Dr. Eric Durand
Prof. Antoine Lafont,
Aspirin, unfractionated or low molecular weight heparin, GP IIb-IIIa inhibitors, and clopidogrel have successively reduced adverse events in unstable Angina (UA) and Non ST segment elevation myocardial infarction (NSTEMI) [1-4]. However, the efficacy and the safety of this "quadruple therapy" have not been prospectively evaluated.
Aspirin was first evaluated by Theroux et al in 1988 . Aspirin was associated with a reduced incidence of myocardial infarction . Since this pioneering study, aspirin has been given to almost all patients with unstable angina. However, the optimal dose of aspirin is not really established. In the ACC/AHA guidelines, it is recommended to initiate aspirin at a daily dose of 160 or 325 mg to establish a high blood level rapidly. Thereafter, daily doses of 75 to 325 mg are prescribed. Heparin is a key component in the antithrombotic management of UA/NSTEMI [1, 2]. The combination of aspirin and either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with the use of aspirin alone reduced the rate of death or MI of 50% to 60%. LMWH, and particularly enoxaparin, is actually preferred to UFH because LMWH does not require monitoring, is less frequently associated with heparin-induced thrombocytopenia and variability in anticoagulant response among patients. Moreover, enoxaparin has shown a moderate benefit over UFH . However, LMWH is associated with significantly more frequent minor, but not major, bleeding . GP IIb-IIIa inhibitors, in association with aspirin and UFH, have shown a significant reduction of the incidence of death or MI in UA/NSTEMI as compared to aspirin with UFH alone . GP IIb-IIIa inhibitors are particularly of benefit in high risk patients (i.e., continuing ischemia and/or troponin elevation) and if percutaneous revascularisation is planned. In other cases, the benefit is absent or very low. Treatment with GP IIb-IIIa inhibitors increases the risk of bleeding. Recently, it has been shown that it is possible to associate LMWH and GP IIb-IIIa inhibitors.
Clopidogrel has been recently evaluated in UA/NSTEMI in the CURE trial  with a loading dose of 300 mg following by 75 mg daily as compared to placebo. Cardiovascular death, MI or stroke was significantly reduced - by 20%. A significant excess of major bleeding was observed in the clopidogrel group. However, this clinical trial was performed in hospitals in which there was no routine policy of invasive strategy, therefore revascularisation was only performed in 23% of the patients. Moreover, fewer than 10% of the patients received GP IIb-IIIa inhibitors, although the combination with a GP IIb-IIIa inhibitor appeared to be well tolerated. In the new ACC/AHA guidelines published in 2002, unsolved questions concerning the association of these drugs have been postulated. They recommended to use Clopidogrel (in association with aspirin and UFH or LMWH) for patients with UA/NSTEMI in whom a noninterventional approach is planned. In contrast, patients in whom an interventional approach is planned, a GP IIb-IIIa inhibitor (in association with aspirin and UFH or LMWH) is recommended since no head-to-head comparison of Clopidogrel, a GP IIb-IIIa inhibitor, and their combination has been performed. We actually are performing a randomised, double blind, multicenter European study (the PRACTICE study), comparing Integrillin and placebo in 800 patients with ST-segment deflection and positive tromponine levels; all patients in both groups receive heparin, aspirin and plavix as well. The goal is to evaluate within the first 24-hours after the acute event, the efficacy and the safety of this quadruple therapy in a high risk population of patients with an interventional approach.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, deGuise P. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1998;319:1105-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3050522&dopt=Abstract
2. Cohen M, Demers C, Gurfinkel EP, Turpie AGG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KAA, Premmereur J, Bigonzi F, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9250846&dopt=Abstract
3. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999;353:227-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9923894&dopt=Abstract
4. 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. Circulation 2002;106:1622-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11519503&dopt=Abstract
Dr E. Durand and Dr A. Lafont Paris, France Vice-Chairman of the ESC Working Group on Interventional Cardiology
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