CLARITY - TIMI (clopidogrel as adjunctive reperfusion therapy - thrombolysis in myocardial infarction)

• Clopidogrel as Adjunctive Reperfusion Therapy — Thrombolysis in Myocardial Infarction 28 study (CLARITY TIMI 28)
  • this study provides evidence that the that adding clopidogrel to standard thrombolytic therapy and aspirin soon after an ST-segment elevation myocardial infarction (STEMI) improves the patency of infarct-related arteries and reduces ischaemic complications, without increasing the risk of major bleeding.
  • a double-blind randomised controlled trial involving 3,491 patients (mean age 57 years, 80% male) who presented within 12 hours (median 2.7 hours) after the onset of a STEMI
  • patients were randomised to receive clopidogrel 300mg loading dose followed by 75mg daily) or placebo, both in addition to asprin 150–325mg loading dose, 75–162mg daily thereafter) and thrombolytic therapy with a fibrinolytic agent (selected by the physician), and, where appropriate, heparin for 48 hours. Study medication was given for a maximum of eight days (median 3.5 days) up to and including the day of coronary angiography
    • if a patient underwent coronary artery stenting then open-label clopidogrel was recommended after angiography (300mg loading dose, 75mg daily thereafter)
  • the composite primary endpoint used in the study was occluded infarct-related artery on angiography [TIMI flow grade 0 or 1], death, or recurrent MI before angiography)
    • the rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001) (NNT=15, P<0.001)
    • by 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03) (NNT=40, P=0.03)
  • rates of major bleeding and intracranial hemorrhage were similar in the two groups
• various study limitations have been noted (2):
  • patients in the study were at relatively low risk (30-day mortality <5%) and all were less than 75 years old;
  • the study excluded many people at increased risk of bleeding and those who had previously undergone coronary artery bypass graft surgery (CABG);
  • the effects of clopidogrel in patients undergoing an early invasive strategy, or who underwent CABG subsequently, were not addressed;
  • although the addition of open-label clopidogrel before and following coronary artery stenting (57% in both groups) was appropriate,the time from initial dosing to carrying out the procedure in the placebo group may have been insufficient to obtain adequate clopidogrel plasma levels
• however despite these limitations, the CLARITY TIMI 28 provides good angiographic evidence to support the short-term use of clopidogrel (up to 8 days) in patients receiving fibrinolytics and aspirin following a STEMI

Reference:

1. 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;352:1179–89.
2. Lange RA, Hills LD. Concurrent antiplatelet and fibrinolytic therapy. N Engl J Med 2005;352:1248–1250