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Meta-Analysis
. 2023 Jan 26;1(1):CD012144.
doi: 10.1002/14651858.CD012144.pub3.

Antithrombotic treatment after stroke due to intracerebral haemorrhage

Alexia Cochrane  1 , Chen Chen  2   3   4 , Jacqueline Stephen  5 , Ole Morten Rønning  6 , Craig S Anderson  7   8 , Graeme J Hankey  9   10 , Rustam Al-Shahi Salman  11
Affiliations
Meta-Analysis

Antithrombotic treatment after stroke due to intracerebral haemorrhage

Alexia Cochrane et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding.

Objectives: To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH.

Search methods: We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs.

Selection criteria: We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator.

Data collection and analysis: In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow-up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention-to-treat populations of RCTs using a fixed-effect model for meta-analysis, but used a random-effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I2 ≥ 75%) in their results. We applied GRADE to assess the certainty of the evidence.

Main results: We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was: random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short-term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short-term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P = 1.00; 3 RCTs; very low-certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P = 0.49; 4 RCTs; very low-certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P = 0.11; 2 RCTs; very low-certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P = 0.15; 1 RCT; very low-certainty evidence) over 90 days. For starting versus avoiding long-term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long-term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P = 0.02; 3 RCTs; moderate-certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P = 0.0002; 3 RCTs; moderate-certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P = 0.86; 3 RCTs; moderate-certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P = 0.09; 3 RCTs; moderate-certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P = 0.87; 2 RCTs; low-certainty evidence) over one to three years. For starting versus avoiding long-term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long-term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P = 0.46; 1 RCT; moderate-certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P = 0.66; 1 RCT; moderate-certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P = 0.90; 1 RCT; moderate-certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P = 0.06; 1 RCT; moderate-certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P = 0.67; 1 RCT; moderate-certainty evidence) over a median follow-up of two years. For adults within 180 days of non-cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long-term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P = 0.34; subgroup of 1 RCT; low-certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P = 0.37; subgroup of 1 RCT; low-certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P = 0.70; subgroup of 1 RCT; low-certainty evidence) over a median follow-up of 1.8 years; all major occlusive vascular events and functional status were not reported.

Authors' conclusions: We did not identify beneficial or hazardous effects of short-term prophylactic dose parenteral anticoagulation and long-term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long-term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH.

Trial registration: ClinicalTrials.gov NCT02565693 NCT02998905 NCT01013532 NCT01573169 NCT03153150 NCT02801669 NCT02966119 NCT03243175 NCT03907046 NCT03950076 NCT04522102 NCT04820972 NCT03996772.

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Conflict of interest statement

Alexia Cochrane: none

Chen Chen: none

Jacqueline Stephen: none

Ole Morten Rønning: Trial Steering committee member for NCT03186729.

Craig S Anderson: Trial steering committee member for NCT04522102. He has received grant funding as follows:

(1) Credit pharma, China: Grant / Contract Contract Start Date: Jan 1, 2020 Contract End Date: Ongoing / No Known End Date Additional Information: grant support paid to my institution

(2) Genesis Pharma: Grant / Contract Contract Start Date: Jan 1, 2020 Contract End Date: Ongoing / No Known End Date Additional Information: grant support paid to my institution

(3) National Health and Medical Research Council: Grant / Contract Contract Start Date: Jan 1, 2020 Contract End Date: Ongoing / No Known End Date Additional Information: grant support

(4) Penumbra, Inc: Grant / Contract Contract Start Date: Jun 30, 2021 Contract End Date: Ongoing / No Known End Date Additional Information: grant support paid to my institution

Graeme J Hankey: in the past three years, GJH has received honoraria from AC Immune for chairing the data safety monitoring committee of two clinical trials of vaccines for Alzheimer’s disease, from Bayer for lecturing about stroke prevention in atrial fibrillation at sponsored scientific symposia, and from Medscape, Web MD for participating in a discussion about stroke prevention in atrial fibrillation for theheart.org. NCT04522102 Trial Steering Committee member.

Summary of interests: Company or Organization

(1) AC Immune Data And Safety Monitoring Category: Data And Safety Monitoring Contract Description: DSMB member of ACI‐35‐1802 Phase Ib/IIa trial of tau‐targeted vaccines in early Alzheimers Disease End Date: Ongoing / No Known End Date

(2) Bayer Category: Consultant Contract Description: Stroke Prevention Initiative End Date: Oct 20, 2020

(3) Bristol‐Myers Squibb Category: Other Contract Description: Member of the Steering Committee of the AXIOMATIC‐SSP phase 2 trial of milvexian End Date: Ongoing / No Known End Date

(4) Janssen Research and Development Category: Consultant Contract Description: Review of clinical trial protocol End Date: Ongoing / No Known End Date

Intellectual Property Description: Antiplatelet Secondary Prevention International Randomised Trial After Intracerebral Haemorrhage

Rustam Al‐Shahi Salman: UK chief investigator of RESTART 2019, SoSTART 2021, and NCT03950076. Trial Steering Committee member for NCT03186729, NCT04522102, and NCT02966119. He has received grant funding as follows:

(1) British Heart Foundation: Grant / Contract Contract Start Date: Aug 1, 2018 Contract End Date: Jul 31, 2021 Additional Information: Clinical study grant for the SoSTART trial

(2) British Heart Foundation: Grant / Contract Contract Start Date: Mar 1, 2013 Contract End Date: Jul 31, 2021 Additional Information: Special project grant for RESTART

(3) Population Health Research Institute: Grant / Contract Contract Start Date: Apr 22, 2019 Contract End Date: Ongoing / No Known End Date Additional Information: Grant for the ENRICH‐AF trial

Figures

1
1
Flow diagram of study screening, eligibility assessment and inclusion
2
2
1.1
1.1. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 1: Death
1.2
1.2. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 2: Deep vein thrombosis
1.3
1.3. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 3: Pulmonary embolism
1.4
1.4. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 4: Venous thromboembolism
1.5
1.5. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 5: Intracerebral haemorrhage
1.6
1.6. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 6: Major extracerebral haemorrhage
1.7
1.7. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 7: Growth of qualifying intracerebral haemorrhage
1.8
1.8. Analysis
Comparison 1: Short‐term prophylactic dose anticoagulation (start versus avoid), Outcome 8: Functional status (modified Rankin Scale 0‐2)
2.1
2.1. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 1: All major adverse cardiovascular events (MACE)
2.2
2.2. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 2: Death
2.3
2.3. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 3: Ischaemic stroke
2.4
2.4. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 4: Myocardial infarction
2.5
2.5. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 5: All major occlusive vascular events
2.6
2.6. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 6: Intracranial haemorrhage
2.7
2.7. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 7: Major extracerebral haemorrhage
2.8
2.8. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 8: Vascular death
2.9
2.9. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 9: Functional status (modified Rankin Scale score 0‐2) at 1 year
2.10
2.10. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 10: Any stroke (ischaemic or haemorrhagic)
2.11
2.11. Analysis
Comparison 2: Long‐term therapeutic dose oral anticoagulation for atrial fibrillation (start versus avoid), Outcome 11: Any stroke (ischaemic or haemorrhagic) or vascular death
3.1
3.1. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 1: All major adverse cardiovascular events (MACE)
3.2
3.2. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 2: Death
3.3
3.3. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 3: Ischaemic stroke
3.4
3.4. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 4: Myocardial infarction
3.5
3.5. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 5: All major occlusive vascular events
3.6
3.6. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 6: Intracerebral haemorrhage
3.7
3.7. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 7: Major extracerebral haemorrhage
3.8
3.8. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 8: Vascular death
3.9
3.9. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 9: Functional status (modified Rankin Scale score 0‐2) at 1 year
3.10
3.10. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 10: Deep vein thrombosis
3.11
3.11. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 11: All major haemorrhagic events
3.12
3.12. Analysis
Comparison 3: Long‐term antiplatelet therapy (start versus avoid), Outcome 12: Major vascular events as defined by the Antithrombotic Trialists’ Collaboration
4.1
4.1. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 1: All major adverse cardiovascular events (MACE)
4.2
4.2. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 2: Death
4.3
4.3. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 3: Ischaemic stroke
4.4
4.4. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 4: Myocardial infarction
4.5
4.5. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 5: Intracerebral haemorrhage
4.6
4.6. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 6: Vascular death
4.7
4.7. Analysis
Comparison 4: Long‐term antiplatelet therapy (cilostazol versus aspirin), Outcome 7: Any stroke (ischaemic or haemorrhagic)
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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SoSTART 2021 {published data only}
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Boeer 1991 {published data only}
    1. Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1991;54(5):466-7. [DOI: 10.1136/jnnp.54.5.466] - DOI - PMC - PubMed
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Frontera 2014 {published data only}
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IST 1997 {published data only}
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Kuramatsu 2018 {published data only}
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Li 2013 {published data only}
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ELDERCARE‐AF 2020 {published data only (unpublished sought but not used)}
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References to ongoing studies

NCT02966119 {published data only}
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NCT03186729 {published data only}
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NCT03243175 {published data only}
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NCT03950076 {published data only}
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