Publications by authors named "Werner Hacke"

300 Publications

Successful implementation of best medical treatment for patients with asymptomatic carotid artery stenosis within a randomized controlled trial (SPACE-2).

Neurol Res Pract 2021 Oct 19;3(1):62. Epub 2021 Oct 19.

Department of Neurology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Background: Asymptomatic carotid artery stenosis (ACS) can be treated with carotid endarterectomy (CEA), carotid artery stenting (CAS), or best medical treatment (BMT) only. For all treatment options, optimization of vascular risk factors such as arterial hypertension, hyperlipidemia, smoking, obesity, and insufficient physical activity is essential. Data on adherence to BMT and lifestyle modification in patients with ACS are sparse. The subject of this investigation is the implementation and quality of risk factor adjustment in the context of a randomized controlled trial.

Methods: A total of 513 patients in the prematurely terminated, randomized, controlled, multicenter SPACE-2 trial (ISRCTN 78592017) were analyzed within one year after randomization into 3 groups (CEA, CAS, and BMT only) for implementation of prespecified BMT recommendations and lifestyle modifications. Measurement time points were the screening visit and visits after one month (D30), 6 months (M6), and one year (A1). Differences between groups and follow-up visits (FUVs) relative to the screening visit were investigated.

Findings: For all FUVs, a significant increase in statin medication (91% at A1; p < 0.0001) was demonstrated to be associated with a significant decrease (p < 0.01) in cholesterol levels (median 167 mg/dl at A1) and LDL cholesterol levels (median 93 mg/dl at A1). The lowest cholesterol levels were achieved by patients in the BMT group. Seventy-eight percent of all patients reached predefined target cholesterol levels (< 200 mg/dl), with significantly better rates in the BMT group (p = 0.036 at D30). Furthermore, a significant decrease in arterial blood pressure at all FUVs (p < 0.05) was associated with a significant increase in antihypertensive medication (96% at A1, p < 0.0001). However, only 28% of patients achieved the predefined treatment goal of a systolic blood pressure of ≤ 130 mmHg. Forty-two of a total of 100 smokers at the screening visit quit smoking within one year, resulting in a significant increase in nonsmokers at all FUVs (p < 0.0001). Recommended HbA1c levels (< 7%) were achieved in 82% without significant changes after one year. Only 7% of obese (BMI > 25) patients achieved sufficient weight reduction after one year without significant changes at all FUVs (median BMI 27 at A1; p = 0.1201). The BMT group showed significantly (p = 0.024) higher rates of adequate physical activity than the intervention groups. Furthermore, after one year, the BMT group showed a comparatively significantly better implementation of risk factor modification (77%; p = 0.027) according to the treating physician.

Interpretation: SPACE-2 demonstrated sustained improvement in the noninterventional management of vascular risk factors in patients treated in a clinical trial by general practitioners, internists and neurologists. The best implemented treatment targets were a reduction in cholesterol and HbA1c levels. In this context, a significant increase in statin use was demonstrated. Blood pressure control missed its target but was significantly reduced by intensification of antihypertensive medication. Patients on BMT only had better adjusted lipid parameters and were more physically active. However, all groups failed to achieve sufficient weight reduction. Due to insufficient patient recruitment, the results must be interpreted cautiously.

Trial Registration: ISRCTN Registry, ISRCTN78592017, Registered 16 June 2007, https://www.isrctn.com/search?q=78592017 .
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http://dx.doi.org/10.1186/s42466-021-00153-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524978PMC
October 2021

Embotrap Extraction & Clot Evaluation & Lesion Evaluation for NeuroThrombectomy (EXCELLENT) Registry design and methods.

J Neurointerv Surg 2021 Oct 13. Epub 2021 Oct 13.

Grady Memorial Hospital, Chickasha, Georgia, USA.

Background: Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes.

Methods: Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation.

Results: Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality.

Conclusions: The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings.

Trial Registration Number: NCT03685578.
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http://dx.doi.org/10.1136/neurintsurg-2021-017671DOI Listing
October 2021

A full year of the COVID-19 pandemic with two infection waves and its impact on ischemic stroke patient care in Germany.

Eur J Neurol 2021 Aug 9. Epub 2021 Aug 9.

Department of Neurology, St. Josef Hospital Bochum, Ruhr University Bochum, Bochum, Germany.

Background And Purpose: Many countries worldwide, including Germany, reported that the first wave of the coronavirus disease 2019 (COVID-19) pandemic in early 2020 influenced the care of acute ischemic stroke (AIS) patients, but data are lacking for further pandemic wave periods.

Methods: We conducted a nationwide, retrospective, cross-sectional study of all hospitalized patients with the main diagnosis of AIS in 2019 and 2020. Primary outcomes were the number of hospitalizations for AIS, the application of stroke unit care, intravenous thrombolysis (IVT), and mechanical thrombectomy (MT), as well as the in-hospital mortality during the different pandemic periods in 2020 compared to the corresponding periods in 2019. Secondarily, we analyzed differences in outcomes between patients with and without concurrent COVID-19.

Results: We included 429,841 cases with AIS, of which 1268 had concurrent COVID-19. Hospitalizations for AIS declined during both pandemic wave periods in 2020 (first wave: -10.9%, second wave: -4.6%). MT rates were consistently higher throughout 2020 compared to 2019, whereas the IVT rate dropped during the second wave period (16.0% vs. 17.0%, p < 0.001). AIS patients with concurrent COVID-19 frequently received recanalization treatments, with an overall MT rate of 8.4% and IVT rate of 15.9%. The in-hospital mortality was high (22.8% vs. 7.5% in noninfected AIS patients, p < 0.001).

Conclusions: These findings demonstrate a smaller decline in hospitalizations for AIS in the more severe second wave of the COVID-19 pandemic. AIS patients with and without concurrent COVID-19 who did seek acute care continued to receive recanalization treatments in Germany.
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http://dx.doi.org/10.1111/ene.15057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444778PMC
August 2021

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke.

Stroke 2021 Oct 26;52(10):3258-3265. Epub 2021 Jul 26.

Julius Center for Health Sciences and Primary Care (N.A.H., A.A., J.P.G.), University Medical Center Utrecht, Utrecht University, the Netherlands.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.031755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478107PMC
October 2021

Letter to the Editor: Analysis of stroke patient migration for mechanical thrombectomy and changes in neurointerventional center size in Germany.

Neurol Res Pract 2021 Jun 7;3(1):32. Epub 2021 Jun 7.

Medical Faculty, Ruhr University Bochum, Bochum, Germany.

Aim And Methods: To analyse nationwide changes in neurointerventional center size of all German hospitals performing mechanical thrombectomy (MT) in stroke patients from 2016 to 2019. Furthermore, we assessed cross-district patient migration for MT for the first time using hospitals' structured quality reports and German Diagnosis-Related Groups data in 2019.

Findings: Number of hospitals performing more than 100 MT procedures/year doubled in Germany from 2016 (n = 36) to 2019 (n = 71), and these neurointerventional centers performed 71% of all MT procedures in 2019. The overall increase in MT procedures was largely driven by these high-volume neurointerventional centers with ability to perform MT 24/7 (121% increase as compared with 8% increase in hospitals performing less than 100 MT procedures/year). The highest cross-district patient mobility/transfer of stroke patients for MT was observed in districts adjacent to these high-volume neurointerventional centers with existing neurovascular networks.

Conclusion: The substantial increase in MT procedures observed in Germany between 2016 and 2019 was almost exclusively delivered by high-volume stroke centers performing more than 100 MT procedures per year in established neurovascular networks. As there is still a reasonable number of districts with low MT rates, further structural improvement including implementation of new or expansion of existing neurovascular networks and regional tailored MT triage concepts is needed.
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http://dx.doi.org/10.1186/s42466-021-00131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182903PMC
June 2021

[Telemedicine in Stroke Care].

Authors:
Werner Hacke

Nervenarzt 2021 06 27;92(6):591-592. Epub 2021 May 27.

Universität Heidelberg, 69121, Heidelberg, Deutschland.

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http://dx.doi.org/10.1007/s00115-021-01131-yDOI Listing
June 2021

Acute ischemic stroke care in Germany - further progress from 2016 to 2019.

Neurol Res Pract 2021 Apr 1;3(1):14. Epub 2021 Apr 1.

Department of Neurology, St. Josef-Hospital Bochum, Ruhr University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.

Background: Stroke Unit Care (SUC), intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are evidence-based treatment options for acute ischemic stroke (AIS). Using nationwide comprehensive administrative data from Germany, we recently reported nationwide development of AIS admissions, SUC rates, IVT rates and MT rates in Germany between 2010 and 2016. In this update paper, we analyze data on the further development of these data to 2019 after publication of time window extensions for recanalization therapies.

Methods: We considered all hospitalized cases with the main diagnosis of the ICD-10-GM code I63 (AIS) for the year 2019. We identified stroke therapies by using the corresponding Operating and Procedure Keys for IVT, MT and SUC out of the DRG statistics. Regional analyses are based on data from the 412 German administrative districts and cities. We compared the results with those from 2016.

Results: Number of hospitalized AIS patients showed a mild decrease in 2019 (n = 225,531) compared with 2016 (n = 227,687), with significant more AIS patients treated on a stroke unit in 2019 (n = 167,799; 74.4% vs. n = 164,270; 72.1%, p < 0.001). The rate of IVT further increased from 14.9% (n = 33,916) in 2016 to 16.3% (n = 36,745) in 2019 (p < 0.001). Similarly, the MT rate increased from 4.3% (n = 9795) in 2016 to 7.2% (n = 16,135) in 2019 (p < 0.001). There was still a high regional variability for MT (1.4 to 15.2%) according to the place of residence of the AIS patients.

Conclusions: In Germany, the rates of recanalization therapies in patients with AIS continued to increase from 2016 to 2019. Compared to IVT-rates and numbers, the respective data for MT procedures showed an even more pronounced increase.
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http://dx.doi.org/10.1186/s42466-021-00115-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012074PMC
April 2021

Bleeding and related mortality with NOACs and VKAs in newly diagnosed atrial fibrillation: results from the GARFIELD-AF registry.

Blood Adv 2021 02;5(4):1081-1091

Thrombosis Research Institute, London, United Kingdom.

In atrial fibrillation (AF), lower risks of death and bleeding with non-vitamin-K oral anticoagulants (NOACs) were reported in meta-analyses of controlled trials, but whether these findings hold true in real-world practice remains uncertain. Risks of bleeding and death were assessed in 52 032 patients with newly diagnosed AF enrolled in GARFIELD-AF (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation), a worldwide prospective registry. Baseline treatment was vitamin K antagonists (VKAs) with or without antiplatelet (AP) agents (VKA ± AP) (20 151; 39.3%), NOACs ± AP agents (14 103; 27.5%), AP agents only (10 748; 21.0%), or no antithrombotics (6219; 12.1%). One-year follow-up event rates (95% confidence interval [CI]) of minor, clinically relevant nonmajor (CRNM), and major bleedings were 2.29 (2.16-2.43), 1.10 (1.01-1.20), and 1.31 (1.21-1.41) per 100 patient-years, respectively. Bleeding risk was lower with NOACs than VKAs for any bleeding (hazard ratio (HR) [95% CI]), 0.85 [0.73-0.98]) or major bleeding (0.79 [0.60-1.04]). Compared with no bleeding, the risk of death was higher with minor bleeding (adjusted HR [aHR], 1.53 [1.07-2.19]), CRNM bleeding (aHR, 2.59 [1.80-3.73]), and major bleeding (aHR, 8.24 [6.76-10.04]). The all-cause mortality rate was lower with NOACs than with VKAs (aHR, 0.73 [0.62-0.85]). Forty-five percent (114) of all deaths occurred within 30 days, and 40% of these were from intracranial/intraspinal hemorrhage (ICH). The rates of any bleeding and all-cause death were lower with NOACs than with VKAs. Major bleeding was associated with the highest risk of death. CRNM bleeding and minor bleeding were associated with a higher risk of death compared to no bleeding. Death within 30 days after a major bleed was most frequently related to ICH. This trial was registered at www.clinicaltrials.gov as #NCT01090362.
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http://dx.doi.org/10.1182/bloodadvances.2020003560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903226PMC
February 2021

The impact of the DWI-FLAIR-mismatch in the ECASS-4 trial - A post hoc analysis.

Eur Stroke J 2020 Dec 23;5(4):370-373. Epub 2020 Apr 23.

Heidelberg University Hospital, Department of Neurology, Heidelberg, Germany.

Introduction: To investigate the impact of a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) on functional outcome in patients with acute stroke in a prolonged time window or unknown time of symptom onset randomized to intravenous thrombolysis or placebo.

Patients And Methods: We performed a post-hoc analysis of the European Cooperative Acute Stroke Study-4 (ECASS-4) trial. ECASS-4 was an investigator driven, phase 3, multi-center, double-blind, placebo-controlled study which randomized ischemic stroke patients presenting within 4.5 and 9h of stroke onset or unknown time-window to either rt-PA or placebo after MR-imaging. Two subgroups "no mismatch" (nMM) and "any mismatch" (aMM) were created by applying a DWI-FLAIR-mismatch criterion. We calculated frequency of nMM and aMM and performed a univariate analysis (Fisher's Test) for excellent clinical outcome (mRS 0-1) and mortality (mRS=6).

Results: MR-Imaging of n=111/119 (93.2%) patients was suitable for this analysis. DWI-FLAIR mismatch was found in 49 patients (44.1%). Proportions of mismatch nMM and aMM were comparable in treatment-groups (aMM: Placebo 46.3%, Alteplase 42.1%; p=0.70). Patients with nMM showed no benefit of rt-PA-treatment (OR (95%CI) mRS 0-1: 0.95 (0.29-3.17)). Patients with aMM showed a point estimate of the odds ratio in favour of a treatment benefit of rt-PA (mRS 0-1: OR (95%CI) 2.62 (0.68-11.1)). Mortality within 90 days was not different in patients treated with rt-PA if nMM (15.2%) or aMM (12.5%) was present.

Discussion: In this analysis no significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging.

Conclusion: A DWI-FLAIR mismatch in the region of ischemia as imaging based surrogate parameter for patient selection for i.v. rt-PA should be strongly pursued.
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http://dx.doi.org/10.1177/2396987320920114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856579PMC
December 2020

Rivaroxaban versus warfarin in patients with atrial fibrillation enrolled in Latin America: Insights from ROCKET AF.

Am Heart J 2021 06 8;236:4-12. Epub 2021 Feb 8.

Division of Cardiology, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Durham, NC. Electronic address:

Background: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW).

Methods: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region.

Results: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77).

Conclusions: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted.
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http://dx.doi.org/10.1016/j.ahj.2021.02.004DOI Listing
June 2021

Neurological research and practice: the first milestone has been reached.

Authors:
Werner Hacke

Neurol Res Pract 2021 13;3. Epub 2021 Jan 13.

Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

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http://dx.doi.org/10.1186/s42466-021-00101-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805428PMC
January 2021

Analysis of Nationwide Stroke Patient Care in Times of COVID-19 Pandemic in Germany.

Stroke 2021 01 24;52(2):716-721. Epub 2020 Dec 24.

Department of Neurology, St Josef-Hospital Bochum (D.R., D.B., C.K.), Ruhr University Bochum, Germany.

Background And Purpose: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, many countries have introduced strict hygiene measures of social distancing to prevent further spreading of the disease. This may have led to a decreased presentation to hospital of patients with acute medical conditions and time-dependent management, such as stroke.

Methods: We conducted a nationwide cohort study using administrative database of all hospitalized patients with main diagnosis of acute ischemic stroke (AIS), transient ischemic attack, or intracerebral hemorrhage. Data from a total of 1463 hospitals in Germany were included. We compared case numbers and treatment characteristics of pandemic (March 16 to May 15, 2020) and prepandemic (January 16 to March 15, 2020) cases and also with corresponding time period in 2019.

Results: We identified a strong decline for hospitalization of AIS (-17.4%), transient ischemic attack (-22.9%), and intracerebral hemorrhage (-15.8%) patients during the pandemic compared with prepandemic period. IVT rate in patients with AIS was comparable (prepandemic versus pandemic: 16.4% versus 16.6%, =0.448), whereas mechanical thrombectomy rate was significantly higher during the pandemic (8.1% versus 7.7%, =0.044). In-hospital mortality was significantly increased in patients with AIS during the pandemic period (8.1% versus 7.6%, =0.006).

Conclusions: Besides a massive decrease in absolute case numbers, our data suggest that patients with AIS who did seek acute care during the pandemic, continued to receive acute recanalization treatment in Germany.
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http://dx.doi.org/10.1161/STROKEAHA.120.033160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834653PMC
January 2021

Neurological research and practice: the first year.

Authors:
Werner Hacke

Neurol Res Pract 2020 28;2. Epub 2020 Feb 28.

University of Heidelberg, Department of Neurology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

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http://dx.doi.org/10.1186/s42466-020-0054-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650136PMC
February 2020

Inpatient TIA and stroke care in adult patients in Germany - retrospective analysis of nationwide administrative data sets of 2011 to 2017.

Neurol Res Pract 2019 1;1:39. Epub 2019 Dec 1.

Northwest-German Stroke Circle e.V, Bochum, Germany.

Background: Comprehensive administrative data on TIA and stroke cases and treatment modalities are fundamental for improving structural conditions and adjusting future strategies of stroke care.

Methods: The nationwide administrative database (German federal statistical office) was used to extract all adult inpatient TIA and stroke cases and corresponding procedural codes for the period 2011-2017. Numbers were specified according to age, sex, stroke unit (SU) and critical care treatment (ICU), early transfer, and in-hospital mortality.

Findings: Inpatient adult TIA/stroke cases increased from annually 102,406 / 250,199 (2011) to 106,245 / 264,208 (2017). 84% of strokes were ischemic (AIS) also having the highest relative increase most likely due to more accurate coding within the time period, 68.2% of AIS were treated on SUs. 78% of hemorrhagic strokes were intracerebral hematomas (ICH; rather than subarachnoid hemorrhages [SAH]). Hemorrhagic strokes were increasingly treated on SUs (32.6% [2011], 37.8% [2017]). 68.8% of SAH were treated on ICUs (ICH:36.3%, AIS:10.3%). Early transfer in AIS increased (2.0 to 3.1%). Hemorrhagic strokes were associated with higher in-hospital mortality (SAH:19.6%, ICH:28.2%, AIS:7.3%).

Interpretation: The absolute increase of strokes presumably reflects the aging society and more awareness for cerebrovascular disease. The relative increase of AIS may be attributable to an increased neurological expertise. The increasing amount of early transfers in AIS reflects new specialized treatment options. Our findings reflect the need for structural adjustments in inpatient stroke care.
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http://dx.doi.org/10.1186/s42466-019-0044-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650112PMC
December 2019

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Surgical Decompression for Space-Occupying Hemispheric Infarction: A Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials.

JAMA Neurol 2021 Feb;78(2):208-216

Department of Neurology, University of Würzburg, Würzburg, Germany.

Importance: In patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about the benefit of this treatment for specific patient groups.

Objective: To assess whether surgical decompression for space-occupying hemispheric infarction is associated with a reduced risk of death and an increased chance of favorable outcomes, as well as whether this association is modified by patient characteristics.

Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Stroke Trials Registry were searched from database inception to October 9, 2019, for English-language articles that reported on the results of randomized clinical trials of surgical decompression vs conservative treatment in patients with space-occupying hemispheric infarction.

Study Selection: Published and unpublished randomized clinical trials comparing surgical decompression with medical treatment alone were selected.

Data Extraction And Synthesis: Patient-level data were extracted from the trial databases according to a predefined protocol and statistical analysis plan. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the Cochrane Collaboration's tool for assessing risk of bias were used. One-stage, mixed-effect logistic regression modeling was used for all analyses.

Main Outcomes And Measures: The primary outcome was a favorable outcome (modified Rankin Scale [mRS] score ≤3) at 1 year after stroke. Secondary outcomes included death, reasonable (mRS score ≤4) and excellent (mRS score ≤2) outcomes at 6 months and 1 year, and an ordinal shift analysis across all levels of the mRS. Variables for subgroup analyses were age, sex, presence of aphasia, stroke severity, time to randomization, and involved vascular territories.

Results: Data from 488 patients from 7 trials from 6 countries were available for analysis. The risk of bias was considered low to moderate for 6 studies. Surgical decompression was associated with a decreased chance of death (adjusted odds ratio, 0.16; 95% CI, 0.10-0.24) and increased chance of a favorable outcome (adjusted odds ratio, 2.95; 95% CI, 1.55-5.60), without evidence of heterogeneity of treatment effect across any of the prespecified subgroups. Too few patients were treated later than 48 hours after stroke onset to allow reliable conclusions in this subgroup, and the reported proportions of elderly patients reaching a favorable outcome differed considerably among studies.

Conclusions And Relevance: The results suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients. The benefit of surgery after day 2 and in elderly patients remains uncertain.
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http://dx.doi.org/10.1001/jamaneurol.2020.3745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551237PMC
February 2021

Challenging the Ischemic Core Concept in Acute Ischemic Stroke Imaging.

Stroke 2020 10 16;51(10):3147-3155. Epub 2020 Sep 16.

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.).

Endovascular treatment is a highly effective therapy for acute ischemic stroke due to large vessel occlusion and has recently revolutionized stroke care. Oftentimes, ischemic core extent on baseline imaging is used to determine endovascular treatment-eligibility. There are, however, 3 fundamental issues with the core concept: First, computed tomography and magnetic resonance imaging, which are mostly used in the acute stroke setting, are not able to precisely determine whether and to what extent brain tissue is infarcted (core) or still viable, due to variability in tissue vulnerability, the phenomenon of selective neuronal loss and lack of a reliable gold standard. Second, treatment decision-making in acute stroke is multifactorial, and as such, the relative importance of single variables, including imaging factors, is reduced. Third, there are often discrepancies between core volume and clinical outcome. This review will address the uncertainty in terminology and proposes a direction towards more clarity. This theoretical exercise needs empirical data that clarify the definitions further and prove its value.
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http://dx.doi.org/10.1161/STROKEAHA.120.030620DOI Listing
October 2020

GARFIELD-AF: a worldwide prospective registry of patients with atrial fibrillation at risk of stroke.

Future Cardiol 2021 01 22;17(1):19-38. Epub 2020 Jul 22.

Department of Clinical Research, Thrombosis Research Institute, London SW3 6LR, UK.

The Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) examined real-world practice in a total of 57,149 (5069 retrospective, 52,080 prospective) patients with newly diagnosed AF at risk of stroke/systemic embolism, enrolled at over 1000 centers in 35 countries. It aimed to capture data on AF burden, patients' clinical profile, patterns of clinical practice and antithrombotic management, focusing on stroke/systemic embolism prevention, uptake of new oral anticoagulants, impact on death and bleeding. GARFIELD-AF set new standards for quality of data collection and analysis. A total of 36 peer-reviewed articles were already published and 73 abstracts presented at international congresses, covering treatment strategies, geographical variations in baseline risk and therapies, adverse outcomes and common comorbidities such as heart failure. A risk prediction tool as well as innovative observational studies and artificial intelligence methodologies are currently being developed by GARFIELD-AF researchers. NCT01090362 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fca-2020-0014DOI Listing
January 2021

Alteplase for Acute Ischemic Stroke in Patients Aged >80 Years: Pooled Analyses of Individual Patient Data.

Stroke 2020 08 2;51(8):2322-2331. Epub 2020 Jul 2.

The School of Medicine, Dentistry & Nursing, University of Glasgow, United Kingdom (K.R.L.).

Background/purpose: Expert guidelines specify no upper age limit for alteplase for thrombolysis of acute ischemic stroke (AIS) but, until recently, European regulatory criteria restricted its use to patients aged 18 to 80 years. We performed pooled analyses of randomized controlled trial (RCT) and registry data to evaluate the benefit-risk profile of alteplase for AIS among patients aged >80 years to support a regulatory application to lift the upper age restriction.

Methods: Individual patient data were evaluated from 7 randomized trials of alteplase (0.9 mg/kg) versus placebo or open control for AIS, and the European SITS-UTMOST registry database. Clinical outcomes, including good functional outcome (score 0-1, modified Rankin Scale day 90 or Oxford Handicap Score day 180), were evaluated in the full RCT and registry populations, and specified age-based subgroups (≤80 or >80 years) who met existing European regulatory criteria for alteplase, excluding upper age restriction.

Results: Regardless of treatment allocation, 90-day mortality was lower among RCT patients aged ≤80 versus >80 years who otherwise met existing European regulatory criteria (246/2405 [10.2%] versus 307/1028 [29.9%], respectively). Among patients aged >80 years, alteplase versus placebo was associated with a higher proportion of good stroke outcome (modified Rankin Scale score 0-1; 99/518 [19.1%] versus 67/510 [13.1%]; =0.0109) and similar 90-day mortality (153/518 [29.5%] versus 154/510 [30.2%]; =0.8382). The odds of a good stroke outcome following alteplase allocation in the full RCT population were independent of age (=0.7383). Good stroke outcome was reported for almost half (4821/11 169 [43.2%]) of the patients who received alteplase in routine practice. Outcomes in routine practice supported those achieved in RCTs.

Conclusions: Alteplase for AIS has a positive benefit-risk profile among patients aged >80 years when administered according to other regulatory criteria. Alteplase for AIS should be evaluated on an individual benefit-risk basis.
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http://dx.doi.org/10.1161/STROKEAHA.119.028396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382542PMC
August 2020

International Impact of .

Stroke 2020 Mar 19;51(3):1036-1039. Epub 2020 Feb 19.

From the Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Australia (S.M.D., G.A.D.).

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http://dx.doi.org/10.1161/STROKEAHA.119.028422DOI Listing
March 2020

Prior stroke and transient ischemic attack as risk factors for subsequent stroke in atrial fibrillation patients: A report from the GARFIELD-AF registry.

Int J Stroke 2020 04 17;15(3):308-317. Epub 2019 Dec 17.

Department of Clinical Research, Thrombosis Research Institute, London, UK.

Background: It is not always possible to verify whether a patient complaining of symptoms consistent with transient ischemic attack has had an actual cerebrovascular event.

Research Question: To characterize the risk of cardiovascular events associated with a history of stroke/transient ischemic attack in patients with atrial fibrillation.

Study Design And Methods: This study investigated the clinical characteristics and outcomes of patients with a history of stroke/transient ischemic attack among 52,014 patients enrolled prospectively in GARFIELD-AF registry. The diagnosis of stroke or transient ischemic attack was not protocol defined but based on physicians' assessment. Patients' one-year risk of death, stroke/systemic embolism, and major bleeding was assessed by multivariable Cox regression.

Results: At enrollment, 5617 (10.9%) patients were reported to have a history of stroke or transient ischemic attack. Patients with stroke or transient ischemic attack were older and had a greater burden of diabetes, moderate-to-severe kidney disease, and atherothrombosis and higher median CHADS-VASc and HAS-BLED scores than those without history of stroke or transient ischemic attack. After adjustment, prior stroke/transient ischemic attack was associated with significantly higher risk for all-cause mortality (hazard ratio (HR), 1.26; 95% confidence interval (CI), 1.12-1.42), cardiovascular death (HR, 1.22; 95% CI, 1.01-1.48), non-cardiovascular death (HR, 1.39; 95% CI, 1.15-1.68), and stroke/systemic embolism (HR, 2.17; 95% CI, 1.80-2.63) than patients without history of stroke/transient ischemic attack. In patients with a prior stroke alone higher risk was observed for all-cause mortality (HR, 1.29; 95% CI, 1.11-1.50), non-cardiovascular death (HR, 1.39; 95% CI, 1.10-1.77), and stroke/systemic embolism (HR, 2.29; 95% CI, 1.83-2.86). No significantly elevated risk of adverse events was seen for patients with history of transient ischemic attack alone.

Interpretation: A history of prior stroke or transient ischemic attack is a strong independent risk factor for mortality and stroke/systemic embolism. This excess risk is mainly attributed to a history of stroke (with or without transient ischemic attack), whereas history of transient ischemic attack is a weaker predictor. NCT01090362.
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http://dx.doi.org/10.1177/1747493019891516DOI Listing
April 2020

World Stroke Organization (WSO): Global Stroke Fact Sheet 2019.

Int J Stroke 2019 10;14(8):806-817

National Institute for Stroke and Applied Neurosciences, Auckland University of Technology, Auckland, New Zealand.

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http://dx.doi.org/10.1177/1747493019881353DOI Listing
October 2019

Age and Sex Differences in Ischemic Stroke Treatment in a Nationwide Analysis of 1.11 Million Hospitalized Cases.

Stroke 2019 12 18;50(12):3494-3502. Epub 2019 Oct 18.

Department of Neurology, University of Heidelberg, Germany (W.H.).

Background and Purpose- To date, there is still uncertainty about age and sex differences in access to stroke unit treatment and use of intravenous thrombolysis (IVT), while age and sex differences have not been investigated for the new treatment option of mechanical thrombectomy (MT). We, therefore, undertook a complete nationwide analysis of all hospitalized ischemic stroke patients in Germany from 2013 to 2017. Methods- We used the nationwide administrative database of the German Federal Statistical Office and investigated access to stroke unit treatment, IVT, MT, and in-hospital mortality. Patients were subdivided into 6 predefined age groups (20-44, 45-59, 60-69, 70-79, 80-89, and >90 years). Pooled overall and age group estimates were calculated using the random-effects model. To evaluate potential sex disparities, we estimated odds ratios (ORs) with 95% CIs. Results- A total of 1 112 570 patients were hospitalized for first or recurrent ischemic stroke from 2013 to 2017. Overall, stroke unit treatment increased significantly from 66.8% in 2013 to 73.5% in 2017, as did IVT (from 12.4% to 15.9%) and MT (from 2.4% to 5.8%; all <0.001). Although the difference became smaller over time, patients ≥80 years of age still received significantly less often treatments. Men of all age groups had a significantly higher probability receiving stroke unit treatment (OR, 1.11; 95% CI, 1.09-1.12) and lower in-hospital mortality (OR, 0.91; 95% CI, 0.89-0.93). No disparity was observed in the use of IVT (OR, 1.00; 95% CI, 0.98-1.01), while women of all ages were treated more often with MT (OR, 1.26; 95% CI, 1.22-1.30). Conclusions- Access to stroke unit treatment has to be increased in both older patients and women of all ages. While there was no sex difference in IVT use, it is important to further investigate the significantly higher frequency of MT in women with ischemic stroke irrespective of age.
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http://dx.doi.org/10.1161/STROKEAHA.119.026723DOI Listing
December 2019

Special topic section: linkages among cerebrovascular, cardiovascular, and cognitive disorders: Preventing dementia by preventing stroke: The Berlin Manifesto.

Int J Stroke 2019 Sep 22:1747493019871915. Epub 2019 Sep 22.

Prevent Alzheimer Disease (PAD2020), Potamac, MD, USA.

The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer's Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1177/1747493019871915DOI Listing
September 2019

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

Cardiol Ther 2019 Dec 2;8(2):283-295. Epub 2019 Aug 2.

Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA.

Introduction: Patient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.

Methods: ROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).

Results: A total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.

Conclusions: Study drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.

Funding: The ROCKET AF trial was funded by Johnson & Johnson and Bayer.
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http://dx.doi.org/10.1007/s40119-019-00146-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828909PMC
December 2019

Preventing dementia by preventing stroke: The Berlin Manifesto.

Alzheimers Dement 2019 07;15(7):961-984

Prevent Alzheimer Disease (PAD2020), Potamac, MD, USA.

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.
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http://dx.doi.org/10.1016/j.jalz.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001744PMC
July 2019

Antiplatelet Therapy After Noncardioembolic Stroke.

Stroke 2019 07 10;50(7):1812-1818. Epub 2019 Jun 10.

From the Julius Center for Health Sciences and Primary Care (J.P.G., J.B.R., A.A.).

Background and Purpose- We assessed the efficacy and safety of antiplatelet agents after noncardioembolic stroke or transient ischemic attack and examined how these vary according to patients' demographic and clinical characteristics. Methods- We did a network meta-analysis (NMA) of data from 6 randomized trials of the effects of commonly prescribed antiplatelet agents in the long-term (≥3 months) secondary prevention of noncardioembolic stroke or transient ischemic attack. Individual patient data from 43 112 patients were pooled and reanalyzed. Main outcomes were serious vascular events (nonfatal stroke, nonfatal myocardial infarction, or vascular death), major bleeding, and net clinical benefit (serious vascular event or major bleeding). Subgroup analyses were done according to age, sex, ethnicity, hypertension, qualifying diagnosis, type of vessel involved (large versus small vessel disease), and time from qualifying event to randomization. Results- Aspirin/dipyridamole combination (RR, 0.83; 95% CI, 0.74-0.94) significantly reduced the risk of vascular events compared with aspirin, as did clopidogrel (RR, 0.88; 95% CI, 0.78-0.98), and aspirin/clopidogrel combination (RR, 0.83; 95% CI, 0.71-0.96). Clopidogrel caused significantly less major bleeding and intracranial hemorrhage than aspirin, aspirin/dipyridamole combination, and aspirin/clopidogrel combination. Aspirin/clopidogrel combination caused significantly more major bleeding than aspirin, aspirin/dipyridamole combination, and clopidogrel. Net clinical benefit was similar for clopidogrel and aspirin/dipyridamole combination (RR, 0.99; 95% CI, 0.93-1.05). Subgroup analyses showed no heterogeneity of treatment effectiveness across prespecified subgroups. The excess risk of major bleeding associated with aspirin/clopidogrel combination compared with clopidogrel alone was higher in patients aged <65 years than it was in patients ≥65 years (RR, 3.9 versus 1.7). Conclusions- Results favor clopidogrel and aspirin/dipyridamole combination for long-term secondary prevention after noncardioembolic stroke or transient ischemic attack, regardless of patient characteristics. Aspirin/clopidogrel combination was associated with a significantly higher risk of major bleeding compared with other antiplatelet regimens.
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http://dx.doi.org/10.1161/STROKEAHA.118.024497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594726PMC
July 2019
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