Question: What is the effectiveness of adding aspirin versus aspirin and clopidogrel to improve outcome in…
9
Grading: 1++ High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
Reference number 5183
Bhatt DL;Fox KAA;Hacke W;Berger PB;Black HR;Boden WE;Cacoub P;Cohen EA;Creager MA;Easton JD;Flather MD;Haffner SM;Hamm CW;Hankey GJ;Johnston SC;Mak KH;Mas JL;Montalescot G;Pearson TA;Steg PG;Steinhubl SR;Weber MA;Brennan DM;Fabry-Ribaudo L;Booth J;Topol E
Clopidogrel and aspirin versus aspirin alone for the prevention of Atherothrombotic events
2006354New England Journal of Medicine pgs
Study Type: Randomised Controlled Trial
Patient Characteristics Inclusion criteria: Aged 45 years or older and one of the following conditions: Multiple atherothrombotic risk factors such as diabetes, diabetic nephropathy, ankle-brachial < 0.9, asymptomatic carotid stenosis ≥ 70% of luminal diameter, ≥ 1 carotid.
Intervention Clopidogrel 75 mg once daily plus aspirin 75 mg once daily: 7802 patients.
Comparisons Placebo once daily plus aspirin 75 mg once daily: 7801 patients.
Study Length Median follow-up 28 months.
Outcomes Primary: Composite of myocardial infarction, stroke (of any cause), or death from cardiovascular causes (including haemorrhage). Secondary: Composite of myocardial infarction, stroke (of any cause), death from cardiovascular causes, hospitalisation.
Funding Sanofi-Aventis, Bristol-Myers Squibb.
Effect Primary: First occurrence of composite of myocardial infarction, stroke (from any cause) or death from cardiovascular causes: 534/7802 (6.8%) clopidogrel plus aspirin versus 573/7801 (7.3%) placebo plus aspirin, RR of 0.93 (95% CI 0.83 to 1.05, P = 0.22). Secondary: Composite of myocardial infarction, stroke, death from cardiovascular causes, hospitalisation for unstable angina, transient ischaemic attack, or revascularisation: 1301/7802 (16.7%) clopidogrel plus aspirin versus 1395/7801 (17.9%) placebo plus aspirin, RR of 0.92 (95% CI 0.82 to 0.98, P = 0.04). Death from any cause: 371/7802 (4.8%) clopidogrel plus aspirin versus 374/7801 (4.8%) placebo plus aspirin, RR of 0.99 (95% CI 0.86 to 1.14, P = 0.90). Death from cardiovascular causes: 238/7802 (3.1%) clopidogrel plus aspirin versus 229/7801 (2.9%) placebo plus aspirin, RR of 1.04 (95% CI 0.87 to 1.25, P = 0.68). Nonfatal MI: 147/7802 (1.9%) clopidogrel plus aspirin versus 1.59/7801 (2.0%) placebo plus aspirin, RR of 0.92 (95% CI 0.74 to 1.16, P = 0.48). Nonfatal ischaemic stroke: 132/7802 (1.7%) clopidogrel plus aspirin versus 160/7801 (2.1%) placebo plus aspirin, RR of 0.82 (95% CI 0.66 to 1.04, P = 0.10). Nonfatal stroke: 149/7802 (1.9%) clopidogrel plus aspirin versus 185/7801 (2.4%) placebo plus aspirin, RR of 0.80 (95% CI 0.65 to 0.997, P = 0.05). Hospitalisation for unstable angina, transient ischaemic attack or revascular-isation: 886/7802 (11.1%) clopidogrel plus aspirin versus 957/7801 (12.3%) placebo plus aspirin, RR of 0.90 (95% CI 0.82 to 0.98, P = 0.02). Subgroup analysis: Documented CV disease ‘symptomatic’: Enrolled with multiple vascular risk factors ‘asymptomatic’ (some of whom had a reported history of cardiovascular events: 10.4% prior MI, 5.8% prior stroke, 5.2% prior TIA, 7.7% had undergone PCI and 9.8% prior CABG although did not meet the criteria for established cardiovascular disease as defined in the study). Primary endpoint: Among 3284 asymptomatic patients, there was a 20% relative increase in primary events with clopidogrel plus aspirin compared with placebo plus aspirin (6.6% versus 5.5% respectively, P = 0.20). Among 12153 symptomatic patients there was a marginal significant reduction in the primary endpoint with clopidogrel plus aspirin compared with placebo plus aspirin (6.9% versus 7.9% respectively, P = 0.046). Death from all causes and cardiovascular cause: Among 3284 asymptomatic patients, there was a significant increase in death from any cause with clopidogrel plus aspirin compared with placebo plus aspirin (5.4% versus 3.8% respectively, P = 0.04), as well as a significant increase in the rate of death from cardiovascular disease with clopidogrel plus aspirin compared with placebo plus aspirin (3.9% versus 2.2% respectively, P = 0.01). In contrast, the addition of clopidogrel had no significant effect on death from cardiovascular causes in the symptomatic subgroup. Safety end points: Severe bleeding: 130/7802 (1.7%) clopidogrel plus aspirin versus 104/7801 (1.3%) placebo plus aspirin, RR of 1.25 (95% CI 0.97 to 1.61, P = 0.09). Fatal bleeding: 26/7802 (0.3%) clopidogrel plus aspirin versus 17/7801 (0.2%) placebo plus aspirin, RR of 1.53 (95% CI 0.83 to 2.82, P = 0.17). Primary intracranial haemorrhage: 26/7802 (0.3%) clopidogrel plus aspirin versus 27/7801 (0.3%) placebo plus aspirin, RR of 0.96 (95% CI 0.56 to 1.65, P = 0.89). Moderate bleeding: 164/7802 (2.1%) clopidogrel plus aspirin versus 101/7801 (1.3%) placebo plus aspirin, RR of 1.62 (95% CI 1.27 to 2.1, P < 0.001). Subgroup analysis Severe bleeding: Asymptomatic patients: Clopidogrel plus aspirin: 2%, Placebo plus aspirin 1.2% (P = 0.07). Symptomatic patients: Clopidogrel plus aspirin: 1.6%, Placebo plus aspirin 1.4% (P = 0.39). Moderate bleeding: Asymptomatic patients: Clopidogrel plus aspirin: 2.2%, Placebo plus aspirin 1.4% (P = 0.08). Symptomatic patients: Clopidogrel plus aspirin: 2.1% Placebo plus aspirin 1.3% (P < 0.001).
Reference number 1822
Yusuf S;Zhao F;Mehta SR;Chrolavicius S;Tognoni G;Fox KK;
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment
2001345New England Journal of Medicinepgs 494 502
Study Type: Randomised Controlled Trial
Patient Characteristics Inclusion criteria: Hospitalised within 24 h of onset of symptoms of acute coronary syndromes without ST elevation. Exclusion criteria: contraindications to antiplatelet / anticoagulant therapy, high risk for bleeding or heart failure, taking oral coagulants, revascularization in previous 3 months, received intravenous glycoprotein IIb / IIIa receptor inhibitors in previous 3
Intervention Clopidogrel 300 mg immediately followed by 75 mg daily plus aspirin. 6259 patients.
Comparisons Placebo plus aspirin. 6303 patients.
Study Length 3 to 12 months, mean duration of treatment 9 months, no patient < 3 months.
Outcomes Primary: Death from CV causes non fatal MI or stroke. Death from CV causes, nonfatal MI, stroke or refractory ischemia. Reinfarction. Secondary: Revascularization.
Funding Not listed.
Effect Death from CV causes, non fatal MI or stroke: clopidogrel 582/6259 (9.3%) versus placebo 719/6303 (11.4%), RR 0.80 (95%CI 0.72 to 0.90, P < 0.001). Death from CV causes, nonfatal MI, stroke or refractory ischemia: clopidogrel 1035/6259 (16.5%) versus placebo 1187/6303 (18.8%), RR 0.86 (95%CI 0.79 to 0.94, P < 0.001). Reinfarction: clopidogrel 85/6259 (1.4%) versus placebo 126/6303 (2.0%), RR 0.69 (95%CI 0.52 to 0.90, P < 0.007). Slightly fewer patients in the clopidogrel group underwent revascularization: 36% versus placebo 36.5%. Major bleeding was significantly higher in clopidogrel group (3.7%) versus placebo (2.7%), RR 1.38 95% CI 1.13 to 1.67, P = 0.001. but there were not significantly more patients with episodes of life-threatening bleeding or hemorrhagic strokes (Clopidogrel 2.2% versus placebo 1.8%, RR 1.21, 95%CI 0.95 to 1.56).
Grading: 1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
Reference number 2278
Sabatine MS;Cannon CP;Gibson CM;L¾pez-Send¾n JL;Montalescot G;Theroux P;Claeys MJ;Cools F;Hill KA;Skene AM;McCabe CH;Braunwald E;
Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation
2005352New England Journal of Medicinepgs 1179 1189
Study Type: Randomised Controlled Trial
Patient Characteristics Inclusion criteria: enrolled within 12 h after onset ST-elevation MI, aged 18 to 75 years, mean 57 years, men and women (20%), scheduled to receive a fibrinolytic agent, an anticoagulant (if a fibrin-specific lytic agent was prescribed), aspirin and undergo angiography 48 to 192 hours after the start of study medication. Exclusion criteria: treatment with clopidogrel within 7 days before enrolment or planned treatment with Clopidogrel or a glycoprotein 11b/11a inhibitor before angiography, contraindications to fibrinolytic therapy, planned angiography within 48 h in the absence of a new clinical indication, cardiac shock, prior CABG, weight 67 kg or less and receipt of more than 4000-U bolus of unfractionated heparin, weight more than 67 kg and receipt of more than 5000-U bolus of unfractionated heparin, or receipt of more than standard dose of low-molecular-weight heparin.
Intervention Clopidogrel 300 mg loading dose, followed by 75 mg once daily. Aspirin. Fibrinolytic agent: 1752 patients.
Comparisons Clopidogrel placebo. Aspirin. Fibrinolytic agent: 1739 patients.
Study Length 30 days.
Outcomes Primary: Composite occluded infarct related artery on angiography, death or recurrent MI before angiography. Composite death from CV causes, recurrent MI, recurrent ischemia requiring revascularisation at 30 days.
Funding Sanofi-Aventis, Bristol-Myers Squibb.
Effect Before angiography: Rates of the primary efficacy endpoint 21.7% in placebo group and 15.0% in clopidogrel group: 36% odds reduction with clopidogrel therapy (95% CI 24 to 47%, P < 0.001). At 30 days: Primary endpoint: clopidogrel therapy odds reduction = 20%, P < 0.03. There was no significant difference in major or minor bleeding between the two treatment

From: Appendix C, Clinical Evidence Extractions

Cover of Post Myocardial Infarction
Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet].
NICE Clinical Guidelines, No. 48.
National Collaborating Centre for Primary Care (UK).
Copyright © 2007, National Collaborating Centre for Primary Care.

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