Antithrombotic Trialists’ CollaborationAntithrombotic Trialists’ Collaboration

An updated collaborative overview of An updated collaborative overview of randomised trials of antiplatelet therapy randomised trials of antiplatelet therapy

among high-risk patientsamong high-risk patients

Antithrombotic Trialists’ CollaborationAntithrombotic Trialists’ Collaboration

Definitions:Definitions:““Serious vascular event” : combined outcome of Serious vascular event” : combined outcome of

non-fatal myocardial infarction, non-fatal non-fatal myocardial infarction, non-fatal stroke, or death from a vascular (or unknown) stroke, or death from a vascular (or unknown) cause cause

““High-risk” : risk of a serious vascular event High-risk” : risk of a serious vascular event more than about 3% per annum because of more than about 3% per annum because of previous occlusive disease or a predisposing previous occlusive disease or a predisposing condition condition

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: VASCULAR EVENTSVASCULAR EVENTS

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 13.5%13.5% 17.0%17.0% 25%±425%±4

Acute MIAcute MI 10.4%10.4% 14.2%14.2% 30%±430%±4

Prior stroke/TIAPrior stroke/TIA 17.8%17.8% 21.4%21.4% 22%±422%±4

Acute strokeAcute stroke 8.2%8.2% 9.1%9.1% 11%±311%±3

Other high riskOther high risk 8.0%8.0% 10.2%10.2% 26%±326%±3

All except All except 11.7%11.7% 14.8%14.8% 25%±225%±2acute strokeacute stroke

All trialsAll trials 10.7%10.7% 13.2%13.2% 22%±222%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: VASCULAR EVENTSVASCULAR EVENTS

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 13.5%13.5% 17.0%17.0% 25%±425%±4

Acute MIAcute MI 10.4%10.4% 14.2%14.2% 30%±430%±4

Prior stroke/TIAPrior stroke/TIA 17.8%17.8% 21.4%21.4% 22%±422%±4

Acute stroke Acute stroke 8.2%8.2% 9.1%9.1% 11%±311%±3

Other high risk*Other high risk*

CADCAD 6.2%6.2% 8.9%8.9% 37%±537%±5

Embolic riskEmbolic risk 13.5%13.5% 16.8%16.8% 26%±726%±7

PADPAD 5.8%5.8% 7.1%7.1% 23%±823%±8

OtherOther 11.3%11.3% 12.6%12.6% 13%±713%±7

All trialsAll trials 10.7%10.7% 13.2%13.2% 22%±222%±2

1.01.00.50.50.00.0 1.51.5 2.02.0

Benefit per 1000(SE):Benefit per 1000(SE):

AA13.5%13.5%

AA10.4%10.4%

AA17.8%17.8%

AA8.2%8.2%

AA8.1%8.1%

CC21.4%21.4%

CC14.2%14.2%

CC17.0%17.0%

CC9.1%9.1%

CC10.2%10.2%

0%0%

10%10%

20%20%

Prior MIPrior MI Acute MIAcute MI PriorPriorstroke/TIAstroke/TIA

AcuteAcutestrokestroke

Other highOther highriskrisk

CATEGORY:CATEGORY:

A = Antiplatelet therapyA = Antiplatelet therapy

C = ControlC = Control

Average duration:Average duration: 27 m27 m

36(5)36(5)

1m1m

38(5)38(5)

29 m29 m

36(6)36(6)

0.7 m0.7 m

9(3)9(3)

22 m22 m

22(3)22(3)

P-value:P-value: <0.0001<0.0001 <0.0001<0.0001 <0.0001<0.0001 0.00090.0009 <0.0001<0.0001

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: Absolute effects on VASCULAR EVENTSAbsolute effects on VASCULAR EVENTS

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: NON-FATAL MYOCARDIAL INFARCTIONNON-FATAL MYOCARDIAL INFARCTION

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 4.7%4.7% 6.5%6.5% 30%±630%±6

Acute MIAcute MI 1.0%1.0% 2.3%2.3% 55%±855%±8

Prior stroke/TIAPrior stroke/TIA 1.7%1.7% 2.3%2.3% 31%±931%±9

Acute strokeAcute stroke No dataNo data

Other high riskOther high risk 2.7%2.7% 3.8%3.8% 32%±532%±5

All trialsAll trials 2.6%2.6% 3.7%3.7% 34%±334%±3

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: NON-FATAL STROKENON-FATAL STROKE

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 0.9%0.9% 1.4%1.4% 39%±1139%±11

Acute MIAcute MI 0.3%0.3% 0.6%0.6% 40%±1740%±17

Prior stroke/TIAPrior stroke/TIA 8.3%8.3% 10.8%10.8% 25%±525%±5

Acute strokeAcute stroke 2.1%2.1% 2.6%2.6% 18%±618%±6

Other high riskOther high risk 1.5%1.5% 2.2%2.2% 30%±730%±7

All trialsAll trials 2.6%2.6% 3.5%3.5% 25%±325%±3

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: VASCULAR DEATHVASCULAR DEATH

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 8.0%8.0% 9.4%9.4% 15%±515%±5

Acute MIAcute MI 9.1%9.1% 11.4%11.4% 22%±422%±4

Prior stroke/TIAPrior stroke/TIA 8.0%8.0% 8.7%8.7% 11%±511%±5

Acute strokeAcute stroke 6.1%6.1% 6.5%6.5% 8%±48%±4

Other high riskOther high risk 4.5%4.5% 5.3%5.3% 17%±417%±4

All trialsAll trials 6.8%6.8% 7.6%7.6% 15%±215%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration: Antithrombotic Trialists’ Collaboration: ANY DEATHANY DEATH

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Prior MIPrior MI 9.2%9.2% 10.3%10.3% 12%±512%±5

Acute MIAcute MI 9.2%9.2% 11.5%11.5% 22%±422%±4

Prior stroke/TIAPrior stroke/TIA 11.3%11.3% 12.8%12.8% 14%±514%±5

Acute strokeAcute stroke 6.1%6.1% 6.5%6.5% 8%±48%±4

Other high riskOther high risk 5.9%5.9% 6.7%6.7% 15%±415%±4

All trialsAll trials 7.7%7.7% 8.8%8.8% 14%±214%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

AA 4714719 9849 984(4.7%)(4.7%)

AA 83 83 9 2229 222(0.9%)(0.9%)

AA 799 799 9 9849 984(8.0%)(8.0%)

AA 914 914 9 9849 984(9.2%)(9.2%)

CC 939 939 10 02210 022(9.4%)(9.4%)

CC 129 129 9 2509 250(1.4%)(1.4%)

CC 654 654

10 02210 022(6.5%)(6.5%)

CC 1 035 1 035 10 02210 022(10.3%)(10.3%)

0%0%

5%5%

10%10%

Non-fatalNon-fatalreinfarctionreinfarction

Non-fatal Non-fatal strokestroke

Vascular Vascular deathdeath

A = Antiplatelet therapyA = Antiplatelet therapy(mean 2 years)(mean 2 years)

C = ControlC = Control

Benefit per 1000Benefit per 1000patients (SE)patients (SE)

2P2P <0.0001<0.0001 0.0020.002 0.00060.0006 0.020.02

12 (5)12 (5)18 (3)18 (3) 5 (1)5 (1) 14 (4)14 (4)

Any deathAny death

Absolute effects in patients with PREVIOUS MYOCARDIAL INFARCTIONAbsolute effects in patients with PREVIOUS MYOCARDIAL INFARCTION

AA 95 95 9 5349 534(1.0%)(1.0%)

AA 32 32 9 3009 300(0.3%)(0.3%)

AA 883 883 9 6589 658(9.1%)(9.1%)

AA 886 886 9 6589 658(9.2%)(9.2%)

CC 1104 1104 96449644

(11.4%)(11.4%)

CC 54 54 9 2919 291(0.6%)(0.6%)

CC 215 215 9 5219 521(2.3%)(2.3%)

CC 1 112 1 112 9 6449 644

(11.5%)(11.5%)

0%0%

5%5%

10%10%

Non-fatalNon-fatalreinfarctionreinfarction

Non-fatal Non-fatal strokestroke

Vascular Vascular deathdeath

A = Antiplatelet therapyA = Antiplatelet therapy(mean 1 month)(mean 1 month)

C = ControlC = Control

Benefit per 1000Benefit per 1000patients (SE)patients (SE)

2P2P <0.0001<0.0001 0.020.02 <0.0001<0.0001 <0.0001<0.0001

24 (4)24 (4)13 (2)13 (2) 2 (1)2 (1) 23 (4)23 (4)

Any deathAny death

Absolute effects in patients with ACUTE MYOCARDIAL INFARCTIONAbsolute effects in patients with ACUTE MYOCARDIAL INFARCTION

AA 191 191

11 31011 310(1.7%)(1.7%)

AA957 957

11 49311 493(8.3%)(8.3%)

AA 915 915 11 49311 493(8.0%)(8.0%)

AA 1 303 1 303 11 49311 493(11.3%)(11.3%)CC

1 003 1 003 11 52711 527(8.7%)(8.7%)

CC1 248 1 248 11 52711 527(10.8%)(10.8%)

CC 261261

11 33811 338(2.3%)(2.3%)

CC1 475 1 475 11 52711 527(12.8%)(12.8%)

0%0%

5%5%

10%10%

Non-fatalNon-fatalmyocardial myocardial infarctioninfarction

Non-fatal Non-fatal strokestroke

recurrencerecurrence

Vascular Vascular deathdeath

A = Antiplatelet therapyA = Antiplatelet therapy(mean 3 years)(mean 3 years)

C = ControlC = Control

Benefit per 1000Benefit per 1000patients (SE)patients (SE)

2P2P 0.00090.0009 <0.0001<0.0001 0.040.04 0.0020.002

15 (5)15 (5)6 (2)6 (2) 25 (5)25 (5) 7 (4)7 (4)

Any deathAny death

Absolute effects in patients with PREVIOUS STROKE or TIAAbsolute effects in patients with PREVIOUS STROKE or TIA

AA432 432

20 23820 238(2.1%)(2.1%)

AA 1 238 1 238 20 41820 418(6.1%)(6.1%)

AA 1 238 1 238 20 41820 418(6.1%)(6.1%)

CC 1 335 1 335 20 40320 403(6.5%)(6.5%)

CC 522 522

20 22020 220(2.6%)(2.6%)

CC 1 335 1 335 20 40320 403(6.5%)(6.5%)

0%0%

5%5%

10%10%

Non-fatalNon-fatalmyocardial myocardial infarctioninfarction

Non-fatal Non-fatal strokestroke

recurrencerecurrence

Vascular Vascular deathdeath

A = Antiplatelet therapyA = Antiplatelet therapy(mean 3 weeks)(mean 3 weeks)

C = ControlC = Control

Benefit per 1000Benefit per 1000patients (SE)patients (SE)

2P2P 0.0030.003 0.050.05 0.050.05

5 (2)5 (2)4 (2)4 (2) 5 (2)5 (2)

Any deathAny death

Absolute effects in patients with ACUTE STROKE (presumed ISCHAEMIC)Absolute effects in patients with ACUTE STROKE (presumed ISCHAEMIC)

NotNotrecordedrecorded

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration

Effects on VASCULAR EVENTS in patients with Effects on VASCULAR EVENTS in patients with CORONARY ARTERY DISEASECORONARY ARTERY DISEASE

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Unstable anginaUnstable angina 8.0%8.0% 13.3%13.3% 46%±746%±7

Post-CABGPost-CABG 4.8%4.8% 4.7%4.7% 4%±144%±14

Post-PTCAPost-PTCA 2.7%2.7% 5.5%5.5% 53%±1453%±14

Stable angina/CADStable angina/CAD 9.9%9.9% 14.1%14.1% 33%±933%±9

Heart failureHeart failure 6.1%6.1% 10.3%10.3% 41%±5641%±56

All high-risk patientsAll high-risk patients 22%±222%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ CollaborationAntithrombotic Trialists’ Collaboration

Effects on VASCULAR EVENTS in patients Effects on VASCULAR EVENTS in patients at HIGH RISK OF EMBOLISMat HIGH RISK OF EMBOLISM

CategoryCategory APTAPT CTRLCTRL ReductionReduction

Atrial fibrillationAtrial fibrillation 15.3%15.3% 18.4%18.4% 24%±924%±9

Valve diseaseValve disease 18.0%18.0% 18.0%18.0% 0%±190%±19

Valve surgeryValve surgery 7.6%7.6% 13.2%13.2% 45%±1245%±12

All high-risk patientsAll high-risk patients 22%±222%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ CollaborationAntithrombotic Trialists’ Collaboration

Effects on VASCULAR EVENTS in patients with PERIPHERAL Effects on VASCULAR EVENTS in patients with PERIPHERAL ARTERIAL DISEASEARTERIAL DISEASE

CategoryCategory APTAPT CTRLCTRL ReductionReduction

IntermittentIntermittent 6.4%6.4% 7.9%7.9% 23%±923%±9claudicationclaudication

Peripheral graftPeripheral graft 5.4%5.4% 6.5%6.5% 22%±1622%±16

PeripheralPeripheral 2.5%2.5% 3.6%3.6% 29%±3529%±35angioplastyangioplasty

All high-risk patientsAll high-risk patients 22%±222%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration

Effects on VASCULAR EVENTS in patients with Effects on VASCULAR EVENTS in patients with OTHER HIGH-RISK CONDITIONSOTHER HIGH-RISK CONDITIONS

CategoryCategory APTAPT CTRLCTRL ReductionReduction

HaemodialysisHaemodialysis 2.9%2.9% 4.9%4.9% 41%±1641%±16

DiabetesDiabetes 15.7%15.7% 16.7%16.7% 7%±87%±8

Carotid diseaseCarotid disease 10.6%10.6% 12.8%12.8% 19%±2219%±22

All high-risk patientsAll high-risk patients 22%±222%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Risks of serious bleeding with Risks of serious bleeding with antiplatelet therapyantiplatelet therapy

• Intracranial bleeds are increased by Intracranial bleeds are increased by about a quarter, and extracranial bleeds about a quarter, and extracranial bleeds by about a halfby about a half

• Proportional increase in risk of each Proportional increase in risk of each type of bleeding is similar in all high-risk type of bleeding is similar in all high-risk patientspatients

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration Aspirin vs control: effect of doseAspirin vs control: effect of dose

Aspirin doseAspirin dose ASAASA CTRLCTRL ReductionReduction

500-1500mg daily500-1500mg daily 14.5%14.5% 17.2%17.2% 19%±319%±3

160-325mg daily160-325mg daily 11.5%11.5% 14.8%14.8% 26%±326%±3

75-150mg daily75-150mg daily 10.9%10.9% 15.2%15.2% 32%±632%±6

<75 mg daily<75 mg daily 17.3%17.3% 19.4%19.4% 13%±813%±8

Any aspirin doseAny aspirin dose 12.9%12.9% 16.0%16.0% 23%±223%±2

(P<0.0001)(P<0.0001)

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration Higher vs lower doses of aspirinHigher vs lower doses of aspirin

ComparisonComparison Regimen 1Regimen 1 Regimen 2Regimen 2 ReductionReduction

Asp 500-1500 Asp 500-1500 14.1%14.1% 14.5%14.5% 3%±103%±10vsvs 75-325mg daily75-325mg daily

Asp Asp 75 vs75 vs 14.2%14.2% 13.2%13.2% -8%±10-8%±10<75mg daily<75mg daily

Higher dose vsHigher dose vs 14.1%14.1% 13.8%13.8% -3%±7-3%±7lower doselower dose

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration Other antiplatelet drugs vs aspirinOther antiplatelet drugs vs aspirin

ComparisonComparison APTAPT AspAsp Redn Redn P-P-valuevalue

SulphinpyrazoneSulphinpyrazone 16.2%16.2% 13.1%13.1% -18%±19-18%±19 NSNS

TriflusalTriflusal 10.1%10.1% 10.9%10.9% 7%±127%±12 NSNS

RidogrelRidogrel 9.6%9.6% 12.2%12.2% 26%±1826%±18 NSNS

DipyridamoleDipyridamole 16.7%16.7% 16.5%16.5% -2%±9-2%±9 NSNS

IndobufenIndobufen 5.3%5.3% 4.1%4.1% -29%±29-29%±29 NSNS

Ticlopidine Ticlopidine 21.1% 21.1% 23.2%23.2% 12%±712%±7 NSNS

ClopidogrelClopidogrel 10.1%10.1% 11.1%11.1% 10%±410%±4 0.030.03

Other antiplateletOther antiplatelet 1.3%1.3% 1.4%1.4% 6%±456%±45 NSNS

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ Collaboration Antithrombotic Trialists’ Collaboration Aspirin plus another antiplatelet vs aspirinAspirin plus another antiplatelet vs aspirin

ComparisonComparison APTAPT AspAsp Reduction Reduction

Asp plusAsp plus 11.8%11.8% 12.4%12.4% 6%±66%±6dipyridamoledipyridamole

Asp plusAsp plus 13.4%13.4% 17.3%17.3% 26%±2026%±20sulphinpyrazonesulphinpyrazone

Asp+ ticlopidineAsp+ ticlopidine 4.8%4.8% 5.9%5.9% 20%±2420%±24

Asp + iv IIb/IIIa- Asp + iv IIb/IIIa- 9.9%9.9% 11.8%11.8% 19%±419%±4inhibitorinhibitor

1.01.00.50.50.00.0 1.51.5 2.02.0

Antithrombotic Trialists’ CollaborationAntithrombotic Trialists’ CollaborationConclusionsConclusions

• Aspirin (or another antiplatelet drug) prevents serious vascular events in a wide range of high-risk patients, including people with intermittent claudication, stable angina, andif oral anticoagulants are unsuitable atrial fibrillation

• Low-dose aspirin (75-150mg daily) is as effective as higher aspirin doses for long-term use

• Clopidogrel is an effective alternative in patients with a contraindication to aspirin

• In some clinical circumstances, adding a second antiplatelet drug (e.g. clopidogrel or a GPIIb/IIIa antagonist) to aspirin may produce additional benefits