Browsing by Author "Arauz, Antonio"
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Item Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial(2018) Kasner, Scott E.; Lavados, Pablo; Sharma, Mukul; Wang, Yongjun; Wang, Yilong; Dávalos, Antoni; Shamalov, Nikolay; Cunha, Luis; Lindgren, Arne; Mikulik, Robert; Arauz, Antonio; Lang, Wilfried; Czlonkowska, Anna; Eckstein, Jens; Gagliardi, Rubens; Amarenco, Pierre; Ameriso, Sebastián F.; Tatlisumak, Turgut; Hart, Robert G.; NAVIGATE ESUS Steering Committee and InvestigatorsBackground: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.Item COVID-19 Lockdown Effects on Acute Stroke Care in Latin America(2021) Pujol-Lereis, Virginia A.; Flores, Alan; Barboza, Miguel A.; Abanto-Argomedo, Carlos; Amaya, Pablo; Bayona, Hernán; Bonardo, Pablo; Díaz-Escobar, Luis; Gómez-Schneider, Maia; Góngora-Rivera, Fernando; Lavados, Pablo; León, Carolina; Luraschi, Adriana; Márquez-Romero, Juan Manuel; Ouriques-Martins, Sheila C.; Navia, Víctor; Ruiz-Franco, Angélica; Vences, Miguel Angel; Zurru, María Cristina; Arauz, Antonio; Ameriso, Sebastián; Latin American Stroke rEgistry (LASE) COVID-19 Collaborators.Objectives: COVID-19 pandemic has forced important changes in health care worldwide. Stroke care networks have been affected, especially during peak periods. We assessed the impact of the pandemic and lockdowns in stroke admissions and care in Latin America. Materials and Methods: A multinational study (7 countries, 18 centers) of patients admitted during the pandemic outbreak (March-June 2020). Comparisons were made with the same period in 2019. Numbers of cases, stroke etiology and severity, acute care and hospitalization outcomes were assessed. Results: Most countries reported mild decreases in stroke admissions compared to the same period of 2019 (1187 vs. 1166, p = 0.03). Among stroke subtypes, there was a reduction in ischemic strokes (IS) admissions (78.3% vs. 73.9%, p = 0.01) compared with 2019, especially in IS with NIHSS 0 5 (50.1% vs. 44.9%, p = 0.03). A substantial increase in the proportion of stroke admissions beyond 48 h from symptoms onset was observed (13.8% vs. 20.5%, p < 0.001). Nevertheless, no differences in total reperfusion treatment rates were observed, with similar door-to-needle, door-toCT, and door-to-groin times in both periods. Other stroke outcomes, as all-type mortality during hospitalization (4.9% vs. 9.7%, p < 0.001), length of stay (IQR 1 5 days vs. 0 9 days, p < 0.001), and likelihood to be discharged home (91.6% vs. 83.0%, p < 0.001), were compromised during COVID-19 lockdown period. Conclusions: In this Latin America survey, there was a mild decrease in admissions of IS during the COVID-19 lockdown period, with a significant delay in time to consultations and worse hospitalization outcomes.Item Demographics, socio-economic characteristics, and risk factor prevalence in patients with non-cardioembolic ischaemic stroke in low- and middle-income countries: the OPTIC registry.(Sage Publications, 2013) Abboud, Halim; Labreuche, Julien; Arauz, Antonio; Bryer, Alan; Lavados, Pablo; Massaro, Ayrton; Muñoz, Mario; Steg, Philippe; Yamout, Bassem; Vicaut, Eric; Amarenco, PierreBACKGROUND: There is a paucity of data on patients with stroke/transient ischaemic attack in low- and middle-income countries. We sought to describe the characteristics and management of patients with an ischaemic stroke and recent transient ischaemic attack or minor ischaemic strokes in low- or middle-income countries. METHODS: The Outcomes in Patients with TIA and Cerebrovascular disease registry is an international, prospective study. Patients ≥ 45 years who required secondary prevention of stroke (either following an acute transient ischaemic attack or minor ischaemic strokes (National Institutes of Health Stroke Scale <4) of <24 h duration, or recent (<6 months), stable, first-ever, non-disabling ischaemic stroke) were enrolled in 17 countries in Latin America, the Middle East, and Africa. The main measures of interest were risk factors, comorbidities, and socio-economic variables. RESULTS: Between January 2007 and December 2008, 3635 patients were enrolled in Latin America (n = 1543), the Middle East (n = 1041), North Africa (n = 834), and South Africa (n = 217). Of these, 63% had a stable, first-ever ischaemic stroke (median delay from symptom onset to inclusion, 25 days interquartile range, 7-77); 37% had an acute transient ischaemic attack or minor ischaemic stroke (median delay, two-days; interquartile range, 0-6). Prevalence of diabetes was 46% in the Middle East, 29% in Latin America, 35% in South Africa, and 38% in North Africa; 72% had abdominal obesity (range, 65-78%; adjusted P < 0.001); prevalence of metabolic syndrome was 78% (range, 72-84%, P < 0.001). Abnormal ankle brachial index (<0.9) was present in 22%, peripheral artery disease in 7.6%, and coronary artery disease in 13%. Overall, 24% of patients had no health insurance and 27% had a low educational level. INTERPRETATION: In this study, patients in low- and middle-income countries had a high burden of modifiable risk factors. High rates of low educational level and lack of health insurance in certain regions are potential obstacles to risk factor control. FUNDING: The Outcomes in Patients with TIA and Cerebrovascular disease registry is supported by Sanofi-Aventis, Paris, France.Item Fighting Against Stroke in Latin America: A Joint Effort of Medical Professional Societies and Governments(2021) Ouriques Martins, Sheila Cristina; Lavados, Pablo; Secchi, Thaís Leite; Brainin, Michael; Ameriso, Sebastián; Gongora-Rivera, Fernando; Sacks, Claudio; Cantú-Brito, Carlos; Álvarez Guzmán, Tony Fabián; Pérez-Romero, Germán Enrique; Muñoz Collazos, Mario; Barboza, Miguel A.; Arauz, Antonio; Abanto Argomedo, Carlos; Novarro-Escudero, Nelson; Amorin Costabile, Héctor Ignacio; Crosa, Roberto; Camejo, Claudia; Mernes, Ricardo; Maldonado, Nelson; Mora Cuervo, Daissy Liliana; Pontes Neto, Octávio Marques; Sampaio Silva, Gisele; Carbonera, Leonardo Augusto,; Souza, Ana Claudia; Gomes de Sousa, Eduardo David; Flores, Alan; Melgarejo, Donoban; Santos Carquín, Irving R.; Hoppe, Arnold; Freitas de Carvalho, João José; Mont'Alverne, Francisco; Amaya, Pablo; Bayona, Hernán; Navia, Víctor; Duran, Juan Carlos; Urrutia, Víctor C.; Vianna Araujo, Denizar; Feigin, Valery L.; Nogueira, Raúl G.Introduction: Stroke is one of the leading causes of death in Latin America, a region with countless gaps to be addressed to decrease its burden. In 2018, at the first Latin American Stroke Ministerial Meeting, stroke physician and healthcare manager representatives from 13 countries signed the Declaration of Gramado with the priorities to improve the region, with the commitment to implement all evidence-based strategies for stroke care. The second meeting in March 2020 reviewed the achievements in 2 years and discussed new objectives. This paper will review the 2-year advances and future plans of the Latin American alliance for stroke. Method: In March 2020, a survey based on the Declaration of Gramado items was sent to the neurologists participants of the Stroke Ministerial Meetings. The results were confirmed with representatives of the Ministries of Health and leaders from the countries at the second Latin American Stroke Ministerial Meeting. Results: In 2 years, public stroke awareness initiatives increased from 25 to 75% of countries. All countries have started programs to encourage physical activity, and there has been an increase in the number of countries that implement, at least partially, strategies to identify and treat hypertension, diabetes, and lifestyle risk factors. Programs to identify and treat dyslipidemia and atrial fibrillation still remained poor. The number of stroke centers increased from 322 to 448, all of them providing intravenous thrombolysis, with an increase in countries with stroke units. All countries have mechanical thrombectomy, but mostly restricted to a few private hospitals. Pre-hospital organization remains limited. The utilization of telemedicine has increased but is restricted to a few hospitals and is not widely available throughout the country. Patients have late, if any, access to rehabilitation after hospital discharge. Conclusion: The initiative to collaborate, exchange experiences, and unite societies and governments to improve stroke care in Latin America has yielded good results. Important advances have been made in the region in terms of increasing the number of acute stroke care services, implementing reperfusion treatments and creating programs for the detection and treatment of risk factors. We hope that this approach can reduce inequalities in stroke care in Latin America and serves as a model for other under-resourced environments.Item Impact of living and socioeconomic characteristics on cardiovascular risk in ischemic stroke patients(Wiley, 2014) Amarenco, Pierre; Abboud, Halim; Labreuche, Julien; Arauz, Antonio; Bryer, Alan; Lavados, Pablo; Massaro, Ayrton; Steg, Philippe; Munoz, Mario; Yamout, Bassem; Vicaut, EricOBJECTIVE: We aimed to stratify the risk of vascular event recurrence in patients with cerebral infarction according to living and socioeconomic characteristics and geographic region. METHOD: The Outcomes in Patients with TIA and Cerebrovascular Disease (OPTIC) study is an international prospective study of patients aged 45 years or older who required secondary prevention of stroke [following either an acute transient ischemic attack, minor ischemic strokes, or recent (less than six-months previous), stable, first-ever, nondisabling ischemic stroke]. A total 3635 patients from 245 centers in 17 countries in four regions (Latin America, Middle East, North Africa, South Africa) were enrolled between 2007 and 2008. The outcome measure was the two-year rate of a composite of major vascular events (vascular death, myocardial infarction and stroke). RESULTS: During the two-year follow-up period, 516 patients experienced at least one major cardiovascular event, resulting in an event rate of 15·6% (95% confidence interval 14·4-16·9%). Event rates varied across geographical region (P < 0·001), ranging from 13·0% in Latin America to 20·7% in North Africa. Unemployment status, living in a rural area, not living in fully serviced accommodation (i.e., house or apartment with its own electricity, toilet and water supply), no health insurance coverage, and low educational level (less than two-years of schooling) were predictors of major vascular events. Major vascular event rates steeply increased with the number of low-quality living/socioeconomic conditions (from 13·4% to 47·9%, adjusted P value for trend <0·001). CONCLUSION: Vascular risk in stroke patients in low- and middle-income countries varies not only with the number of arterial beds involved but also with socioeconomic variables.Item Impact of low ankle-brachial index on the risk of recurrent vascular events. Insights from the OPTIC Registry(American Heart Association, 2019-04) Abboud, Halim; Monteiro, Linsay; Labreuche, Julien; Arauz, Antonio; Bryer, Alan; Lavados, Pablo; Massaro, Ayrton; Munoz Collazos, Mario; Steg, Philippe; Yamout, Bassem; Vicaut, Eric; Amarenco, PierreBackground and Purpose- Low ankle-brachial index (ABI) identifies a stroke subgroup with high risk of recurrent stroke, cardiovascular events, and death. However, limited data exist on the relationship between low ABI and stroke in low and middle-income countries. Therefore, we evaluated the prevalence of ABI ≤0.90 (which is diagnostic of peripheral artery disease) in nonembolic stroke patients or transient ischemic attack and assessed the correlation of low ABI with stroke risk, factors, and recurrent vascular events and death. Methods- Patients ≥45 years with acute transient ischemic attack or minor ischemic strokes were recruited consecutively from over 17 low-income and middle-income countries (Latin America [1543 patients], Middle East [1041 patients], North Africa [834 patients], and South Africa [217 patients]). The ABI measurement was performed at a single visit. Stroke recurrence and risk of new vascular events were assessed after 24 months of follow-up. Results- Among 3487 enrolled patients, abnormal ABI (<0.9) was present in 22.3 %. Patients with an ABI of ≤0.9 were more likely ( P<0.05) to be male, older, and have a history of peripheral artery disease, hypertension, and diabetes mellitus. During 2-year follow-up, the rate of major cardiovascular event was higher in patients with ABI <0.9 than those with ABI ≥0.9 (Kaplan-Meier estimates, 22.5%; 95% CI, 19.6-25.8 versus 13.7%; 21.4-15.1; P<0.001), and when ABI was categorized into 4 groups (≤0.6; 95% CI, 0.6-0.9; 0.9-1; 1-1.4), the rate of major cardiovascular event was higher in those with ABI ≤0.6 than the other groups (Kaplan-Meier estimates, 32.6%; 95% CI, 21.0-48.3 for ABI≤0.6 versus 21.7%; 95% CI, 18.8-25.0 for ABI 0.6-0.9 versus 14.3%; 95% CI, 12.4-16.6 for ABI 0.9-1 versus 13.3%; 95% CI, 11.6-15.2 for ABI 1-1.4; P<0.001). Conclusions- Among patients with nonembolic ischemic stroke or transient ischemic attack, those with low ABI had a higher rate of vascular events and death in this population. Screening for ABI in stroke patients may help identify patients at high risk of future events.Item INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge clusterrandomized controlled trial(2021) Song, Lili; Hu, Xin; Ma, Lu; Chen, Xiaoying; Ouyang, Menglu; Billot, Laurent; Li, Qiang; Muñoz Venturelli, Paula; Abanto, Carlos; Pontes-Neto, Octavio M.; Arauz, Antonio; Wasay, Mohammad; Silva, Asita de; Nguyen, Huy Thang; Pandian, Jeyaraj Durai; Wahab, Kolawole Wasiu; You, Chao; Anderson, Craig S.; INTERACT3 investigatorsBackground: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH. Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), clusterrandomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1–7.8 mmol/L and 7.8– 10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7- day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions. Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established. Trial registration: ClinicalTrials.gov NCT03Publication LATAM INTERACT3 Consensus Statement Panel(2024) Allende, Maria; Munoz Venturelli, Paula; Gonzalez, Francisca; Bascur, Francisca; Anderson, Craig; Ouyang, Menglu; Cabieses, Báltica; Alexandra Obach; Obach, Alexandra; Cano, Vanessa; Arauz, Antonio; LATAM INTERACT3 Consensus Statement PanelIntroduction: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). Methods: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). The pre-defined consensus threshold was 75%. Results: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects, but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. Conclusions: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.Publication Recommendations for Implementing the INTERACT3 CareBundle for Intracerebral Hemorrhagein Latin America: Results of a Delphi Method(2024) Allende, María Ignacia; Munoz Venturelli, Paula; González, Francisca; Bascur, Francisca; Craig S., Anderson; Ouyang, Menglu; Cabieses, Báltica; Obach, Alexandra; Cano-Nigenda, Vanessa; Arauz, Antonio; LATAM INTERACT3 Consensus Statement PanelIntroduction: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). Methods: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). The pre-defined consensus threshold was 75%. Results: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects, but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. Conclusions: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.Item Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial(Sage Publications, 2016) Hart, Robert; Sharma, Mukul; Mundl, Hardi; Shoamanesh, Ashkan; Kasner, Scott; Berkowitz, Scott; Pare, Guillaume; Kirsch, Bodo; Pogue, Janice; Pater, Calin; Peters, Gary; Davalos, Antoni; Lang, Wilfried; Wang, Yongjun; Wang, Yilong; Cunha, Luis; Eckstein, Jens; Tatlisumak, Turgut; Shamalov, Nikolay; Mikulik, Robert; Lavados, Pablo; Hankey, Graeme; Czlonkowska, Anna; Toni, Danilo; Ameriso, Sebastian; Gagliardi, Rubens; Amarenco, Pierre; Bereczki, Daniel; Uchiyama, Shinichiro; Lindgren, Arne; Endres, Matthias; Brouns, Raf; Yoon, Byung-Woo; Ntaios, George; Veltkamp, Roland; Muir, Keith; Ozturk, Serefnur; Arauz, Antonio; Bornstein, Natan; Bryer, Alan; O’Donnell, Martin; Weitz, Jeffrey; Peacock, Frank; Themeles, Ellison; Connolly, StuartBackground: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRIdetermined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.Publication Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial(2024) Sharma, Mukul; Molina, Carlos; Toyoda, Kazunori; Bereczki, Daniel; Bangdiwala, Shrikant; Kasner, Scott; Lutsep, Helmi; Tsivgoulis, Georgios; Ntaios, George; Czlonkowska, Anna; Shuaib, Ashfaq; Amarenco, Pierre; Endres, Matthias; Yoon, Byung-Woo; Tanne, David; Toni, Danilo; Yperzeele, Laetitia; Weitzel, Paul; Sampaio, Gisele; Avezum, Alvaro; Dawson, Jesse; Strbian, Daniel; Tatlisumak, Turgut; Eckstein, Jens; Ameriso, Sebastián; Weber, Joerg; Sandset, Else; Pogosova, Nana; Lavados, Pablo; Arauz, Antonio; Gailani, David; Diener, Hans-Christoph; Bernstein, Richard; Cordonnier, Charlotte; Kahl, Anja; Abelian, Grigor; Donovan, Mark; Pachai, Chahin; Li, Danshi; Hankey, GraemeBackground: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA.Item Specificities of ischemic stroke risk factors in arab-speaking countries(Karger, 2017) OPTIC Registry and PERFORM Trial Investigators; Abboud, Halim; Sissani, L; Labreuche, J; Arauz, Antonio; Bousser, M; Bryer, A; Chamorro, A; Fisher, M; Ford, I; Fox, K; Hennerici, M; Lavados, Pablo; Massaro, A; Mattle, Heinrich; Munoz Collazos, M; Rothwell, P; Steg, P; Vicaut, E; Yamouth, B; Amarenco, PierreBackground: Stroke is largely preventable, and therefore, a better understanding of risk factors is an essential step in reducing the population stroke rate and resulting disease burden in Arab countries. Summary: We performed 2 separate analyses in 2 similar populations of patients with noncardioembolic ischemic stroke. This first involved 3,635 patients in the Outcomes in Patients with TIA and Cerebrovascular disease (OPTIC) registry (followed for 2 years), with baseline collection of the usual risk factors and 5 socioeconomic variables (unemployment status, residence in rural area, living in fully serviced accommodation, no health-insurance coverage, and low educational level). The second involved patients in the PERFORM trial (n = 19,100 followed up for 2 years), with baseline collection of the usual risk factors and 1 socioeconomic variable (low educational level). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. Stroke risk factors were more prevalent in patients in Arab countries. The incidence of major cardiovascular events (MACE; age- and gender-adjusted) was higher in Arab countries (OPTIC, 18.5 vs. 13.3%; PERFORM, 18.4 vs. 9.7%; both p ≤ 0.0001). These results remained significant after adjustment on risk factors and were attenuated in OPTIC after further adjustment on socioeconomic variables (hazard ratio 1.24; 95% CI 0.98-1.55; p = 0.07). Key Messages: Patients with ischemic stroke living in Arab countries had a lower mean socioeconomic status, a much higher prevalence of diabetes mellitus, and a higher rate of MACE compared with patients from non-Arab countries. This finding is partly explained by a higher prevalence of risk factors and also by a high prevalence of poverty and low educational level.Item Stroke care and collaborative academic research in Latin America(2022) Muñoz, Paula; González, Francisca; Urrutia, Francisca; Mazzon, Enrico; Navia, Víctor; Brunser, Alejandro; Lavados, Pablo; Olavarría, Verónica; Almeida, Juan; Guerrero, Rodrigo; Rojo, Alexis; Gigoux, Juan; Vallejos, José; Conejan, Nathalie; Esparza, Tomas; Escobar, Arturo; Soto, Álvaro; Pontes, Octavio; Arauz, Antonio; Abanto, Carlos; Carce, Cheryl; Zafra, Jessica; Liu, Hueiming; Song, Lili; Miranda, Jaime; Anderson, CraigObjective: A narrative overview of regional academic research collaborations to address the increasing burden and gaps in care for patients at risk of, and who suffer from, stroke in Latin America (LA). Materials and methods: A summary of experiences and knowledge of the local situation is presented. No systematic literature review was performed. Results: The rapidly increasing burden of stroke poses immense challenges in LA, where prevention and manage-ment strategies are highly uneven and inadequate. Clinical research is increasing through various academic consortia and networks formed to overcome structural, funding and skill barriers. However, strengthening the ability to generate, analyze and interpret randomized evidence is central to further develop effective therapies and healthcare systems in LA. Conclusions: Regional networks foster the conduct of multicenter studies -particularly randomized controlled trials-, even in resource-poor regions. They also contribute to the external validity of international studies and strengthen systems of care, clinical skills, critical thinking, and international knowledge exchange.Publication The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial(2023) Ma, Lu; Hu, Xin; Song, Lili; Chen, Xiaoying; Ouyang, Menglu; Billot, Laurent; Li, Qiang; Malavera, Alejandra; Li, Xi; Munoz Venturelli, Paula; De Silva, Asita; Huy Thang, Nguyen; Wahab, Kolawole; Pandian, Jeyaraj; Wasay, Mohammad; Pontes, Octavio; Abanto, Carlos; Arauz, Antonio; Shi, Haiping; Tang, Guanghai; Zhu, Sheng; She, Xiaochun; Liu, Leibo; Sakamoto, Yuki; You, Shoujiang; Han, Qiao; Crutzen, Bernard; Cheung, Emily; Li, Yunke; Wang, Xia; Chen, Chen; Liu, Feifeng; Zhao, Yang; Li, Hao; Liu, Yi; Jiang, Yan; Chen, Lei; Wu, Bo; Liu, Ming; Xu, Jianguo; INTERACT3 InvestigatorsBackground: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. Methods: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. Findings: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). Interpretation: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. Funding: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.