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The Role of Clopidogrel in ST-segment Elevation Acute Coronary Syndrome Appears "Clear". The dose, however, is "Unclear".

Sarah A. Spinler, Pharm.D., FCCP
May, 2005

Previous studies have documented the value of adding clopidogrel to aspirin therapy in patients presenting with non-ST-segment elevation acute coronary syndrome (NSTE ACS) and in patients undergoing percutaneous coronary intervention.1,2 New data regarding adding clopidogrel to aspirin and fibrinolytic therapy in patients with ST segment elevation (STE) ACS were presented at the March 2004 meeting of the American College of Cardiology in Orlando, Florida. In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) - Thrombolysis in Myocardial Infarction (TIMI) 28 trial, 3491 patients presenting with STE ACS presenting within 12 hours of symptom onset were randomized to receive either clopidogrel (administered as a 300 mg loading dose followed by 75 mg once daily) or placebo in addition to standard therapy which included aspirin (administered as a 150-325mg dose on the first day followed by 75-162mg once daily thereafter), anticoagulant (either unfractionated heparin or low-molecular-weight heparin) and fibrinolytic therapy.3 The primary end point of the study was a composite of TIMI flow (grade 0 or 1 indicating no or slow coronary artery blood flow) in the infarct associated artery determined at coronary angiography performed after 48 hrs (median time 84 hrs), all-cause mortality before angiography or reinfarction occurring before angiography. 40% of the patients had anterior wall myocardial infarctions. 46% were treated with unfractionated heparin. 30% were treated with low-molecular-weight heparin. 48% of patients were treated with tenecteplase, 12% with reteplase and 31% with streptokinase. The primary end point was reduced by 64% in clopidogrel-treated patients (15.0% versus 21.7%, P<0.001) with an absolute benefit of 6.7%. Optimal coronary artery flow (TIMI grade 3) was achieved by 67.8% of clopidogrel-treated patients compared to 60.8% of placebo-treated patients which is a 36% increase (P<0.001). Clopidogrel's benefit appeared to be in improving the efficacy of fibrinolytic as a decrease in coronary artery thrombus was observed at angiography. At 30 days, the cumulative risk of death from cardiovascular causes, recurrent MI or recurrent ischemic leading to urgent revascularization was reduced by 20% as well (P=0.03). At the time of initial angiography, 57.2% of clopidogrel-treated patients and 56.6% of placebo-treated patients underwent percutaneous coronary intervention (PCI) and received open label clopidogrel so this benefit may be underestimated. The rate of major bleeding occurring through the day following angiography was low and not different between groups (1.3% versus 1.1%, P=0.64). Therefore, improvement in artery flow and clinical events was seen without and increased risk of major hemorrhage.

The angiographic benefits of clopidogrel were complimented by the presentation of the results of the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) at the same meeting.4,5 In a 2 X 2 factorial design, 45849 patients with suspected MI (< 24 hours from symptom onset) and ST segment changes or new left bundle branch block (LBBB) were randomized to one of 4 treatment groups:

  1. clopidogrel 75 mg daily and metoprolol (50 mg orally every 6 hours)
  2. clopidogrel and placebo
  3. placebo and metoprolol
  4. placebo and placebo

Either in addition to usual medical therapy which included aspirin, anticoagulant and fibrinolytics (in patients presenting with STE ACS within 12 hours). Unlike CLARITY, COMMIT did not utilize a clopidogrel loading dose. Most patients had STE ACS or new LBBB (93%) and almost 50% were treated with fibrinolytics. The primary end point, 28-day death, non-fatal infarction or stroke, was reduced by 9% with clopidogrel compared to placebo (9.3% versus 10.1%, P=0.02). Mortality was reduced by 7% (7.7% versus 8.1%, P=0.03) and reinfarction by 13% (2.1% versus 2.4%, P=0.02). The rate of death, reinfarction or stroke was also significantly reduced in the subgroup of patients receiving fibrinolytics (8.8% versus 9.9%, no P value given). In hospital major bleeding (0.5%) and hemorrhagic stroke rates (0.2%) were low and not different between groups. However, "very few" patients underwent revascularization in COMMIT which may underestimate the bleeding risk. Complete publication of the results of this landmark trial are eagerly awaited.

Overall, traditional primary PCI standards of care and both CLARITY and COMMIT support early administration of clopidogrel to patients with STE ACS who are either:

  1. undergoing primary PCI
  2. receiving fibrinolysis
  3. not actively bleeding but not eligible for fibrinolysis

Patients undergoing primary PCI should receive a clopidogrel dose of 300 mg. The dose for patients receiving fibrinolysis is not firm as CLARITY used 300 mg and COMMIT used 75 mg. Perhaps in patients at higher risk of bleeding per physician judgment should receive 75 mg while those at low risk of bleeding should receive 300 mg but there are no firm recommendations at this time.

References

  1. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.

  2. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.

  3. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-1189.

  4. Collins R. March 9, 2005. American College of Cardiology meeting. Orlando, FL available from URL: http://www.clinicaltrialresults.org. Accessed 04/27/05.

  5. Anonymous. COMMIT trial confirms clopidogrel benefit in MI. Available from URL: http://www.theheart.org/viewArticle.do?primaryKey=401761&from=/searchLayout.do.
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Friday, April 28, 2017