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Clopidogrel plus aspirin or aspirin alone in unstable angina
  1. Shweta Gidwani, Clinical Effectiveness Fellow,
  2. Richard Body, Clinical Research Fellow
  1. Manchester Royal Infirmary

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    Report by Shweta Gidwani, Clinical Effectiveness FellowSearch checked by Richard Body, Clinical Research FellowManchester Royal Infirmary

    A short cut review was carried out to establish whether clopidogrel and aspirin is better than aspirin alone in improving cardiovascular outcome in patients with unstable angina. 676 papers were found using the reported searches, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that clopidogrel together with aspirin gives a better cardiovascular outcome than aspirin alone in patients with unstable angina.

    Clinical scenario

    A 55 year old man, known to have angina, presents to the Emergency Department with new-onset typical ischaemic rest pain that is not relieved by his nitrate spray at home. His ECG shows ST depression in V3-V6. He is haemodynamically stable. You treat him with oxygen, aspirin, nitrates, beta-blockers and heparin, after which he becomes pain free. You also give him clopidogrel 300 mg because you have heard that patients with unstable angina and non ST-elevation MI have a better cardiovascular outcome when treated with a combination of clopidogrel and aspirin versus aspirin alone. You wonder whether there is any evidence to support this.

    Three part question

    In [patients suspected to have unstable angina] is [the use of clopidogrel plus asprin better than asprin alone] at [improving cardiovascular outcome]

    Search strategy

    Medline 1966–11/2005 using the OVID interface: [{unstable angina.mp.OR exp Angina, Unstable/OR acute coronary syndrome.mp. OR non-ST elevation MI.mp. OR non-ST elevation infarction.mp. OR non-ST elevation myocardial infarction.mp OR ACS.mp.} AND {exp Platelet Aggregation Inhibitors/OR exp Ticlopidine/OR exp Adenosine Diphosphate/OR clopidogrel.mp. OR adenosine 5’-diphosphate antagonist.mp. OR plavix.mp. OR Thienopyridines.mp.} AND {aspirin.mp. OR exp ASPIRIN/ OR ASA.mp. OR exp Aminosalicylic Acids/}] LIMIT to Human AND English

    The Cochrane Library Issue 4 2005: [Angina, Unstable {MeSH explode all trees} AND clopidogrel {All fields} OR Platelet Aggregation Inhibitors/TU {MeSH this term only, therapeutic use} OR adenosine NEXT diphosphate {All fields} OR Ticlopidine {MeSH explode all trees} AND Aspirin {MeSH explode all trees} OR Aminosalicylic Acids/TU {MeSH explode all trees, therapeutic use}] (47 papers)

    Embase 1980–2005 week 47: [{exp unstable angina pectoris/OR unstable angina.mp. OR acute coronary syndrome.mp. OR non-ST elevation MI.mp. OR non-ST elevation infarction.mp. OR non-ST elevation myocardial infarction.mp OR ACS.mp. OR non-STEMI.mp.} AND {platelet aggregation inhibitor$.mp. OR exp Ticlopidine/ OR exp Adenosine Diphosphate/ OR adenosine 5’-diphosphate antagonist.mp. OR plavix.mp. OR exp clopidogrel/ OR Thienopyridines.mp} AND { aspirin.mp. OR exp Acetylsalicylic Acid/ OR exp Aminosalicylic Acid Derivative/}] LIMIT to Human AND English and Clinical Queries “treatment – high specificity” (190 papers)

    Search outcome

    676/47 /190 papers were identified. The CURE trial is the only RCT relevant to the question. It is also the only article in a systematic review which looked at the clinical and cost effectiveness of using clopidogrel in combination with aspirin in ACS.

    Comments

    To date only one randomised controlled trial has been conducted to compare the effects of clopidogrel and aspirin versus aspirin alone in non-ST elevation acute coronary syndromes. This large trial, which included 12,562 patients, yielded promising results. It appears that clopidogrel decreases the 12 month cardiovascular event rate. Interestingly, there was a significant reduction in the incidence of the second primary outcome by 24 hours after starting therapy and there was evidence of separation of the cumulative hazard rate curves within as early as a few hours. This has significant implications for Emergency Medicine, suggesting that clopidogrel loading should commence as soon as possible following presentation.

    Analysis of the data from the CURE trial reveals that the number needed to treat (NNT) with clopidogrel to prevent the first primary outcome is 47. The number needed to harm (NNH) with clopdigrel to cause one major haemorrhage is 99. This means that, for every 100 patients with non-ST elevation acute coronary syndrome treated for 3–12 months, clopidogrel will prevent two cardiovascular deaths, MI’s or strokes while causing one major haemorrhage.

    Subgroup analysis of the CURE trial demonstrates that patients who at high clinical risk (as judged by the TIMI risk score) gain particular benefit from clopidogrel therapy, although lower risk patients with non-ST elevation acute coronary syndromes may still stand to benefit. In low-risk patients, 16 patients would need to be treated (NNT) for 3–12 months to prevent one primary outcome, while treating 143 patients for the same period (NNH) would lead to one major haemorrhage. For intermediate-risk patients, NNT is 63 while NNH is 83. For high-risk patients, NNT is 21 while NNH is 100.

    As such, if 1,000 patients in each category were treated, 16 low-risk patients would be saved from a primary outcome, while 7 would have a major haemorrhage. For intermediate-risk patients, 16 would be saved while 12 would have a major haemorrhage. For high-risk patients, 48 would be saved while 10 would have a major haemorrhage.

    While the benefit of clopidogrel is maintained in all risk groups, the effect was most profound in the high-risk group. A careful risk-benefit consideration should be made before prescribing the drug for prolonged periods in low-risk patients.

    CLINICAL BOTTOM LINE

    Clopidogrel should be given to patients with non-ST elevation acute coronary syndromes in the Emergency Department.

    Table 3

    Report by Shweta Gidwani, Clinical Effectiveness FellowSearch checked by Richard Body, Clinical Research FellowManchester Royal Infirmary

    References

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