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RR 0.77 (0.69-0.86) Low cardiovascular risk population ◊ 27 MI per 1000 § 6 fewer MI per 1000 (from 8 fewer to 4 fewer) Moderate cardiovascular risk population ◊ 83 MI per 1000 § 19 fewer MI per 1000 (from 26 fewer to 12 fewer) High cardiovascular risk population ◊ 136 per 1000 § 31 fewer per 1000 (from 42 fewer to 19 fewer)

RR 0.95 (0.85-1.06) Low cardiovascular risk population ◊ 23 strokes per 1000 § No significant difference 1 fewer stroke per 1000 (from 3 fewer to 1 more) Moderate cardiovascular risk population ◊ 65 strokes per 1000 § No significant difference 3 fewer strokes per 1000 (from 10 fewer to 4 more) High cardiovascular risk population ◊ 108 strokes per 1000 § No significant difference 5 fewer strokes per 1000 (from 16 fewer to 8 more) Major extracranial bleed •• 95,000 (3), 3.8 to 10 years ⊕⊕⊕⊕

RR 1.54 (1.30-1.82) Low cardiovascular risk population ������ 8 bleeds per 1000 § 4 more bleeds per 1000 (from 2 more to 7 more) Moderate cardiovascular risk population ������ 24 bleeds per 1000 § 16 more bleeds per 1000 (from 7 more to 20 more) High cardiovascular risk population ������ 40 bleeds per 1000 § 22 more bleeds per 1000 (from 12 more to 33 more)

HR 0.88 (0.80-0.98) Low cancer risk population 10 cancers per 1000** 1 fewer cancer per 1000 (from 2 fewer to 0 fewer) Moderate risk cancer risk population 50 cancers per 1000** 6 fewer cancers per 1000 (from 10 fewer to 1 fewer) High cancer risk population 100 cancers per 1000** 12 fewer cancers per 1000 (from 20 fewer to 2 fewer)

HR 0.88 (0.80-0.98) Low cancer risk population 10 cancers per 1000** 1 fewer cancer per 1000 (from 2 fewer to 0 fewer) Moderate risk cancer risk population 50 cancers per 1000** 6 fewer cancers per 1000 (from 10 fewer to 1 fewer) High cancer risk population 100 cancers per 1000** 12 fewer cancers per 1000 (from 20 fewer to 2 fewer) GRADE: Grades of Recommendations, Assessment, Development, and Evaluation; RR: risk ratio. * This systematic review reports total mortality and includes the most recent trials. Other meta-analyses that utilize individual patient data report relative risk estimates for vascular mortality (RR 0.97, 95% CI, 0.87-1.09), cancer mortality (RR 0.66, 95% CI, 0.50-0.87), and fatal intracranial bleeds (RR 1.73, 95% CI, 0.96-3.13). The risk of a fatal bleed (including extracranial and intracranial) was low (0.3 percent with aspirin and 0.2 percent with control). • The 95% CI for the absolute effect includes no benefit of aspirin. We did not rate down for risk of bias, but this was a borderline decision. Three of the trials did not blind patients, caregivers, or outcome adjudicator. Sensitivity analyses in meta-analysis by Raju et al did not show evidence of risk of bias. Δ Control group risk estimate for 10-year mortality apply to a 60-year-old male and come from population-based data from Statistics Norway. Mortality increases with age (eg, 50-year-old male; 50 deaths per 1000 in 10 years) and is lower in females than in males (eg, 3 percent in women aged 50 years versus 5 percent in men aged 50 years). ◊ Risk groups correspond to low risk (5 percent), medium risk (15 percent), and high risk (25 percent) according to the Framingham score (or other risk tool) to estimate 10-year risk. § Control group risk estimates in low, moderate, and high cardiovascular risk groups are based on the Framingham score. We have used data from an individual patient data meta-analysis to provide estimated risks for patient-important outcomes not covered by the Framingham risk score. We have also adjusted for 20 percent overestimation associated with Framingham risk score. ¥ Of the strokes in the trials, 89 of 682 (13 percent) without aspirin were hemorrhagic and 116 of 655 (18 percent) with aspirin were hemorrhagic. ‡ In the individual patient data meta-analysis risk for future major bleeding correlated with risk for future cardiovascular events. Therefore, we make the assumption that a patient at low, medium, or high risk of future cardiovascular events (determined by Framingham score) will be at low, medium, or high risk of future major bleeding events, respectively. † The 95% confidence interval for absolute effect borders no benefit of aspirin. ** Moderate control group risk estimate derived from meta-analysis by Rothwell et al. •• Major extracranial bleeds are usually from the gastrointestinal tract and are most often defined in those requiring transfusion or resulting in death.

GRADE: Grades of Recommendations, Assessment, Development, and Evaluation; RR: risk ratio. * This systematic review reports total mortality and includes the most recent trials. Other meta-analyses that utilize individual patient data report relative risk estimates for vascular mortality (RR 0.97, 95% CI, 0.87-1.09), cancer mortality (RR 0.66, 95% CI, 0.50-0.87), and fatal intracranial bleeds (RR 1.73, 95% CI, 0.96-3.13). The risk of a fatal bleed (including extracranial and intracranial) was low (0.3 percent with aspirin and 0.2 percent with control). • The 95% CI for the absolute effect includes no benefit of aspirin. We did not rate down for risk of bias, but this was a borderline decision. Three of the trials did not blind patients, caregivers, or outcome adjudicator. Sensitivity analyses in meta-analysis by Raju et al did not show evidence of risk of bias. Δ Control group risk estimate for 10-year mortality apply to a 60-year-old male and come from population-based data from Statistics Norway. Mortality increases with age (eg, 50-year-old male; 50 deaths per 1000 in 10 years) and is lower in females than in males (eg, 3 percent in women aged 50 years versus 5 percent in men aged 50 years). ◊ Risk groups correspond to low risk (5 percent), medium risk (15 percent), and high risk (25 percent) according to the Framingham score (or other risk tool) to estimate 10-year risk. § Control group risk estimates in low, moderate, and high cardiovascular risk groups are based on the Framingham score. We have used data from an individual patient data meta-analysis to provide estimated risks for patient-important outcomes not covered by the Framingham risk score. We have also adjusted for 20 percent overestimation associated with Framingham risk score. ¥ Of the strokes in the trials, 89 of 682 (13 percent) without aspirin were hemorrhagic and 116 of 655 (18 percent) with aspirin were hemorrhagic. ‡ In the individual patient data meta-analysis risk for future major bleeding correlated with risk for future cardiovascular events. Therefore, we make the assumption that a patient at low, medium, or high risk of future cardiovascular events (determined by Framingham score) will be at low, medium, or high risk of future major bleeding events, respectively. † The 95% confidence interval for absolute effect borders no benefit of aspirin. ** Moderate control group risk estimate derived from meta-analysis by Rothwell et al. •• Major extracranial bleeds are usually from the gastrointestinal tract and are most often defined in those requiring transfusion or resulting in death. References:

GRADE: Grades of Recommendations, Assessment, Development, and Evaluation; RR: risk ratio. * This systematic review reports total mortality and includes the most recent trials. Other meta-analyses that utilize individual patient data report relative risk estimates for vascular mortality (RR 0.97, 95% CI, 0.87-1.09), cancer mortality (RR 0.66, 95% CI, 0.50-0.87), and fatal intracranial bleeds (RR 1.73, 95% CI, 0.96-3.13). The risk of a fatal bleed (including extracranial and intracranial) was low (0.3 percent with aspirin and 0.2 percent with control). • The 95% CI for the absolute effect includes no benefit of aspirin. We did not rate down for risk of bias, but this was a borderline decision. Three of the trials did not blind patients, caregivers, or outcome adjudicator. Sensitivity analyses in meta-analysis by Raju et al did not show evidence of risk of bias. Δ Control group risk estimate for 10-year mortality apply to a 60-year-old male and come from population-based data from Statistics Norway. Mortality increases with age (eg, 50-year-old male; 50 deaths per 1000 in 10 years) and is lower in females than in males (eg, 3 percent in women aged 50 years versus 5 percent in men aged 50 years). ◊ Risk groups correspond to low risk (5 percent), medium risk (15 percent), and high risk (25 percent) according to the Framingham score (or other risk tool) to estimate 10-year risk. § Control group risk estimates in low, moderate, and high cardiovascular risk groups are based on the Framingham score. We have used data from an individual patient data meta-analysis to provide estimated risks for patient-important outcomes not covered by the Framingham risk score. We have also adjusted for 20 percent overestimation associated with Framingham risk score. ¥ Of the strokes in the trials, 89 of 682 (13 percent) without aspirin were hemorrhagic and 116 of 655 (18 percent) with aspirin were hemorrhagic. ‡ In the individual patient data meta-analysis risk for future major bleeding correlated with risk for future cardiovascular events. Therefore, we make the assumption that a patient at low, medium, or high risk of future cardiovascular events (determined by Framingham score) will be at low, medium, or high risk of future major bleeding events, respectively. † The 95% confidence interval for absolute effect borders no benefit of aspirin. ** Moderate control group risk estimate derived from meta-analysis by Rothwell et al. •• Major extracranial bleeds are usually from the gastrointestinal tract and are most often defined in those requiring transfusion or resulting in death. References: Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: Meta-analysis of randomized controllwed trials. Arch Intern Med 2012; 172:209.

GRADE: Grades of Recommendations, Assessment, Development, and Evaluation; RR: risk ratio. * This systematic review reports total mortality and includes the most recent trials. Other meta-analyses that utilize individual patient data report relative risk estimates for vascular mortality (RR 0.97, 95% CI, 0.87-1.09), cancer mortality (RR 0.66, 95% CI, 0.50-0.87), and fatal intracranial bleeds (RR 1.73, 95% CI, 0.96-3.13). The risk of a fatal bleed (including extracranial and intracranial) was low (0.3 percent with aspirin and 0.2 percent with control). • The 95% CI for the absolute effect includes no benefit of aspirin. We did not rate down for risk of bias, but this was a borderline decision. Three of the trials did not blind patients, caregivers, or outcome adjudicator. Sensitivity analyses in meta-analysis by Raju et al did not show evidence of risk of bias. Δ Control group risk estimate for 10-year mortality apply to a 60-year-old male and come from population-based data from Statistics Norway. Mortality increases with age (eg, 50-year-old male; 50 deaths per 1000 in 10 years) and is lower in females than in males (eg, 3 percent in women aged 50 years versus 5 percent in men aged 50 years). ◊ Risk groups correspond to low risk (5 percent), medium risk (15 percent), and high risk (25 percent) according to the Framingham score (or other risk tool) to estimate 10-year risk. § Control group risk estimates in low, moderate, and high cardiovascular risk groups are based on the Framingham score. We have used data from an individual patient data meta-analysis to provide estimated risks for patient-important outcomes not covered by the Framingham risk score. We have also adjusted for 20 percent overestimation associated with Framingham risk score. ¥ Of the strokes in the trials, 89 of 682 (13 percent) without aspirin were hemorrhagic and 116 of 655 (18 percent) with aspirin were hemorrhagic. ‡ In the individual patient data meta-analysis risk for future major bleeding correlated with risk for future cardiovascular events. Therefore, we make the assumption that a patient at low, medium, or high risk of future cardiovascular events (determined by Framingham score) will be at low, medium, or high risk of future major bleeding events, respectively. † The 95% confidence interval for absolute effect borders no benefit of aspirin. ** Moderate control group risk estimate derived from meta-analysis by Rothwell et al. •• Major extracranial bleeds are usually from the gastrointestinal tract and are most often defined in those requiring transfusion or resulting in death. References: Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: Meta-analysis of randomized controllwed trials. Arch Intern Med 2012; 172:209. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849.

Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: Meta-analysis of randomized controllwed trials. Arch Intern Med 2012; 172:209. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849. Raju N, Sobieraj-Teague M, Hirsh J, et al. Effect of Aspirin on Cardiovascular and All-Cause Mortality in Primary Prevention of Cardiovascular Disease: A Meta-analysis of Randomized Controlled Trials. Am J Med 2011; 124:621. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012; 379:1602. Modified with permission from: the American College of Chest Physicians. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e637S. Copyright © 2012.