Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants

Background and aimsUncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date.MethodsINTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days.ResultsBetween March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024.ConclusionsINTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke.Trial registrationClinicalTrials.gov NCT03790800; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534, registered on 7 January 2019.

An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized clinical trials

Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate’s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: −14.8% ± 3.1%, pone-sample t-test = 0.001; SPRINT: −17.6% ± 3.6%, pone-sample t-test < 0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all simulations with Cox regression-derived p value of < 0.01 for the effect of the intervention on the respective primary outcome). This adaptive framework has the potential to maximize RCT enrollment efficiency.

Cardiological hypertensive emergencies: real word data compared to guidelines indications

Abstract Background The 2018 ESH guidelines have revised the therapeutic goals of cardiological Hypertensive Emergencies (HE) with an indication for a more intensive (target &amp;lt; 140/90 mmHg) and rapid (immediate) Blood Pressure (BP) reduction. Cardiac acute organ damage during HE includes acute myocardial infarction, pulmonary edema, unstable angina pectoris and aortic dissection. However, how much these indications have been applied in clinical practice to date it’s unknown. Aims The first purpose of our study is to analyze the prevalence and clinical characteristics of cardiological HE in our institution. The second purpose is to compare the year before the release of the 2018 guidelines (2017) with the subsequent years (2019) trying to verify adherence to guidelines. Methods This is a single-center retrospective study conducted at a hospital. All patients aged ≥ 18 years with Systolic BP≥ 180 mmHg and/or a Diastolic BP ≥ 120 mmHg with Cardiological Emergency were enrolled. From the Emergency Department (ED) data clinical, anamnestic, blood pressure, symptoms, drug treatment and target achievement were registered. Results Patients with BP &amp;gt; 180/120 mmHg in 2017 were 706 out of a total of 73795 accesses (0.96%) and 601 over 67273 (0.89%) in 2019. 246 (34.84%) in 2017 were HE of which 144 (58.53%) were cardiological: aortic dissection 1 (0.69%), acute coronary syndrome 52 (36.11%), acute pulmonary edema 35 (24.30%), cardiac decompensation 91 (63.19%). During 2019 similar figures were founded with 286 (47.58%) HE of which 286 (47.58%) were cardiological: aortic dissection 2 (1.43%), acute coronary syndrome 43 (30.93%), acute pulmonary edema 20 (14.39%), cardiac decompensation 76 (54.68%). The reduction in BP obtained in ED was significantly greater in 2017 than in 2019 (44.7±31.4 vs 35.4±24.5 mmHg, p = 0.011) with a lower target reaching in 2019 (28.9 vs 51.4%, p&amp;lt;0.001). Pulmonary edema is the cardiological HE on which a greater pressure reduction is obtained and therefore in which the target set by the guidelines is more frequently reached. Conclusions The recommendation for a more intense and rapid BP reduction in cardiological HE seems to be not accepted from ED clinicians that persist to reduce BP accordingly to previous guidelines.

Abstract 15639: An Explainable Machine Learning-Based Phenomapping Strategy for Adaptive Predictive Enrichment in Randomized Controlled Trials of Preventive Interventions

Introduction: Randomized controlled trials (RCT) are the cornerstone of evidence-based preventive cardiovascular care but are resource intensive. We propose a novel machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT efficiency. Methods: In simulated group sequential analyses of two cardiovascular outcomes RCTs of (1) a drug (pioglitazone vs placebo; IRIS), and (2) a management strategy (intensive vs standard blood pressure reduction; SPRINT), we constructed dynamic phenomaps to infer patient profiles benefiting from the intervention vs control during interim analyses. We examined their ability to adaptively enrich subsequent trial enrollment. We compared the final study size and effect estimates between the adaptive and original study designs. Results: Across 3 interim analyses, our strategy learned dynamic signatures of individualized benefit. By conditioning prospective participant enrollment on dynamic estimates of personalized benefit, our approach enabled a robust reduction in the trial size across simulations (-18% ± 4.7% in IRIS, p=0.008 [ A ] and -27.4% ± 3.4% in SPRINT, p=0.002 [ B ]), also preserving the original average treatment effect (IRIS: hazard ratio of 0.71 ± 0.01 for pioglitazone vs placebo; vs 0.76 in the original trial [ C ]; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure; vs 0.75 in the original trial; all p&lt;0.01 [ D ]). Hierarchical assessment of safety endpoints revealed no safety concerns with adaptive enrichment, whereas post-hoc review of the enriched populations confirmed that no specific demographic groups were excluded from the analysis. Conclusions: We present an explainable ML algorithm for adaptive predictive enrichment in RCTs leveraging phenome-wide computational measures of personalized benefit. These findings propose a new paradigm to maximize clinical trial efficiency through dynamic data-driven inference.

Intensive Blood Pressure Reduction is Associated with Reduced Hematoma Growth in Fast Bleeding Intracerebral Hemorrhage A Secondary Analysis of the ATACH-2 Randomized Clinical Trial.

Spontaneous intracerebral hemorrhage (ICH) patients at highest risk of hematoma growth are those with the most potential to benefit from anti-expansion treatment. Large clinical trials have not definitively shown a clear benefit of blood pressure (BP) reduction. We aim to determine whether intensive blood pressure reduction could benefit patients with fast bleeding ICH. An exploratory analysis of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) randomized controlled trial was performed. In order to capture not just early bleeding (even if a small amount), but the rate of bleeding (mL/hour), we restricted the study to "Fast bleeding ICH," defined as an ICH volume/onset-to-CT time >5mL/hr. Hematoma growth, as defined as an increase of hematoma volume > 33% between baseline and 24 hours. A total of 940 patients were included (mean age 62.1 years, 61.5% male), of whom 214 (22.8%) experienced hematoma expansion. Of these, 567(60.3%) met the definition of "fast bleeding" with baseline ICH volume/time to presentation of at least 5mL/hr. Intensive blood pressure reduction was associated with a significantly lower rate of hematoma growth in fast bleeding patients (20.6% vs 31.0%, p=0.005). In a subgroup of 266 (46.9%) fast-bleeding patients who received treatment within 2 hours after symptom onset, intensive BP lowering was associated with improved functional independence (OR, 1.98; 95% CI,1.06-3.69; p=0.031). Our results suggest that early use of intensive BP reduction may reduce hematoma growth and improve outcome in fast bleeding patients. This article is protected by copyright. All rights reserved.

C89 CARDIOLOGICAL HYPERTENSIVE EMERGENCIES: REAL WORD DATA COMPARED TO GUIDELINES INDICATIONS

Abstract Background The 2018 ESH guidelines have revised the therapeutic goals of cardiological Hypertensive Emergencies (HE) with an indication for a more intensive (target &amp;lt; 140/90 mmHg) and rapid (immediate) Blood Pressure (BP) reduction. Cardiac acute organ damage during HE includes acute myocardial infarction, pulmonary edema, unstable angina pectoris and aortic dissection. However, how much these indications have been applied in clinical practice to date it’s unknown. Aims The first purpose of our study is to analyze the prevalence and clinical characteristics of cardiological HE in our institution. The second purpose is to compare the year before the release of the 2018 guidelines (2017) with the subsequent years (2019) trying to verify adherence to guidelines. Methods This is a single–center retrospective study conducted at the Niguarda Hospital. All patients aged ≥ 18 years with Systolic BP≥ 180 mmHg and/or a Diastolic BP ≥ 120 mmHg with Cardiological Emergency were enrolled. From the Emergency Department (ED) data clinical, anamnestic, blood pressure, symptoms, drug treatment and target achievement were registered. Results Patients with BP &amp;gt; 180/120 mmHg in 2017 were 706 out of a total of 73795 accesses (0.96%) and 601 over 67273 (0.89%) in 2019. 246 (34.84%) in 2017 were HE of which 144 (58.53%) were cardiological: aortic dissection 1 (0.69%), acute coronary syndrome 52 (36.11%), acute pulmonary edema 35 (24.30%), cardiac decompensation 91 (63.19%). During 2019 similar figures were founded with 286 (47.58%) HE of which 286 (47.58%) were cardiological: aortic dissection 2 (1.43%), acute coronary syndrome 43 (30.93%), acute pulmonary edema 20 (14.39%), cardiac decompensation 76 (54.68%). The reduction in BP obtained in ED was significantly greater in 2017 than in 2019 (44.7±31.4 vs 35.4±24.5 mmHg, p = 0.011) with a lower target reaching in 2019 (28.9 vs 51.4%, p&amp;lt;0.001). Pulmonary edema is the cardiological HE on which a greater pressure reduction is obtained and therefore in which the target set by the guidelines is more frequently reached. Conclusions The recommendation for a more intense and rapid BP reduction in cardiological HE seems to be not accepted from ED clinicians that persist to reduce BP accordingly to previous guidelines.

Interaction between cerebral small vessel disease, blood pressure, and remote ischemic lesions in acute spontaneous intracerebral hemorrhage.

Acute blood pressure (BP) reduction is the first-line treatment for acute spontaneous intracerebral hemorrhage (ICH); however, recent research suggests that intensive BP reduction along with cerebral small vessel disease (cSVD) is a risk factor for remote DWI lesions (RDWILs). We aimed to delineate the interplay between cSVD and BP reduction therapy on the risk of RDWILs. We enrolled 303 patients who underwent brain magnetic resonance imaging within 7 days after acute spontaneous ICH. RDWILs were categorized as occurring in borderzone (BZ) or non-BZ areas. We examined the effect of cSVD, acute BP reduction, and their interaction on RDWILs. RDWILs were observed in 34 (11%) patients (59.8 ± 10.3-years-old, 24% male). RDWILs were associated with a larger acute weighted average mean arterial pressure (MAP) reduction in the initial 24 h after ICH onset and a higher total cerebral microbleed (CMB) count. Intensive MAP changes (odds ratio (OR) per 10 mmHg 1.76, 95% confidence interval (CI) 1.03-3.20), total CMBs burden (OR per 10 CMBs 1.21, 95% CI 1.08-1.39), and presence of lobar CMBs (OR 7.33, 95% CI 1.59-55.6) were risk factors for RDWILs at BZ, but not at non-BZ. Furthermore, a significant interaction was observed between lobar CMBs and MAP reduction on increased risk of RDWILs at BZ (p = 0.030). cSVD modulates the effect of acute BP reduction on the risk of RDWILs. Patients with extensive microangiopathy have a higher risk of developing cerebral ischemic changes in BZ during unstable hemodynamic status.

Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention

The degree to which more intensive blood pressure reduction is better than less intensive for secondary stroke prevention has not been delineated. To perform a standard meta-analysis and a meta-regression of randomized clinical trials to evaluate the association of magnitude of differential blood pressure reduction and recurrent stroke in patients with stroke or transient ischemic attack (TIA). PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1980, to June 30, 2022. Randomized clinical trials that compared more intensive vs less intensive blood pressure lowering and recorded the outcome of recurrent stroke in patients with stroke or TIA. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Risk ratio (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive blood pressure lowering with primary and secondary outcomes. The univariate meta-regression analyses were conducted to evaluate a possible moderating effect of magnitude of differential systolic blood pressure (SBP) and diastolic blood pressure (DBP) reduction on the recurrent stroke and major cardiovascular events. The primary outcome was recurrent stroke and the lead secondary outcome was major cardiovascular events. Ten randomized clinical trials comprising 40 710 patients (13 752 women [34%]; mean age, 65 years) with stroke or TIA were included for analysis. The mean duration of follow-up was 2.8 years (range, 1-4 years). Pooled results showed that more intensive treatment compared with less intensive was associated with a reduced risk of recurrent stroke in patients with stroke or TIA (absolute risk, 8.4% vs 10.1%; RR, 0.83; 95% CI, 0.78-0.88). Meta-regression showed that the magnitude of differential SBP and DBP reduction was associated with a lower risk of recurrent stroke in patients with stroke or TIA in a log-linear fashion (SBP: regression slope, -0.06; 95% CI, -0.08 to -0.03; DBP: regression slope, -0.17; 95% CI, -0.26 to -0.08). Similar results were found in the association between differential blood pressure lowering and major cardiovascular events. More intensive blood pressure-lowering therapy might be associated with a reduced risk of recurrent stroke and major cardiovascular events. These results might support the use of more intensive blood pressure reduction for secondary prevention in patients with stroke or TIA.

Cardiac structure and function in resistant hypertension: The beneficial role of blood pressure control.

Cardiac structure and function in resistant hypertension: The beneficial role of blood pressure control.

Risk Stratification of Cardiovascular Disease according to Age Groups in New Prevention Guidelines: A Review.

Age is a strong risk factor for cardiovascular disease. Accordingly, most cardiovascular risk prediction models have included age as an independent risk factor. There is much evidence that effective management of cardiovascular risk factors improves clinical outcomes even in older adults. However, there are concerns that intensive treatment for older adults increases the risk of adverse events. For hypertensive patients, intensive blood pressure reduction with combination therapy increases the risk of syncope, acute kidney injury, and falls. Intensive glucose-lowering therapy among older patients with diabetes increases the risk of hypoglycemia or cognitive impairment. These findings suggest that a balanced approach for older adults is required to increase the benefits and decrease the risk of side effects. In contrast to older people, the estimated 10-year cardiovascular risk in young and healthy individuals is low. However, the lifetime cardiovascular risk in these patients is actually high. The 2021 European Society of Cardiology guideline on cardiovascular disease prevention in clinical practice has been published. It proposed a different risk stratification and recommendation for treatment according to age group, based on the concept of avoiding undertreatment in young people and overtreatment in older persons. Although the guideline recommends age-dependent risk stratification, risk categories should not be applied to the mandatory initiation of drug treatment. In all age groups, other factors such as lifetime cardiovascular risk, treatment benefit and harm, comorbidities, frailty, and patient preferences should be considered when managing patients for primary prevention.

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.