# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=de-DE - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Author=Tao Liu - CreationDate=D:20260516155101+05'30' - Creator=Adobe InDesign 15.1 (Windows) - ModDate=D:20260516155106+05'30' - Producer=Adobe PDF Library 15.0 - Subject=DOI: 10.1161/STROKEAHA.125.053989 Stroke, Volume. 57, Issue. 6, BACKGROUND: Early intensive blood pressure (BP) lowering improves outcomes in acute intracerebral hemorrhage, but its perioperative benefit among patients undergoing surgical hematoma evacuation is uncertain. We evaluated whether earlier achievement of intensive BP targets is associated with improved outcomes in this population. METHODS: Post hoc secondary analysis of the INTERACT3 (the third Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) pragmatic, international, multicenter, blinded-end point, and stepped-wedge cluster-randomized trial. Among 7036 enrolled intracerebral hemorrhage patients at 121 hospitals, those who underwent surgical hematoma evacuation were included. Patients were categorized by time from hospital arrival to achieving the target systolic BP <140 mm Hg: ≤2 hours versus >2 hours. The primary outcome was 6-month mortality. Key secondary outcomes included death or disability (modified Rankin Scale scores 4–6), modified Rankin Scale score shift, health-related quality-of-life (EuroQol 5-Dimension 3-Level [EQ-5D-3L] domains, visual analog scale, and health utility index), and serious adverse events. Adjusted associations were estimated using Cox, logistic, ordinal logistic, and linear regression models, controlling for age, sex, treatment type, and admission Glasgow Coma Scale. RESULTS: Of 7036 patients with acute intracerebral hemorrhage, 1506 underwent surgical hematoma evacuation (mean [SD] age, 59.7 [11.8] years; 33.9% women). Overall, there was no statistically significant difference in 6-month mortality between patients who achieved target BP within 2 hours of treatment initiation and those who achieved it after 2 hours (adjusted hazard ratio, 0.81 [95% CI, 0.63–1.04]; P=0.09). Early BP achievement was associated with a lower risk of death or disability (adjusted odds ratio [OR], 0.71 [95% CI, 0.56–0.90]; P=0.01), a favorable shift in the distribution of modified Rankin Scale scores (adjusted common OR, 0.73 [95% CI, 0.60–0.89]; P<0.01), and fewer serious adverse events (adjusted OR, 0.73 [95% CI, 0.57–0.94]; P=0.02). EuroQol 5-Dimension 3-Level outcomes also favored the early group, with significant improvements in mobility (adjusted OR, 0.76 [95% CI, 0.60–0.97]; P=0.03), pain/discomfort (adjusted OR, 0.72 [95% CI, 0.54–0.95]; P=0.02), and usual activities (adjusted OR, 0.79 [95% CI, 0.62–1.00]; P=0.05), as well as higher visual analog scale (mean difference, 0.08 [95% CI, 0.002–0.17]; P=0.04) and health utility scores (mean difference, 0.05 [95% CI, 0.02–0.09]; P<0.01). CONCLUSIONS: In patients with intracerebral hemorrhage undergoing surgical hematoma evacuation, perioperative intensive BP reduction appears safe. Achieving systolic BP <140 mm Hg within 2 hours was associated with better functional and quality-of-life outcomes, and fewer serious adverse events. These time-sensitive associations support prioritizing ultra-early perioperative BP control; confirmatory prospective analyses are warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03209258. - Title=Impact of Ultra-Early Perioperative Antihypertensive Therapy in Acute Intracerebral Hemorrhage - Trapped=False - dc:format=application/pdf - dc:title=Impact of Ultra-Early Perioperative Antihypertensive Therapy in Acute Intracerebral Hemorrhage - dc:creator=Tao Liu,Linan Chen,Leibo Liu,Yang Liu,Lu Ma,Laurent Billot,Qiang Li,Zhihao Zhao,Alejandra Malavera,Paula Muñoz-Venturelli,Asita de Silva,Huy Thang Nguyen,Kolawole W. Wahab,Jeyaraj D. Pandian,Mohammad Wasay,Octavio M. Pontes-Neto,Rongcai Jiang,Carlos Abanto,Antonio Arauz,Lili Song,Chao You,Craig S. Anderson,Xin Hu,Xiaoying Chen - dc:subject=blood pressure ◼,cerebral hemorrhage ◼ Glasgow Coma Scale ◼ hematoma ◼,quality of life - dc:description=DOI: 10.1161/STROKEAHA.125.053989 Stroke, Volume. 57, Issue. 6, BACKGROUND: Early intensive blood pressure (BP) lowering improves outcomes in acute intracerebral hemorrhage, but its perioperative benefit among patients undergoing surgical hematoma evacuation is uncertain. We evaluated whether earlier achievement of intensive BP targets is associated with improved outcomes in this population. METHODS: Post hoc secondary analysis of the INTERACT3 (the third Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) pragmatic, international, multicenter, blinded-end point, and stepped-wedge cluster-randomized trial. Among 7036 enrolled intracerebral hemorrhage patients at 121 hospitals, those who underwent surgical hematoma evacuation were included. Patients were categorized by time from hospital arrival to achieving the target systolic BP <140 mm Hg: ≤2 hours versus >2 hours. The primary outcome was 6-month mortality. Key secondary outcomes included death or disability (modified Rankin Scale scores 4–6), modified Rankin Scale score shift, health-related quality-of-life (EuroQol 5-Dimension 3-Level [EQ-5D-3L] domains, visual analog scale, and health utility index), and serious adverse events. Adjusted associations were estimated using Cox, logistic, ordinal logistic, and linear regression models, controlling for age, sex, treatment type, and admission Glasgow Coma Scale. RESULTS: Of 7036 patients with acute intracerebral hemorrhage, 1506 underwent surgical hematoma evacuation (mean [SD] age, 59.7 [11.8] years; 33.9% women). Overall, there was no statistically significant difference in 6-month mortality between patients who achieved target BP within 2 hours of treatment initiation and those who achieved it after 2 hours (adjusted hazard ratio, 0.81 [95% CI, 0.63–1.04]; P=0.09). Early BP achievement was associated with a lower risk of death or disability (adjusted odds ratio [OR], 0.71 [95% CI, 0.56–0.90]; P=0.01), a favorable shift in the distribution of modified Rankin Scale scores (adjusted common OR, 0.73 [95% CI, 0.60–0.89]; P<0.01), and fewer serious adverse events (adjusted OR, 0.73 [95% CI, 0.57–0.94]; P=0.02). EuroQol 5-Dimension 3-Level outcomes also favored the early group, with significant improvements in mobility (adjusted OR, 0.76 [95% CI, 0.60–0.97]; P=0.03), pain/discomfort (adjusted OR, 0.72 [95% CI, 0.54–0.95]; P=0.02), and usual activities (adjusted OR, 0.79 [95% CI, 0.62–1.00]; P=0.05), as well as higher visual analog scale (mean difference, 0.08 [95% CI, 0.002–0.17]; P=0.04) and health utility scores (mean difference, 0.05 [95% CI, 0.02–0.09]; P<0.01). CONCLUSIONS: In patients with intracerebral hemorrhage undergoing surgical hematoma evacuation, perioperative intensive BP reduction appears safe. Achieving systolic BP <140 mm Hg within 2 hours was associated with better functional and quality-of-life outcomes, and fewer serious adverse events. These time-sensitive associations support prioritizing ultra-early perioperative BP control; confirmatory prospective analyses are warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03209258. - dc:rights=© 2026 The Authors. - xmp:createdate=2026-05-16T15:51:01+05:30 - xmp:metadatadate=2026-05-16T15:51:06+05:30 - xmp:modifydate=2026-05-16T15:51:06+05:30 - xmp:creatortool=Adobe InDesign 15.1 (Windows) - xmpmm:instanceid=uuid:d0f91973-4f0e-4f16-b768-7373e4bca57b - xmpmm:originaldocumentid=xmp.did:DE4D607E8A24681180838231FB1F3433 - xmpmm:documentid=xmp.id:ad550b52-0c68-bf4a-bb4a-f512be623ea9 - xmpmm:renditionclass=proof:pdf - xmpmm:derivedfrom=xmp.iid:ccb81455-85ea-4c43-885f-23bafc4e0740xmp.did:795853c5-47ef-c044-9e14-55f0c513bc48xmp.did:DE4D607E8A24681180838231FB1F3433default - xmpmm:history=convertedfrom application/x-indesign to application/pdfAdobe InDesign 15.1 (Windows)/2026-05-16T15:51:01+05:30 - xmprights:marked=True - pdf:producer=Adobe PDF Library 15.0 - pdf:trapped=False ## Contents ### Page 1 CLINICAL AND POPULATION SCIENCES # Impact of Ultra-Early Perioperative AntihypertensiveTherapy in Acute Intracerebral Hemorrhage Tao Liu[ ![Equation 1]() ](https://orcid.org/0000-0002-0506-3356) , MD*; Linan Chen[ ![Equation 1]() ](https://orcid.org/0000-0002-4926-0191) , PhD*; Leibo Liu[ ![Equation 1]() ](https://orcid.org/0000-0002-7517-0050) , PhD; Yang Liu[ ![Equation 1]() ](https://orcid.org/0009-0004-3027-4122) , MMed; Lu Ma[ ![Equation 1]() ](https://orcid.org/0009-0000-8095-2236) , MD; Laurent Billot[ ![Equation 1]() ](https://orcid.org/0000-0002-4975-9793) , MRes;Qiang Li, MBiostat; Zhihao Zhao[ ![Equation 1]() ](https://orcid.org/0009-0001-5702-6290) , MMed; Alejandra Malavera[ ![Equation 1]() ](https://orcid.org/0000-0002-6084-4315) , MD; Paula Muñoz-Venturelli[ ![Equation 1]() ](https://orcid.org/0000-0003-1869-2255) , MD, PhD; Asita de Silva[ ![Equation 1]() ](https://orcid.org/0000-0003-2544-6861) , MD, PhD;Huy Thang Nguyen[ ![Equation 1]() ](https://orcid.org/0000-0003-1091-9320) , MD; Kolawole W. Wahab[ ![Equation 1]() ](https://orcid.org/0000-0002-2914-1953) , MD; Jeyaraj D. Pandian[ ![Equation 1]() ](https://orcid.org/0000-0003-0028-1968) , MD; Mohammad Wasay[ ![Equation 1]() ](https://orcid.org/0000-0003-3750-2613) , MD;Octavio M. Pontes-Neto[ ![Equation 1]() ](https://orcid.org/0000-0003-0317-843X) , MD, PhD; Rongcai Jiang[ ![Equation 1]() ](https://orcid.org/0009-0004-2257-7668) , MD, PhD; Carlos Abanto[ ![Equation 1]() ](https://orcid.org/0000-0002-6419-4591) , MPH; Antonio Arauz[ ![Equation 1]() ](https://orcid.org/0000-0002-3340-4138) , PhD; Lili Song[ ![Equation 1]() ](https://orcid.org/0000-0002-6105-1720) , MD, PhD;Chao You[ ![Equation 1]() ](https://orcid.org/0000-0002-1783-3688) , MD; Craig S. Anderson[ ![Equation 1]() ](https://orcid.org/0000-0002-7248-4863) , MBBS, PhD; Xin Hu[ ![Equation 1]() ](https://orcid.org/0000-0002-6084-1341) , MD; Xiaoying Chen[ ![Equation 1]() ](https://orcid.org/0000-0002-8367-542X) , PhD; for the INTERACT3 Investigators BACKGROUND: Early intensive blood pressure (BP) lowering improves outcomes in acute intracerebral hemorrhage, but itsperioperative benefit among patients undergoing surgical hematoma evacuation is uncertain. We evaluated whether earlierachievement of intensive BP targets is associated with improved outcomes in this population. METHODS: Post hoc secondary analysis of the INTERACT3 (the third Intensive Care Bundle With Blood Pressure Reduction in AcuteCerebral Haemorrhage Trial) pragmatic, international, multicenter, blinded-end point, and stepped-wedge cluster-randomized trial.Among 7036 enrolled intracerebral hemorrhage patients at 121 hospitals, those who underwent surgical hematoma evacuationwere included. Patients were categorized by time from hospital arrival to achieving the target systolic BP<140 mm Hg: ≤2 hoursversus>2 hours. The primary outcome was 6-month mortality. Key secondary outcomes included death or disability (modified RankinScale scores 4–6), modified Rankin Scale score shift, health-related quality-of-life (EuroQol 5-Dimension 3-Level [EQ-5D-3L]domains, visual analog scale, and health utility index), and serious adverse events. Adjusted associations were estimated using Cox,logistic, ordinal logistic, and linear regression models, controlling for age, sex, treatment type, and admission Glasgow Coma Scale. RESULTS: Of 7036 patients with acute intracerebral hemorrhage, 1506 underwent surgical hematoma evacuation (mean [SD]age, 59.7 [11.8] years; 33.9% women). Overall, there was no statistically significant difference in 6-month mortality betweenpatients who achieved target BP within 2 hours of treatment initiation and those who achieved it after 2 hours (adjustedhazard ratio, 0.81 [95% CI, 0.63–1.04]; P=0.09). Early BP achievement was associated with a lower risk of death or disability(adjusted odds ratio [OR], 0.71 [95% CI, 0.56–0.90]; P=0.01), a favorable shift in the distribution of modified Rankin Scalescores (adjusted common OR, 0.73 [95% CI, 0.60–0.89]; P<0.01), and fewer serious adverse events (adjusted OR, 0.73 [95%CI, 0.57–0.94]; P=0.02). EuroQol 5-Dimension 3-Level outcomes also favored the early group, with significant improvements inmobility (adjusted OR, 0.76 [95% CI, 0.60–0.97]; P=0.03), pain/discomfort (adjusted OR, 0.72 [95% CI, 0.54–0.95]; P=0.02),and usual activities (adjusted OR, 0.79 [95% CI, 0.62–1.00]; P=0.05), as well as higher visual analog scale (mean difference,0.08 [95% CI, 0.002–0.17]; P=0.04) and health utility scores (mean difference, 0.05 [95% CI, 0.02–0.09]; P<0.01). CONCLUSIONS: In patients with intracerebral hemorrhage undergoing surgical hematoma evacuation, perioperative intensiveBP reduction appears safe. Achieving systolic BP<140 mm Hg within 2 hours was associated with better functional andquality-of-life outcomes, and fewer serious adverse events. These time-sensitive associations support prioritizing ultra-earlyperioperative BP control; confirmatory prospective analyses are warranted. REGISTRATION: URL:; Unique identifier: NCT03209258. GRAPHIC ABSTRACT: A is available for this article. Key Words: blood pressure ◼ cerebral hemorrhage ◼ Glasgow Coma Scale ◼ hematoma ◼ quality of life Correspondence to: Craig S. Anderson, MBBS, PhD, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 201210, China,Email; or Xin Hu, MD, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China, Email; or Xiaoying Chen, PhD, George Institute for Global Health, Faculty of Medicine, University of New South Wales, 55 Botany St, Sydney, NewSouth Wales 2031, Australia, Email *T. Liu and L. Chen contributed equally. Supplemental Material is available at. © 2026 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under theterms of the License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. ### Page 2 Intracerebral hemorrhage (ICH) is among the mostlethal subtypes of stroke, with ≈40% of patients dyingwithin the first month and most survivors experiencingsignificant long-term disability.1 A marked acute elevationin blood pressure (BP) commonly occurs after ICH onsetand is strongly associated with hematoma expansion.Therefore, early intensive BP reduction has emerged asa critical therapeutic strategy to limit hematoma growthand enhance patient outcomes.2 Recent evidence sug-gests that combining BP control with additional physi-ological interventions as part of a protocol-driven carebundle may confer additional clinical benefits.3 The third Intensive Care Bundle (INTERACT3 [thethird Intensive Care Bundle With Blood Pressure Reduc-tion in Acute Cerebral Haemorrhage Trial]) is a large,international, pragmatic clinical trial designed to assesswhether managing multiple critical physiological param-eters in a hospital setting, including early intensive BPlowering, glucose and temperature control, and antico-agulant reversal, can improve functional outcomes forpatients with acute ICH.3 The INTERACT3 demonstratedthat implementing a comprehensive care strategy withinhours of symptom onset can enhance outcomes for thesepatients. Secondary outcomes assessed included mor-tality, serious adverse events (SAEs), health-related qual-ity of life (measured by the EuroQol 5-Dimension 3-Level[EQ-5D-3L] self-report questionnaire), and patient resi-dence (own home versus other). This approach empha-sizes synchronized optimization of multiple parameters,offering a multidimensional, patient-centered standard ofcare for patients with ICH, particularly in resource-limitedlow- and middle-income countries. A notable aspect of INTERACT3 is that participants inboth groups underwent hematoma evacuation at similarrates (26.4% versus 26.9%), though the time taken toreach the target systolic BP varied significantly (median,2.3 hours, interquartile range [IQR] 0.8–8.0 hours versusmedian 4.0 hours [IQR, 1.9–16.0 hours]).3 To date, limitedclinical research exists on intensive BP management duringperioperative management. Available evidence suggeststhat while intensive BP reduction during the perioperativeperiod is generally safe, its impact on improving clinicaloutcomes or reducing rebleeding is limited.4 Theoretically,the association of perioperative BP and AEs could followa U-shaped relationship, a hypothesis recently supportedby research indicating the lowest risk of postoperative AEsat a preoperative SBP of 143 mm Hg.5 A meta-analysis ofrandomized controlled trials further supports that targetinglower BP can reduce mortality, atrial fibrillation, and theneed for transfusions.6 Overall, intensive BP managementis considered safe for perioperative patients. Despite the implementation of strict emergency BPreduction protocols, some patients in clinical practice stillfail to reach target BP levels. The main factors contribut-ing to this are the initial BP level and severity of disease,although these patients receive higher frequencies andlarger doses of antihypertensive medication.7 A second-ary analysis of the ATACH-2 trial (The AntihypertensiveTreatment of Acute Cerebral Hemorrhage II) found thatearly intensive BP reduction (within 2 hours of symptomonset) was associated with reduced hematoma volumeand improved outcomes.8 Similarly, the recently publishedintensive ambulance-delivered BP reduction (INTER-ACT4 study [Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke]) demonstratedthat initiating intensive BP management within 2 hoursof symptom onset in prehospital settings was linked to alower incidence of functional impairment in hemorrhagicstroke patients.9 However, existing research has not spe-cifically investigated the efficacy and safety of ultra-earlyintensive BP reduction in perioperative patients withacute ICH. Because nearly half of the patients in the INTER-ACT3 trial reached the target systolic BP within 2 hoursof treatment, this study offers a unique opportunity toexplore this management approach further. Conse-quently, we conducted a perioperative subgroup analy-sis of INTERACT3 to identify the association betweenachieving target BP within 2 hours (early) versus after 2hours (delayed) and patient outcomes. ## METHODS ### Data Availability Individual, deidentified participant data used in these analysescan be shared on request from any qualified investigator afterapproval of a protocol and signing of a data access agreementvia both the trial steering committee and the Research Officeof The George Institute for Global Health, Sydney, Australia. ### Data Sources and Setting The INTERACT3 trial, an international randomized clinicalstudy, has had its rationale, design, and main results previously Nonstandard Abbreviations and Acronyms ATACH-2 The Antihypertensive Treatment ofAcute Cerebral Hemorrhage II BP blood pressure ICH intracerebral hemorrhage INTERACT3 The third Intensive Care Bundle WithBlood Pressure Reduction in AcuteCerebral Haemorrhage Trial IQR interquartile range mRS modified Rankin Scale OCSP Oxfordshire Community StrokeProject OR odds ratio OXVASC Oxford Vascular Study SAE serious adverse event ### Page 3 published.3,10 This trial was conducted as a prospective, mul-ticenter, stepped-wedge, cluster-randomized, controlled studyacross 121 hospitals in 9 low- and middle-income countries(Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka,and Vietnam) and 1 high-income country (Chile). Briefly, theINTERACT3 was done to implement a goal-directed carebundle incorporating intensive interventions for managinghypertension, hyperglycemia, pyrexia, and abnormal anti-coagulation in patients with acute spontaneous ICH. TheINTERACT3 trial protocol, along with written informed con-sent, received approval from the ethics committees of the par-ticipating hospitals and relevant regulatory authorities. For thissecondary analysis, further ethical approval was not requiredas the data had already been deidentified. We report this sec-ondary analysis in accordance with the STROBE guidelines(Strengthening the Reporting of Observational Studies inEpidemiology), with the completed checklist provided in the. ### Study Population Eligible participants in the INTERACT3 trial were adults,both male and female, aged 18 years or older, with imaging-confirmed spontaneous ICH within 6 hours of symptom onset.For this secondary analysis, only those who underwent surgi-cal hematoma evacuation and achieved a target systolic BPof<140 mm Hg during the perioperative period were included.Patients who did not reach the target within 72 hours of theinitiation of treatment were excluded from the analysis. All otherparticipants meeting the above criteria were included in thispost hoc analysis. ### Data Collection To maintain consistent recruitment, all participating centersregistered patients diagnosed with ICH. Baseline demographicand clinical data were collected on admission for enrolledpatients. Follow-up data on clinical status, management, out-comes on day 1 and day 7 of treatment (or earlier in cases ofdischarge or death), and outcomes at 6 months were gatheredby subcenter researchers and assessed by independent staff.Detailed information on these procedures has been previouslypublished for the INTERACT3 trial.3,10 ### Outcome Measures In this secondary analysis, the primary outcome was mortalityat 6 months. The secondary outcomes included death or dis-ability (modified Rankin Scale [mRS] score 4–6), major disabil-ity in survivors (mRS score 3–5), mRS score shift, hematomaexpansion (defined as>33% relative or>6 mL absolute volumeincrease at 24 hours compared with baseline),11,12 neurologi-cal deterioration (defined as an increase of ≥4 points in theNational Institutes of Health Stroke Scale score at day 7 com-pared with baseline), health-related quality of life (EQ-5D-3Lself-report questionnaire), residence at home, and all-causeSAEs. Baseline and Day 1 (24-hour) hematoma volumes wereobtained from electronic case report forms as reported by par-ticipating sites based on routine clinical imaging assessment.SAEs were recorded throughout the follow-up period and weredefined as events that resulted in death, were life-threatening,required inpatient hospitalization or prolongation of an exist-ing hospitalization, resulted in persistent or significant disabilityor incapacity, involved a congenital anomaly or birth defect, orwere considered other medically important events; a patientcould experience>1 SAE. ### Statistical Analysis Baseline characteristics were categorized based on the earliertime (≤2 hours) versus the delayed time (>2 hours) to reach-ing the targeted BP. Normally distributed continuous variableswere presented as mean (SD), while non-normally distributedones were shown as median (IQR). Categorical variables weredisplayed as frequencies with percentages (%). Group com-parisons were made using t-tests for normally distributed con-tinuous variables, Wilcoxon rank-sum tests for non-normallydistributed variables, and χ2 or Fisher exact tests for binaryvariables. Trends in ordinal categorical variables were assessedusing the Cochran-Armitage test. ![Figure 1]() ### Page 4 (Continued) ### Page 5 A Cox regression model was used to assess the risk ofmortality at 6 months, providing hazard ratios with 95% CIs,adjusting for a parsimonious set of key baseline prognosticcovariates: age, sex, treatment type (care bundle versus usualcare), and baseline Glasgow Coma Scale. To illustrate differ-ences in mortality between the groups, cumulative mortalitycurves at 6 months were plotted. The association (mean difference, 95% CI) between groupsand visual analog scale (VAS) or utility score (measured byEQ-5D-3L) was examined using a linear regression model,with adjustments for the same parsimonious set of key base-line prognostic covariates (age, sex, treatment type, and base-line Glasgow Coma Scale). An ordinal logistic regression modelwas used to explore the shift in the distribution of mRS scores(mRS score shift). The 5 dimensions of health-related qualityof life—mobility, self-care, usual activities, pain/discomfort, andanxiety/depression—were also analyzed using similar methods.A logistic regression model was used to evaluate the associa-tion (odds ratio [OR], 95% CI) between groups and the risk ofother secondary outcomes, adjusting for the same variables. To determine whether age, sex and treatment type affectedthe results, we examined the impact of earlier time (≤2 hours)versus delayed time (>2 hours) on the primary and secondaryoutcomes by age (<60 years (median age) and ≥60 years), sex(male and female), and treatment group (care bundle and usualcare). Furthermore, additional exploratory subgroup analyseswere performed to assess potential effect modification by ICHlocation (cortical, deep, or brainstem/cerebellar) and surgerytype (craniotomy versus minimally invasive surgery). Interactionterms were included in the adjusted models, and P for interac-tion was reported. Sensitivity analyses were performed with additional adjust-ment for premorbid functional status (preonset mRS score),baseline BP (systolic and diastolic), baseline blood glucose,baseline hematoma volume, and the presence of intraventricu-lar hemorrhage across the primary and secondary outcomes.All models were fitted using a complete-case approach, includ-ing only participants with nonmissing data for the exposure,outcome, and covariates included in that model. All analyses were conducted using R version 3.4.2 (R Projectfor Statistical Computing). All hypothesis tests were 2-sided,with a P value of<0.05 considered statistically significant. ## RESULTS Between December 12, 2017, and December 31, 2021,a total of 10 857 patients with acute ICH were screenedfor eligibility, and 7036 were included in the final INTER-ACT3 analysis. Among them, 1860 required surgicalhematoma evacuation. However, 354 patients wereexcluded for not reaching the target within 72 hours,leaving 1506 patients for this secondary analysis. Ofthese, 618 achieved the target BP within 2 hours, while888 took longer (Figure). Included participants had a mean (SD) age of 59.7(11.8) years, with 511 (33.9%) being female. On admission,the mean (SD) systolic BP was 180.5 (26.1) mm Hg, and714 patients (47.4%) received care bundle interventions.Of the participants, 624 (41.43%) had a history of antihy-pertensive medication use, 344 (22.84%) were smokers,and 342 (22.71%) consumed alcohol. Overall, the median(IQR) hematoma volume was 35.0 (20.0–50.0) mL, and677 patients (45.0%) had intraventricular hemorrhage.Further baseline characteristics are detailed in Table 1. Outcomes of comparison between the 2 groups aresummarized in Table 2. Participants who achieved the tar-get BP within 2 hours had a median (IQR) National Insti-tutes of Health Stroke Scale score of 16 (10–28) at 7days, compared with 18 (10–30) for those who reachedthe target beyond 2 hours. At 6 months, all-cause mortal-ity was 18.52% (95% CI, 15.33–22.06) in the ≤2 hourgroup compared with 23.39% (95% CI, 20.42–26.56)in the>2 hours group. The incidence of death or majordisability was 51.67% (95% CI, 47.36–55.96) versus60.45% (95% CI, 56.87–63.94), respectively. Data are mean (SD), n (%), median (IQR). Baseline characteristics were summarized by time-to-BP-target group. Continuous variables are reported as mean (SD) ifnormally distributed and as median (IQR) otherwise; categorical variables as counts (percentages). Between-group comparisons used the t test for normally distributedcontinuous variables and the Wilcoxon rank-sum test for non-normal variables. Binary variables were compared with the χ2 test. Ordinal categorical variables wereassessed using the Cochran-Armitage test for trend. BMI indicates body mass index; BP, blood pressure; DBP, diastolic blood pressure; GCS, Glasgow Coma Scale; ICH,intracerebral hemorrhage; INR, international normalized ratio; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale;and SBP, systolic blood pressure. *Non-Chinese included White or European, Latin American, Mixed, Other Asian, Indian subcontinent, or other known race and ethnicity. †Calculated by dividing weight (kg) by height (m2). ‡Minimally invasive surgery included endoscopy, aspiration, intraventricular drainage, catheterization with/without lysis, and other types. §Scores on the mRS of functional recovery range from 0 (no symptoms) to 6 (death). A score of 0 indicates “no symptoms” and a score ≤2 indicates functionalindependence. The mRS score before stroke onset was assessed by the treating physician with the use of information obtained from patients (if possible) or their familymembers. ‖NIHSS scores range from 0 to 42, with higher scores indicating more severe neurological deficits. ¶GCS scores range from 15 (normal) to 3 (deep coma). ### Page 6 (Continued) ### Page 7 Participants who reached target BP within 2 hoursalso showed higher scores on the VAS and health util-ity scores, with VAS scores of 70 (IQR, 50–80) versus60 (IQR, 40–80), and health utility scores of 0.51 (IQR,0.26–0.80) versus 0.35 (IQR, 0.11–0.78) comparedwith those who reached the target later. SAEs occurredin 22.96 per 100 participants (95% CI, 19.69–26.50)among those who reached the target within 2 hours,compared with 29.04 per 100 participants (95% CI,26.06–32.17) for those with a delay. In analyses adjusted for age, sex, treatment type, andbaseline Glasgow Coma Scale scores, patients whoreached the target BP within 2 hours had a more favor-able distribution of mRS scores at 6 months than thosewho took longer (adjusted common OR, 0.73 [95% CI,0.60–0.89]; P<0.01; Table 3). Overall, the cumulativemortality did not differ significantly between the ≤2 hoursgroup and the>2 hours group (adjusted hazard ratio, 0.81[95% CI, 0.63–1.04]; P=0.09;; Table 3). In theadjusted model, patients who reached target BP within2 hours had a 29% lower risk of death or major disability(adjusted OR, 0.71 [95% CI, 0.56–0.90]; P=0.01) anda 27% lower risk of experiencing SAEs (adjusted OR,0.73 [95% CI, 0.57–0.94]; P=0.02) compared with thosewho took longer. Similarly, earlier target achievement wasassociated with a lower risk of neurological deterioration(adjusted OR, 0.61 [95% CI, 0.43–0.88]; P<0.01). How-ever, no significant differences were observed betweenthe 2 groups regarding hematoma expansion (adjustedOR, 0.93 [95% CI, 0.65–1.34]; P=0.70) or residence athome at 6 months (adjusted OR, 1.07 [95% CI, 0.83–1.39]; P=0.58). Additionally, the ≤2 hour group showed better out-comes in EQ-5D-3L measures, including mobility(adjusted OR, 0.76 [95% CI, 0.60–0.97]; P=0.03), painor discomfort (adjusted OR, 0.72 [95% CI, 0.54–0.95];P=0.02), and usual activities (adjusted OR, 0.79 [95%CI, 0.62–1.00]; P=0.05). Participants in the ≤2 hourgroup also had improvements in VAS and utility scores,which increased by 0.08 (95% CI, 0.002–0.17, P=0.04)and 0.05 (95% CI, 0.02–0.09, P<0.01), respectively,compared with those in the>2 hours group. The subgroup analysis compared the effects of timeto achieving target BP (≤2 versus>2 hours [reference])on patient outcomes. The results suggest that the effectsof time to achieving target BP on patient outcomesvary based on age, sex, and treatment type (care bun-dle versus usual care). Details are provided in Table 4.In additional exploratory subgroup analyses, generallyconsistent associations were observed for the primaryand key secondary outcomes across hemorrhage loca-tion (cortical, deep, or brainstem/cerebellar) and surgerytype (craniotomy versus minimally invasive surgery;). An isolated interaction was noted only for the EQ-5D-3L anxiety/depression domain by surgery type (P forinteraction=0.04), with no other significant interactionsobserved. Sensitivity analyses with additional adjustment forpremorbid functional status (preonset mRS score), base-line BP (systolic and diastolic), baseline blood glucose,baseline hematoma volume, and the presence of intra-ventricular hemorrhage showed no material changes ineffect estimates or conclusions (). ## DISCUSSION The INTERACT3 trial provides the most extensivedata set to date on perioperative intensive BP reduc-tion in patients with acute ICH. In this post hoc analy-sis, we found that the clinical benefits of intensive BP Data are n ( %) or mean (SD), unless noted otherwise. EQ-5D-3L indicates EuroQol 5-Dimension 3-Level; IQR, interquartile range; mRS, modified Rankin Scale;NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; and SAE, serious adverse event. *Hematoma expansion defined as an increase of>6 mL or a growth of>33%. †Assessment at day 7 (or discharge/death if earlier). ‡The time frame for assessing safety outcomes included during hospitalization and follow-up periods. §Serious adverse events were defined as events that resulted in death, were life-threatening, required inpatient hospitalization or prolongation of an existing hospi-talization, resulted in persistent or significant disability or incapacity, involved a congenital anomaly or birth defect, or were considered other medically important events;a patient could experience>1 SAE. ### Page 8 (Continued) ### Page 9 management among patients undergoing hematomaevacuation were strongly time-dependent. Achieving thetarget BP within 2 hours, compared with delayed con-trol (>2 hours), was associated with better functional andquality-of-life outcomes, and fewer SAEs. These findingssuggest that ultra-early BP reduction in the perioperativesetting is both feasible and safe, potentially improvinglong-term functional recovery. There was no statistically significant difference inthe primary outcome of 6-month mortality between thegroups. However, patients who achieved target BP within2 hours showed some other better clinical outcomes,particularly in mRS score shifts and rates of death ordisability at 6 months. Furthermore, EQ-5D-3L analy-sis revealed that early BP control was associated withhigher quality-of-life scores, particularly in domains suchas mobility, pain or discomfort, and usual activities. Thesepatients also had better VAS and health utility scores,aligning with findings from the pooled analysis of INTER-ACT studies, which support the benefits of early BP con-trol on long-term quality of life.13 BP management is a crucial aspect of ICH treat-ment. Epidemiological studies indicate that over half ofpatients with ICH experience hypertension.14,15 Com-pared with patients with other causes of ICH, those withhypertension-induced ICH exhibit persistently highersystolic BP within the first 72 hours after admission.16The hypertensive state observed in patients with ICHis driven by multiple factors and may be independentof catecholamine levels, which adds complexity to itsmanagement.17 The PROGRESS trial (Perindopril Pro-tection Against Recurrent Stroke Study) in 2004 firstdemonstrated that BP management could reduce therelative risk of stroke recurrence by 50% among hem-orrhagic stroke survivors, prompting advancements inBP management standards.18,19 Real-world data fur-ther support the protective effect of antihypertensivetreatment on recurrence risk in patients with ICH. Overthe past 40 years, recurrence rates have declined from10.3 cases per 100 person-years during the OCSPperiod to 3.1 cases per 100 person-years during theOXVASC (Oxford Vascular Study) period. This reductionis especially notable in patients under 75 years of age,in whom the 5-year stroke recurrence risk decreasedfrom 35.4% to 6.9%.20 Elevated BP is a risk factor for stroke recurrence andcognitive decline in patients with ICH, making early andaggressive BP reduction crucial for improving outcomes,particularly in cases of lobar hemorrhage.21–23 Animalmodels have shown that although intensive BP reduc-tion does not significantly impact the blood-brain barrierin acute ICH, it effectively reduces hematoma expansionand improves neurological function in the early stages ofhemorrhage.24 Multiple clinical studies further indicatethat early intensive BP management is especially criticalfor limiting hematoma growth, particularly in patients withrapid hemorrhage expansion, which can improve functionaloutcomes.25–29 However, whether intensive BP reductionconfers benefits to patients with ICH remains unproven. Preoperative hypertension can lead to intraoperativehemodynamic instability, thereby increasing the risk ofcardiovascular and cerebrovascular complications dur-ing the perioperative period.30,31 Retrospective studieshave shown a significant association between periop-erative hypertension and the incidence of postoperativeICH in craniotomy patients.32 A Bayesian meta-analysissuggests that, compared with higher BP targets, alower BP target in the perioperative period may reducemortality by 10% and decrease the incidence of atrialfibrillation as well as the need for transfusions.5 How-ever, a small randomized controlled trial in 2017 foundthat intensive BP reduction in perioperative patientswith ICH, targeting systolic BP between 120 and 140mm Hg, did not significantly reduce rates of rebleeding, Hematoma expansion is defined as an increase of>6 mL or a growth of>33% at 24 hours. Neurological deterioration: defined asan increase of ≥4 points in the NIHSS score at 7 days compared with baseline. EQ-5D-3L indicates EuroQol 5-Dimension 3-Level;GCS, Glasgow Coma Scale; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; and OR, odds ratio. *OR for risks of outcome events for participants who achieved the blood pressure target within 2 hours compared with those whodid not reach the target within 2 hours, adjusted for age, sex, GCS on admission, and randomized treatment group. †The risk of death at 6 months is represented as the hazard ratio, as the results were obtained using the Cox proportional regres-sion hazards model. ‡Statistical significance (P≤0.05). §The risk of outcome events was estimated using an ordinal logistic regression model. ‖The risk of outcome events was estimated using a logistic regression model. ¶The mean differences in the visual analog scale (log transform) and utility score were estimated using a linear regression model. #Serious adverse events were defined as events that resulted in death, were life-threatening, required inpatient hospitalization orprolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, involved a congenital anomaly orbirth defect, or were considered other medically important events; a patient could experience>1 SAE. ### Page 10 (Continued) ### Page 11 Hematoma expansion defined as an increase of>6 mL or a growth of>33% at 24 h. Neurological deterioration: defined as an increase of ≥4 points in the NIHSSscore at 7 days compared with baseline. EQ-5D-3L indicates EuroQol 5-Dimension 3-Level; GCS, Glasgow Coma Scale; mRS, modified Rankin Scale; NIHSS, NationalInstitutes of Health Stroke Scale; OR, odds ratio; and SAE, serious adverse event. *OR for risks of outcome events for participants who achieved the blood pressure target within 2 hours compared with those who did not reach the target within 2hours, adjusted for age, sex, GCS on admission, and randomized treatment group, unless used as grouping variables. †The risk of death at 6 mo is represented as the hazard ratio, as the results were obtained using the Cox proportional regression hazards model. ‡Statistical significance (P≤0.05). §The risk of outcome events was estimated using an ordinal logistic regression model. ‖The risk of outcome events was estimated using a logistic regression model. ¶The mean differences in the visual analog scale (log transform) and utility score were estimated using a linear regression model. #Serious adverse events were defined as events that resulted in death, were life-threatening, required inpatient hospitalization or prolongation of an existing hospi-talization, resulted in persistent or significant disability or incapacity, involved a congenital anomaly or birth defect, or were considered other medically important events;a patient could experience>1 SAE. ### Page 12 mortality, or other SAEs.4 Although this randomizedcontrolled trial did not demonstrate clear benefits ofintensive BP reduction, it suggests that perioperativeBP control is safe. Beyond the small sample size, the timing of interven-tion is a key factor influencing outcomes. A post hocexploratory analysis of ATACH-2 suggests that ultra-early intensive BP reduction (within 2 hours of symp-tom onset) significantly reduces hematoma expansion,enhances functional independence, and improves over-all prognosis.8 Previous studies indicate that early braininjury factors, such as hematoma expansion, emergewithin hours of onset and worsen outcomes overtime.33,34 Secondary analysis of INTERACT2 furthersupports this, showing a 22% reduction in hematomagrowth when intensive BP management begins within2.9 hours of onset, compared with only a 3% reductionwhen initiated after 4.9 hours.35 However, in this analy-sis, no significant difference in hematoma expansionwas found between the early and delayed interventiongroups. We think that for patients with ICH requiringsurgery, who typically present with complex, severe con-ditions and rapid neurological decline, focusing solelyon short-term outcomes, such as hematoma expan-sion, may be inappropriate. Greater emphasis shouldbe placed on improving long-term survival and overallprognosis. This study holds several important clinical implications.Although early intensive BP reduction is the standardof care for patients with spontaneous ICH, its applica-tion in the perioperative setting is often complicatedby concerns about hemodynamic instability related toanesthesia and surgical stress. Our findings help bridgethis evidence gap by showing that ultra-early achieve-ment of the target systolic BP<140 mm Hg within 2hours of treatment initiation is safe and feasible evenin this high-risk population. This reinforces the conceptthat decisions regarding surgical hematoma evacuationshould not delay the initiation of intensive BP control.By demonstrating that ultra-early intervention was asso-ciated with improved health-related quality of life andfewer SAEs, our data support prioritizing immediate BPoptimization as an integral bridge to surgery, rather thanviewing it as a separate or secondary consideration in thecare pathway. Time to BP target may therefore be con-sidered a pragmatic process-of-care indicator for qualityimprovement in the perioperative management of ICH. However, this study also has limitations. As a post hocanalysis, this study is exploratory in nature. We did notapply formal statistical corrections for multiple compari-sons across secondary outcomes, which may increasethe risk of type I error; therefore, these findings shouldbe interpreted with caution and require validation in high-quality randomized controlled trials. Further, the surgi-cal and nursing standards across participating hospitalswere not quantifiable, although such factors are critical topatient outcomes and currently lack standardized assess-ment methods. Despite adjusting for key confounders,there may still be unmeasured confounding factors. Inaddition, we did not impute missing data; complete-caseanalyses may reduce precision and could introduce biasif data are not missing at random. Lastly, due to datarecording limitations, it is unclear whether the target BPwas reached preoperatively, intraoperatively, or postoper-atively, preventing further comparisons based on timing. ## CONCLUSIONS In our post hoc analysis of the INTERACT3 trial, wefound that perioperative patients with ICH who achievedtarget systolic BP within 2 hours of initial treatment hadbetter functional and quality-of-life outcomes and fewerSAEs. Ultra-early intensive BP reduction in the periop-erative period appears both safe and feasible. ## ARTICLE INFORMATION Received September 30, 2025; final revision received January 30, 2026;accepted February 24, 2026. ### Affiliations George Institute for Global Health, Faculty of Medicine, University of New SouthWales, Sydney, Australia (T.L., L.C., L.L., L.B., Q.L., A.M., P.M.-V., L.S., C.S.A., X.C.).Department of Neurosurgery, Tianjin Medical University General Hospital, China(Y.L., Z.Z.). Department of Neurosurgery, West China Hospital, Sichuan University,Chengdu, China (L.M., C.Y., X.H.). Clinical Research Center, Faculty of MedicineClinica Alemana Universidad del Desarrollo, Santiago, Chile (P.M.-V., C.S.A.). Clin-ical Trials Unit, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka(A.d.S.). Stroke Unit, 115 Hospital, Ho Chi Minh City, Vietnam (H.T.N.). Depart-ment of Medicine, University of Ilorin & University of Ilorin Teaching Hospital,Nigeria (K.W.W.). Neurology Department, Christian Medical College and Hospital,Ludhiana, India (J.D.P.). Department of Medicine, The Aga Khan University, Ka-rachi, Pakistan (M.W.). Department of Neuroscience and Behavioral Sciences,Ribeirão Preto Medical School, University of São Paulo, Brazil (O.M.P.-N.). De-partment of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing,China (R.J.). The Cerebrovascular Disease Research Center, National Instituteof Neurological Sciences, Lima, Peru (C.A.). Instituto Nacional de Neurologia yNeurocirugia Manuel Velasco Suarez, Mexico City, Mexico (A.A.). Institute of Sci-ence and Technology for Brain-inspired Intelligence, Fudan University, Shanghai,China (L.S., C.S.A.). Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai, China(L.S., C.S.A.). Department of Neurology, Royal Prince Alfred Hospital, Sydney,Australia (C.S.A.). The George Institute for Global Health China, Beijing, China(C.S.A.). ### Acknowledgments The authors also thank the participants, their relatives, and their families. ### Sources of Funding The study is supported by an award (grant reference number MR/T005009/1)jointly funded by the Department of Health and Social Care, the Foreign, Com-monwealth & Development Office, the Medical Research Council, and the Well-come Trust (all London, United Kingdom); the West China Hospital OutstandingDiscipline Development 1-3-5 program (number ZY2016102); National Healthand Medical Research Council of Australia (number APP1149987); SichuanCredit Pharmaceutical; and Takeda (China). ### Disclosures Dr Muñoz Venturelli reports grants from Boehringer Ingelheim, ANID, and Pfizer.Dr Wahab reports service as Editor for the Nigerian Society of Neurological Sci-ences; service as Member, Guidelines Review Committee for the World StrokeOrganization; and service as Secretary-General for the Nigerian Hypertension ### Page 13 Society. Dr Pontes-Neto reports compensation from Medtronic, Servier Phar-maceuticals LLC, Bayer, and Pfizer for other services and compensation fromBoehringer Ingelheim for consultant services. Dr Anderson is a senior investiga-tor fellow for the National Health and Medical Research Council of Australia. DrAnderson reports grants from the National Health and Medical Research Council;compensation from AstraZeneca Australia and Auzone Pharma, China, for con-sultant services. The other authors report no conflicts. ### Supplemental Material Tables S1–S2 Figure S1 STROBE Checklist ## REFERENCES 1. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ.Incidence, case fatality, and functional outcome of intracerebral haem-orrhage over time, according to age, sex, and ethnic origin: a system-atic review and meta-analysis. Lancet Neurol. 2010;9:167–176. doi:10.1016/S1474-4422(09)70340-0 2. Cordonnier C, Demchuk A, Ziai W, Anderson CS. 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