Clopidogrel in ST-elevation myocardial infarction
Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Corresponding author. E-mail address: msabatine{at}partners.org
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Abstract |
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Platelet adhesion, activation, and aggregation are central to the pathophysiology of the acute coronary syndromes (ACS). Clopidogrel, an oral thienopyridine derivative, is a platelet adenosine diphosphate (ADP)-receptor antagonist capable of inhibiting platelet activation. The benefits of clopidogrel in patients with stable coronary artery disease undergoing elective percutaneous coronary interventions (PCI) and in patients presenting with non-ST-elevation ACS are well established. This article will review the results of recent clinical trials in which the utility of clopidogrel in patients with ST-elevation myocardial infarction was evaluated.
Key Words: Clopidogrel • Fibrinolysis • ST-elevation myocardial infarction
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Introduction |
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TopAbstractIntroductionClopidogrel as Adjunctive...Clopidogrel and Metoprolol in...DiscussionAcknowledgementsReferences |
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Globally, pharmacologic therapy remains the primary means of achieving reperfusion in ST-elevation myocardial infarction (STEMI). Standard thrombolytic regimens consist of a fibrinolytic, aspirin, and, depending on the type of fibrinolytic, heparin. Despite the impressive clinical benefit of this approach,1,2 it remained concerning that approximately one quarter of patients so treated failed to achieve adequate reperfusion or suffered reocclusion of the infarct-related artery,3–5 both of which are associated with increased morbidity and mortality.5,6
Aspirin blocks platelet activation by inhibiting the enzyme cyclo-oxygenase and thereby reducing the generation of thromboxane A2,7 and has been shown to reduce reocclusion, reinfarction, and vascular mortality.1 Clopidogrel is part of a different class of oral antiplatelet agents that block the P2Y12 component of the adenosine diphosphate receptor and thus inhibit platelet activation and aggregation.8 Clopidogrel reduces the risk of death and cardiovascular complications in patients with symptomatic atherosclerotic disease, in the setting of percutaneous coronary intervention (PCI), and in patients with unstable angina or non-STEMI.9–11 An unresolved question was whether clopidogrel added to aspirin would be beneficial in patients with STEMI receiving pharmacologic reperfusion. Two recent randomized controlled trials have now answered this question.
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Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28 |
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Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 enrolled 3491 patients of age 18–75 years with STEMI within 12 h of symptom onset in 23 countries, predominantly Western Europe and North America.12 Patients received a fibrinolytic (69% received a fibrin-specific agent) and aspirin, and 80% received heparin (which was mandated in patients receiving a fibrin-specific lytic, but not required in those receiving a non-fibrin-specific lytic). In accordance with the ACC/AHA guidelines, the recommended unfractionated heparin dosing was 60 U/kg IV bolus (maximum 4000 U) followed by an infusion at 12 U/kg/h (maximum 1000 U/h). Patients were randomized to receive either clopidogrel (300 mg loading dose, then 75 mg once daily) or placebo in a double-blind manner up to and including the day of coronary angiography, which was to be performed per protocol during the index hospitalization 48–192 h after the start of study medication. The primary efficacy endpoint for the trial was the composite of an occluded infarct-related artery (which was defined as TIMI Flow Grade 0 or 1) on the coronary angiogram, or death or recurrent myocardial infarction by the start of coronary angiography, the latter two of which served as surrogates for failed reperfusion or reocclusion of the infarct-related artery.
Treatment with clopidogrel resulted in a high statistically significant 36% reduction in the odds of the primary endpoint (from 21.7% to 15.0%, P<0.001, Figure 1). Among the individual components of the primary endpoint, clopidogrel was most effective in reducing the rate of an occluded infarct-related artery (from 18.4% to 11.7%) and reducing the rate of recurrent myocardial infarction (from 3.6% to 2.5%), but had no significant effect on all-cause mortality (2.2 vs. 2.6%) by the time of angiography (at a median of 3.5 days). The benefit of clopidogrel on the incidence of the primary endpoint was consistent across all the prespecified subgroups, defined by age, gender, type of fibrinolytic, type of heparin, and infarct location.
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Clopidogrel also increased the odds of achieving optimal epicardial flow (TIMI Flow Grade 3) by 36% (from 60.8% to 67.8%, P<0.001) and optimal myocardial reperfusion (TIMI Myocardial Perfusion Grade 3) by 21% (from 51.2% to 55.8%, P=0.008), and reduced the odds of intracoronary thrombus by 27% (from 50.8% to 43.0%, P<0.001). Treatment with clopidogrel was also associated with a 21% reduction in the odds of early angiography (within 48 h) for clinical indications (from 18.6% to 15.4%, P=0.01), a 21% reduction in the odds of urgent revascularization during the index hospitalization (from 23.3% to 19.5%, P=0.005), and a 16% reduction in the odds of using a GP IIb/IIIa inhibitor during the PCI (from 33.0% to 29.3%, P=0.07).
By 30 days, clopidogrel reduced the odds of cardiovascular death, recurrent myocardial infarction, or recurrent ischaemia leading to urgent revascularization by 20% (from 14.1% to 11.6%, P=0.03) (Figure 2). Examining the individual cardiovascular endpoints, there was no difference in cardiovascular mortality, a significant 31% odds reduction in recurrent myocardial infarction (P=0.02), a 24% odds reduction in recurrent myocardial ischaemia leading to urgent revascularization (P=0.11), and a 46% odds reduction in stroke (P=0.052).
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The CLARITY-TIMI 28 ECG substudy has yielded important insights into the potential mechanism of benefit of clopidogrel in STEMI.13 There was no effect of clopidogrel on the degree of ST-segment resolution by 90 or 180 min (non-invasive markers for early recanalization), with a median of 73% resolution with clopidogrel vs. 72% with placebo and with rates of complete ST resolution (defined as >70%) at 180 min of 52.4% and 53.6% in the clopidogrel and placebo groups, respectively. However, compared with placebo, treatment with clopidogrel resulted in greater angiographic benefit among those who achieved early ST resolution by 90 min, with greater odds of optimal epicardial flow (TIMI 3 flow) at late angiography in patients with complete ST resolution (adjusted OR 2.0, 95% CI 1.5–2.8, P<0.001) or partial ST resolution (adjusted OR 1.4, 95% CI 1.0–1.8, P=0.04), but no improvement in those with no ST resolution (adjusted OR 0.89, 95% CI 0.65–1.2, P=0.48) (P for interaction=0.003). Analogously, in terms of clinical events, clopidogrel reduced the odds of in-hospital death or MI in patients who achieved partial (adjusted OR 0.30, 95% CI 0.13–0.67, P=0.003) or complete ST resolution by 90 min (adjusted OR 0.49, 95% CI 0.24–1.02, P=0.056), whereas the clinical benefit of clopidogrel over placebo was not apparent in patients who had no ST resolution (adjusted OR 0.98, 95% CI 0.58–1.68, P=0.95, interaction P=0.027). These data suggest clopidogrel improves clinical outcomes by preventing re-occlusion rather than by facilitating early reperfusion.
The rates of TIMI major bleeding through the calendar day following angiography (the primary safety endpoint) were low and similar in both treatment arms: 1.3% in the clopidogrel group and 1.1% in the placebo group (P=0.64). Similarly, there was no excess in intracranial hemorrhage, with rates of 0.5% in the clopidogrel group and 0.7% in the placebo group (P=0.38), nor in TIMI minor bleeding (1.0 vs. 0.5%, P=0.17). A total of 136 patients underwent CABG during their index hospitalization. In this small group, treatment with clopidogrel was not associated with a significant excess in major bleeding through 30 days (7.5% with clopidogrel vs. 7.2% with placebo, P>0.99), even in those who underwent CABG within 5 days of discontinuation of study medication (9.1 vs. 7.9%, respectively, P>0.99).
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Clopidogrel and Metoprolol in Myocardial Infarction Trial/Chinese Cardiac Study-2 |
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TopAbstractIntroductionClopidogrel as Adjunctive...Clopidogrel and Metoprolol in...DiscussionAcknowledgementsReferences |
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The Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)/Chinese Cardiac Study (CCS)-2 was a 2x2 factorial design trial that randomized patients to clopidogrel (75 mg daily, no loading dose) vs. placebo and to metoprolol vs. placebo in patients within 24 h of symptom onset of a suspected acute MI (ST changes or left bundle branch block).14,15 This mega-trial enrolled 45 852 patients exclusively in China. Twenty-six percent of patients were 70 years or older, 28% were women, and 93% of patients had ST elevations on their ECG. Per protocol, all patients were given 162 mg of aspirin daily. Fibrinolytics (chiefly urokinase) were administered to 50% of all patients at presentation and to 68% of those who presented within 12 h of symptom onset. Seventy-five percent of patients received an anticoagulant. Fewer than 5% of patients underwent PCI.
Treatment with clopidogrel resulted in a 9% relative risk reduction in the rate of death, reinfarction, or stroke through index hospitalization (from 10.1% to 9.3%, P=0.002) and a 7% relative risk reduction in the rate of death alone (from 8.1% to 7.5%, P=0.03; Figure 3)—the two co-primary endpoints. With regard to other individual components of the composite endpoint, treatment with clopidogrel resulted in a significant 13% relative risk reduction in reinfarction (from 2.4% to 2.1%, P=0.02) and a non-significant 14% relative risk reduction in stroke (from 1.1% to 0.9%, P>0.1). The benefit of clopidogrel on the incidence of the composite of death, reinfarction, or stroke was consistent across age subgroups, in both men and women, and whether a fibrinolytic was used or not. Despite the lack of a loading dose, there was a clear effect of clopidogrel on reducing the incidence of death, reinfarction, or stroke within the first 24 h.
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The rates of major bleeding were very low in both arms (<1%) and did not differ statistically. Nor was clopidogrel associated with an excess of major bleeding in patients who received a fibrinolytic or in those aged 70 years or older. The incidence of minor bleeding was higher in the clopidogrel arm (3.6 vs. 3.1%, P=0.005). The rates of intracranial hemorrhage were identical in the two groups (0.2%).
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Discussion |
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TopAbstractIntroductionClopidogrel as Adjunctive...Clopidogrel and Metoprolol in...DiscussionAcknowledgementsReferences |
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A series of clinical trials in the late 1980s and early 1990s helped establish the combination of aspirin, heparin, and fibrin-specific lytics as the foundation for pharmacologic reperfusion therapy for STEMI.1,16 Since then, there have been several attempts to improve on this regimen. Newer bolus fibrinolytics such as reteplase and tenecteplase are easier to administer and have demonstrated non-inferiority, but not superiority, to older fibrin-specific agents.17 More aggressive antiplatelet therapy with intravenous GP IIb/IIIa inhibitors did improve infarct-related artery patency and reduce reinfarction, but, even after reducing the dose of the fibrinolytic, doubled the rate of major bleeding and also, in patients >75 years of age, intracranial hemorrhage, and with no benefit on mortality.18 Recently, the low-molecular-weight heparin enoxaparin has been shown to be superior to unfractionated heparin in reducing death or MI in patients with STEMI in the ExTRACT-TIMI 25 trial.19
CLARITY-TIMI 28 and COMMIT/CCS-2 demonstrate that the addition of clopidogrel to aspirin in patients with STEMI both improves infarct-related artery patency and reduces ischaemic complications including mortality. The benefit was consistent across a broad range of subgroups based on age, gender, use and type of fibrinolytic, and type of heparin. Thus, the optimal pharmacologic reperfusion regimen appears to be the combination of aspirin, clopidogrel, a fibrin-specific lytic, and enoxaparin.20 The two clopidogrel trials offer complementary information that spans a variety of patient demographics and practice patterns, including both a conservative management strategy and a strategy of routine angiography.
Treatment with clopidogrel was very well tolerated with no excess in major bleeding or intracranial hemorrhage. A loading dose was used effectively and safely in CLARITY-TIMI 28 and thus would be reasonable practice in those patients aged 75 years or younger, especially in those in whom angiography and, hence, possibly PCI are planned.21 In patients aged 76 years or older, who are generally at an increased risk of bleeding, treatment without a loading dose appears more prudent.
In conclusion, the addition of clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve angiographic and clinical outcomes in patients with STEMI undergoing thrombolysis.
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Acknowledgements |
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The TIMI Study Group received major research grant support from: Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck & Co., Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, sanofi-aventis, Schering-Plough Research Institute.
Conflict of interest: M.S.S. has been the principal investigator or co-principal investigator on clinical trials that have received research grant support from Bristol-Myers Squibb and sanofi-aventis, has received research support (supplies and/or equipment) from Biosite, diaDexus, and Roche, has received honoraria for educational presentations and/or materials from Bristol-Myers Squibb, Novartis, and sanofi-aventis, and has served on scientific advisory boards for AstraZeneca, Bristol-Myers Squibb, and sanofi-aventis.
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