Oral antiplatelet therapy for acute ischaemic stroke

Peter AG Sandercock; Carl Counsell; Mei‐Chiun Tseng; Emanuela Cecconi

doi:10.1002/14651858.CD000029.pub3

Tratamiento antiplaquetario oral para el accidente cerebrovascular isquémico agudo

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References

References to studies included in this review

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excluded studies
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ongoing studies
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ongoing studies
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ongoing studies
other published versions

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References to other published versions of this review

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included studies
excluded studies
awaiting assessment
ongoing studies
additional references

Sandercock P, Gubitz G, Foley P, Counsell C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD000029]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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CAST 1997

Methods	C = centrally produced, prepacked, sequentially numbered envelopes Double blind Exclusions during trial: none Losses to follow‐up: 451 (219 Rx, 232 control) at 4 weeks
Participants	China 21,106 participants 63% male 28% were more than 70 years old 87% had CT before entry Ischaemic stroke less than 48 hours since stroke onset
Interventions	Rx: aspirin 160 mg once daily orally or via nasogastric tube Control: placebo Duration: 4 weeks, or until death or earlier discharge
Outcomes	Death Recurrent stroke Functional outcome (modified Rankin disability scale less than 3 = independent) Pulmonary embolism (symptomatic) Extracranial haemorrhage
Notes	Ex: not specified by protocol but by responsible physician, possibly including increased risk of adverse effects, or little likelihood of any worthwhile benefit in hospital FU: 4 weeks
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Ciufetti 1990

Methods	R = random number list Double blind Exclusions during trial: none Losses to follow‐up: none
Participants	Italy 30 participants 14 (47%) male Mean age: 73 years (all more than 65 years) 100% CT before entry Hemiparetic ischaemic stroke less than 12 hours since stroke onset
Interventions	Rx: ticlopidine 250 mg orally 12 hourly Control: placebo Duration: 3 weeks
Outcomes	Death Pulmonary embolism (symptomatic) Recurrent stroke
Notes	Ex: cerebral oedema FU: 3 weeks
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

IST 1997

Methods	C = telephone randomisation Unblinded; dependency assessment mainly blinded Exclusions during trial: none Losses to follow‐up: 2 at 14 days (1 Rx, 1 control); 150 at 6 months (81 Rx, 69 control)
Participants	International 19,435 participants 54% male 61% more than 70 years 67% CT prior to randomisation, 29% CT after randomisation Ischaemic stroke less than 48 hours since stroke onset
Interventions	Rx: subcutaneous heparin (5000 IU or 12 500 IU 12 hourly), aspirin 300 mg, both, or neither (factorial design) Duration: 14 days or until discharge from hospital Aspirin by mouth if able to swallow, if not then by rectal suppository or by injection of 100 mg of the lysine salt of aspirin
Outcomes	Death Functional outcome (validated simple questions) Recurrent stroke Pulmonary embolus (symptomatic) Intracranial haemorrhage (symptomatic CT) Extracranial haemorrhage
Notes	Ex: small likelihood of worthwhile benefit; high risk of adverse effect (e.g. hypersensitivity of aspirin, recent GI bleed or peptic ulcer disease, already on long‐term anticoagulation) FU: 6 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

MAST‐I 1995

Methods	C = telephone central office Assessor blind (telephone follow‐up) Exclusions during trial: none Losses to follow‐up: none
Participants	Europe 309 participants 163 (53%) male 22% less than 60 years, 46% 61 to 75 years 100% CT before entry Ischaemic stroke Less than 6 hours since stroke onset
Interventions	Factorial design of streptokinase and aspirin versus no treatment; only aspirin alone versus no aspirin included to prevent confounding influence of streptokinase Rx: aspirin 300 mg oral (or iv/rectal) 24 hourly Control: no treatment Duration: 10 days
Outcomes	Death plus cause of death Functional outcome at 6 months (modified Rankin less than 3 = independent) Intracranial haemorrhage (symptomatic plus systematic) Extracranial haemorrhage Pulmonary embolism (symptomatic) Recurrent stroke Myocardial infarction
Notes	Ex: coma, bleeding risk FU: 6 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Pince 1981

Methods	R = sealed envelope Double blind Exclusions during trial: 9 (5 Rx, 4 control) Losses to follow‐up: none
Participants	France 80 participants 50 (62%) male Mean age: 66 years No CT before entry; 100% had lumbar puncture Presumed ischaemic stroke Less than 6 days since stroke onset
Interventions	Rx: aspirin 330 mg 8 hourly (oral) plus dipyridamole 75 mg 8 hourly (oral) Control: placebo Duration: 1 week
Outcomes	Death DVT (systematic I125 scan) Pulmonary embolism (symptomatic) Intracranial haemorrhage (symptomatic) Extracranial haemorrhage
Notes	Ex: bleeding risk, aspirin allergy FU: 10 days
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Rödén‐Jüllig 2003

Methods	R = randomisation tables, stratified for gender C = sequentially numbered containers from pharmacy Double blind Exclusions during trials: none Losses to follow‐up: none
Participants	Sweden 441 participants 226 (51%) male 100% CT before entry Ischaemic stroke less than 72 hours since stroke onset SSSS 1 point or more
Interventions	Rx: aspirin 325 mg orally once daily Control: placebo Duration: 5 days
Outcomes	Death 2 points or more (may be in different items) worsening on SSSS at 5 days Ability to walk unaided, increased need for ADL help at 3 months
Notes	Ex: specified by protocol ‐ includes severe concomitant medical conditions or pre‐existing neurological illness, bleeding risk, blood pressure above 240/140 mmHg FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Turpie 1983

Methods	R = identical, sequentially numbered bottles from pharmacy Double blind Exclusions during trial: 4 (2 Rx, 2 control) Losses to follow‐up: none
Participants	Canada 53 participants 21 (40%) male Age range 33 to 92 years No CT before entry Any stroke with leg paresis Less than 4 weeks since stroke onset (most less than 2 weeks)
Interventions	Rx: ticlopidine 250 mg orally 12 hourly Control: placebo Duration: 10 to 21 days
Outcomes	Death DVT (systematic I125 scan/plethysmography and venography) Pulmonary embolism (symptomatic) Intracranial haemorrhage (symptomatic) Extracranial haemorrhage
Notes	Ex: unknown FU: 21 days
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Utsumi 1988

Methods	R = unknown Not blind Exclusions during trial: 1 (control) Losses to follow‐up: none
Participants	Japan 29 participants 5 (17%) male Mean age: 63 years CT scanning was not stated Ischaemic stroke less than 4 weeks since stroke onset (only 1 more than 2 weeks)
Interventions	Rx: ticlopidine 100 mg orally 8 to 12 hourly Control: no treatment Duration: up to 3 months (median 1 month)
Outcomes	Death Pulmonary embolism (symptomatic) Intracranial haemorrhage Extracranial haemorrhage
Notes	Ex: unknown FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

ADL: activities of daily living
C: concealment
CT: computerised tomography
DVT: deep venous thrombosis
Ex: exclusions
FU: follow‐up
GI: gastrointestinal
iv: intravenous
R: randomisation
Rx: treatment
SSSS: Scandinavian Stroke Supervision Scale
Systematic: outcome sought by systematically scanning all patients at a predefined time, irrespective of presence or absence of symptoms

Characteristics of excluded studies [ordered by study ID]

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included studies
awaiting classification
ongoing studies

Study	Reason for exclusion
Abciximab 2000	Intravenous antiplatelet therapy
AbESTT 2005	Intravenous antiplatelet therapy
AbESTT‐II/C 2008	Intravenous antiplatelet therapy
AbESTT‐II/P 2008	Intravenous antiplatelet therapy
AbESTT‐II/W 2008	Intravenous antiplatelet therapy
Aoki 2000	Not adequately randomised; participants allocated on alternating basis Not acute therapy
APLAUD 2000	Not acute stroke therapy Randomisation up to 6 months post‐stroke
Apollonia 1989	Not adequately randomised; confounded; people with acute and non‐acute stroke included
ARTIS 2012	Intravenous antiplatelet therapy
Balkuv‐Ulutin 1989	Not randomised
BRAVO 2000	Not acute stroke therapy; people included up to 30 days post‐stroke Trial halted prematurely because of bleeding risk, but trial data remain unpublished
Chen 1988	Not adequately randomised
Cheung 2000	Intravenous antiplatelet therapy
CLEAR trial	Confounded trial
D'Andrea 1993	No control group which did not receive antiplatelet therapy (picotamide versus aspirin versus aspirin and picotamide)
Fan 2003	Ligustrazine, a kind of Chinese herbal medicine, is not an antiplatelet agent
FASTER 2007	No control group (clopidogrel plus aspirin versus aspirin alone in minor stroke and TIA within 24 hours of onset)
Gao 1989	No control group (aspirin versus ligustrazine versus betahistine)
Garcia Tigera 1994	No control group (aspirin versus levamisol)
Hakim 1984	Not randomised
Iida 1984	Not acute stroke therapy
JASAP 2011	No control group (extended‐release dipyridamole 200 mg plus acetylsalicylic acid 50 mg in a capsule, 2 capsules twice daily versus acetylsalicylic acid 81 mg,1 tablet once daily) Not acute stroke therapy; participants included between 1 week and 6 months after stroke
Joseph 1989	Not adequately randomised
Junghans 2002	Not randomised
Kamath 2001	No results published, described as 'discontinued'
Kaye 1989	No control group which did not receive antiplatelet therapy (aspirin and dipyridamole combined versus aspirin alone)
Lecrubier 1977	Not acute stroke therapy
Li 1999	Non‐randomised, dose escalation study
Li 2005	Intravenous antiplatelet therapy
Liu 1994	Method of allocation unclear, no relevant clinical outcomes reported
Matsumoto 2005	Multiple antiplatelet agents
Monreal 1987	No relevant clinical outcomes reported
Ohtomo 1991	Intravenous antiplatelet therapy
SaTIS 2011	Intravenous antiplatelet therapy
Seitz 2004	No relevant clinical outcomes reported
Siebler 2003	No relevant clinical outcomes reported
TACS 2000	Not acute stroke therapy; participants included up to 6 months after stroke
TARDIS	Multiple antiplatelet agents. Ongoing trial
Wu 2005	Ligustrazine, a kind of Chinese herbal medicine, is not an antiplatelet agent
Yan 1998	Not adequately randomised
Zhang 2005	Method of allocation unclear, no relevant clinical outcomes reported

TIA: transient ischaemic attack

Characteristics of studies awaiting assessment [ordered by study ID]

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ongoing studies

Fujimoto 2010

Methods
Participants	People with non‐cardioembolic ischaemic stroke within 72 hours of the onset and NIHSS score ≤ 7
Interventions	Cilostazol (200 mg/d) plus intravenous antithrombotic agents (heparin, ozagrel sodium or argatroban) versus intravenous antithrombotic agents (heparin, ozagrel sodium or argatroban)
Outcomes	Neurological deterioration and stroke recurrence at 14 days, and mRS at 3 months
Notes

Wang 2000

Methods	Randomised, placebo‐controlled trial
Participants	People with ischaemic stroke within 48 hours of the onset and demonstrated by CT
Interventions	Aspirin (160 mg/d for 4 weeks) versus placebo
Outcomes
Notes

CT: computerised tomography
mRS: modified Rankin Scale
NIHSS: National Institutes of Health Stroke Scale

Characteristics of ongoing studies [ordered by study ID]

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excluded studies
awaiting classification

CAIST‐J 2006

Trial name or title	Cilostazol in Acute Ischemic Stroke Trial
Methods	Randomised, single‐blind ‐ participants are blinded
Participants	People with ischaemic stroke within 72 hours after the onset and NIHSS score ≥ 14
Interventions	Cilostazol versus conventional therapy
Outcomes	Primary outcome: mRS 0 to 2 at 3 months Secondary outcome: recurrence of stroke, NIHSS, JSS, Barthel Indes, mRS, MMSE, neurological deterioration, pneumonia
Starting date	2006
Contact information	Norihiro Suzuki Keio University School of Medicine Department of Neurology 35 Shinanomachi Shinjuku‐ku Tokyo 165‐8582 Japan
Notes

CAPS 2009

Trial name or title	A randomised clinical trial of an antiplatelet agent in the treatment of acute stroke: cilostazol in the prevention of acute progressing stroke (CAPS) study
Methods	Randomised, open‐label
Participants	People with non‐cardioembolic cerebral infarction within 24 hours after the onset, aged 20 to 80 years
Interventions	Cilostazol (200 mg/d) plus standard therapy versus standard therapy
Outcomes	mRS at 3 months, progressing stroke, incidence of cardiovascular events
Starting date	2009
Contact information	Teiji Tominaga Tohoku University Graduate School of Medicine Department of Neurosurgery 1‐1, Seiryo‐machi, Aoba‐ku, SENDAI 980‐8574
Notes

JSS: Japan Stroke Scale
MMSE: Mini Mental State Exmanination
mRS: modified Rankin Scale
NIHSS: National Institutes of Health Stroke Scale

Data and analyses

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Comparison 1. Antiplatelet drug versus control in acute presumed ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death or dependence at end of follow‐up Show forest plot	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.91, 0.99]
Open in figure viewer Analysis 1.1 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 1 Death or dependence at end of follow‐up.
1.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.91, 0.99]
2 Deaths from all causes during treatment period Show forest plot	8	41483	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.85, 1.00]
Open in figure viewer Analysis 1.2 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 2 Deaths from all causes during treatment period.
2.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.85, 1.00]
2.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [0.43, 4.99]
2.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.01, 1.20]
3 Deaths from all causes during follow‐up Show forest plot	8	41483	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.87, 0.98]
Open in figure viewer Analysis 1.3 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 3 Deaths from all causes during follow‐up.
3.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.87, 0.98]
3.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [0.43, 4.99]
3.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.02, 0.88]
4 Deep venous thrombosis during treatment period Show forest plot	2	133	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.78 [0.36, 1.67]
Open in figure viewer Analysis 1.4 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 4 Deep venous thrombosis during treatment period.
4.1 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.13, 0.95]
4.2 Ticlopidine versus control	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.37 [0.72, 7.73]
5 Pulmonary embolism during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.53, 0.96]
Open in figure viewer Analysis 1.5 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 5 Pulmonary embolism during treatment period.
5.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.53, 0.97]
5.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.39 [0.15, 372.38]
5.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.06]
6 Recurrent ischaemic/unknown stroke during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.69, 0.87]
Open in figure viewer Analysis 1.6 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 6 Recurrent ischaemic/unknown stroke during treatment period.
6.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.69, 0.87]
6.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Symptomatic intracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.23 [1.00, 1.50]
Open in figure viewer Analysis 1.7 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 7 Symptomatic intracranial haemorrhage during treatment period.
7.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.22 [1.00, 1.50]
7.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.0 [0.14, 7.38]
7.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.70 [0.36, 20.26]
8 Any recurrent stroke/intracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.88 [0.79, 0.97]
Open in figure viewer Analysis 1.8 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 8 Any recurrent stroke/intracranial haemorrhage during treatment period.
8.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.87 [0.79, 0.97]
8.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.0 [0.14, 7.38]
8.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.70 [0.36, 20.26]
9 Major extracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.35, 2.11]
Open in figure viewer Analysis 1.9 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 9 Major extracranial haemorrhage during treatment period.
9.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.35, 2.11]
9.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Complete recovery from stroke (post hoc) Show forest plot	2	40541	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [1.01, 1.11]
Open in figure viewer Analysis 1.10 Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 10 Complete recovery from stroke (post hoc).
10.1 Aspirin versus control	2	40541	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [1.01, 1.11]

Figure 1

Flow diagram.

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Figure 2

Funnel plot of comparison: 1 Antiplatelet agent versus control in acute presumed ischaemic stroke, outcome: 1.1 Death or dependence at end of follow‐up.

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Figure 3

Funnel plot of comparison: 1 Antiplatelet agent versus control in acute presumed ischaemic stroke, outcome: 1.2 Deaths from all causes during treatment period.

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Analysis 1.1

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 1 Death or dependence at end of follow‐up.

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Analysis 1.2

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 2 Deaths from all causes during treatment period.

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Analysis 1.3

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 3 Deaths from all causes during follow‐up.

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Analysis 1.4

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 4 Deep venous thrombosis during treatment period.

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Analysis 1.5

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 5 Pulmonary embolism during treatment period.

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Analysis 1.6

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 6 Recurrent ischaemic/unknown stroke during treatment period.

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Analysis 1.7

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 7 Symptomatic intracranial haemorrhage during treatment period.

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Analysis 1.8

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 8 Any recurrent stroke/intracranial haemorrhage during treatment period.

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Analysis 1.9

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 9 Major extracranial haemorrhage during treatment period.

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Analysis 1.10

Comparison 1 Antiplatelet drug versus control in acute presumed ischaemic stroke, Outcome 10 Complete recovery from stroke (post hoc).

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Table 1. Absolute risk reductions of aspirin treatment in acute stroke

Outcome	Control event rate	No of events avoided	NNTB or NNTH
		Per 1000 people treated (95% CI)	Data are number needed to treat to benefit (NNTB) (95% CI) unless otherwise indicated. NNTH = number needed to treat to harm
	Estimated from the average of the control event rate in the 2 largest trials (CAST 1997 and IST 1997)	Estimated by applying the odds ratio for the outcome for studies of aspirin. Calculator is available at: http://www.dcn.ed.ac.uk/csrg/entity/entity_NNT2.asp	Estimated by applying the odds ratio for the outcome for studies of aspirin. Calculator is available at: http://www.dcn.ed.ac.uk/csrg/entity/entity_NNT2.asp
Death or dependence at end of follow‐up	0.47	13 (3 to 23)	79 (43 to 400)
Deaths from all causes during follow‐up	0.13	9 (2 to 15)	108 (66 to 436)
Pulmonary embolism during treatment period	0.01	1 (0 to 2)	693 (427 to 6700)
Recurrent ischaemic/unknown stroke during treatment period	0.03	7 (4 to 10)	140 (104 to 248)
Symptomatic intracranial haemorrhage during treatment period	0.01	‐2 (i.e. 2 extra) (‐4 to 0)	NNTH 574 (254 to 126 010)
Any recurrent stroke/intracranial haemorrhage during treatment	0.04	5 (1 to 8)	200 (123 to 868)
Major extracranial haemorrhage during treatment period	0.01	‐4 (i.e. 4 extra) (‐7 to ‐2)	NNTH 245 (153 to 481)
Complete recovery from stroke (post hoc)	0.26	11 (2 to 21)	89 (49 to 523)

Table 1. Absolute risk reductions of aspirin treatment in acute stroke

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Comparison 1. Antiplatelet drug versus control in acute presumed ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death or dependence at end of follow‐up Show forest plot	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.91, 0.99]

1.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.91, 0.99]
2 Deaths from all causes during treatment period Show forest plot	8	41483	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.85, 1.00]

2.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.85, 1.00]
2.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [0.43, 4.99]
2.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.01, 1.20]
3 Deaths from all causes during follow‐up Show forest plot	8	41483	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.87, 0.98]

3.1 Aspirin versus control	4	41291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.87, 0.98]
3.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [0.43, 4.99]
3.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.02, 0.88]
4 Deep venous thrombosis during treatment period Show forest plot	2	133	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.78 [0.36, 1.67]

4.1 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.13, 0.95]
4.2 Ticlopidine versus control	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.37 [0.72, 7.73]
5 Pulmonary embolism during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.53, 0.96]

5.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.53, 0.97]
5.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.39 [0.15, 372.38]
5.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.06]
6 Recurrent ischaemic/unknown stroke during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.69, 0.87]

6.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.69, 0.87]
6.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Symptomatic intracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.23 [1.00, 1.50]

7.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.22 [1.00, 1.50]
7.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.0 [0.14, 7.38]
7.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.70 [0.36, 20.26]
8 Any recurrent stroke/intracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.88 [0.79, 0.97]

8.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.87 [0.79, 0.97]
8.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.0 [0.14, 7.38]
8.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.70 [0.36, 20.26]
9 Major extracranial haemorrhage during treatment period Show forest plot	7	41042	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.35, 2.11]

9.1 Aspirin versus control	3	40850	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.35, 2.11]
9.2 Aspirin plus dipyridamole versus control	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Ticlopidine versus control	3	112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Complete recovery from stroke (post hoc) Show forest plot	2	40541	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [1.01, 1.11]

10.1 Aspirin versus control	2	40541	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [1.01, 1.11]

Comparison 1. Antiplatelet drug versus control in acute presumed ischaemic stroke

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References

References to studies included in this review

CAST 1997 {published and unpublished data}

Ciufetti 1990 {published and unpublished data}

IST 1997 {published and unpublished data}

MAST‐I 1995 {published and unpublished data}

Pince 1981 {unpublished data only}

Rödén‐Jüllig 2003 {published data only}

Turpie 1983 {unpublished data only}

Utsumi 1988 {unpublished data only}

References to studies excluded from this review

Abciximab 2000 {published data only}

AbESTT 2005 {published data only}

AbESTT‐II/C 2008 {published data only}

AbESTT‐II/P 2008 {published data only}

AbESTT‐II/W 2008 {published data only}

Aoki 2000 {unpublished data only}

APLAUD 2000 {published data only}

Apollonia 1989 {published data only}

ARTIS 2012 {published data only}

Balkuv‐Ulutin 1989 {published data only}

BRAVO 2000 {published data only}

Chen 1988 {published data only}

Cheung 2000 {published data only}

CLEAR trial {published data only}

D'Andrea 1993 {published data only}

Fan 2003 {published data only}

FASTER 2007 {published data only}

Gao 1989 {published data only}

Garcia Tigera 1994 {published data only}

Hakim 1984 {published data only}

Iida 1984 {unpublished data only}

JASAP 2011 {published data only}

Joseph 1989 {published data only}

Junghans 2002 {published data only}

Kamath 2001 {published data only}

Kaye 1989 {unpublished data only}

Lecrubier 1977 {published data only}

Li 1999 {published data only}

Li 2005 {published data only}

Liu 1994 {published data only}

Matsumoto 2005 {published data only}

Monreal 1987 {published data only}

Ohtomo 1991 {published data only}

SaTIS 2011 {published data only}

Seitz 2004 {published data only}

Siebler 2003 {published data only}

TACS 2000 {unpublished data only}

TARDIS {published data only}

Wu 2005 {published and unpublished data}

Yan 1998 {published data only}

Zhang 2005 {published data only}

References to studies awaiting assessment

Fujimoto 2010 {published data only}

Wang 2000 {published data only}

References to ongoing studies

CAIST‐J 2006 {published data only}

CAPS 2009 {published data only}

Additional references

AbESTT‐II

AHA 2013

ATC 1994a

ATC 1994b

ATC 2002

ATC 2009

Bamford 1989

Bath 2004a

Bath 2004b

CAIST 2011

Candelise 1994

Chairangsarit 2005

CHANCE 2013

Chen 2000

Ciccone 2006

Collins 1996

CSS 2010

Dalen 2006

Davenport 1996