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Prof. Raffaele De Caterina,
Prof. Kurt Huber,
Prof. Felicita Andreotti,
The introduction of coronary stents has changed the indication for percutaneous coronary intervention (PCI). Recently, the problem with the development of in-stent restenosis has partially been overcome by the introduction of drug-eluting stents.
A major concern when performing PCI with stent implantation is the risk of causing acute, subacute or late stent thrombosis. The operator may change a silent, benign lesion into a nidus for thrombus formation and cause acute myocardial infarction - or in the worst cases, cause sudden cardiac death. Initially, the implanted stent is a target for platelet adhesion and thrombus formation. From days to weeks after the intervention, the stent is covered with endothelial cells and the lesion is sealed. This process takes longer if the stent is coated with cytotoxic drugs or if a multitude of long stents are used. Therefore, effective inhibition of thrombus formation is mandatory for some time after stent implantation.
When stents were introduced more than 20 years ago, a heavy anti-thrombotic cocktail of aspirin, dextran and intense anticoagulation therapy (infusion of unfractionated heparin followed by oral anticoagulation with a vitamin K antagonist) was used. Despite this effort, stent thrombosis occurred in 2-10% of patients. The introduction of overdilatation of the stent with high-pressure balloons by Antonio Colombo in 1995 (1) and the use of dual anti-platelet therapy with aspirin and ticlopidine (2,3) reduced the frequency of stent thrombosis to approximately 1%. In randomised studies low dose aspirin plus ticlopidine (4 weeks) was shown to be superior to warfarin and this treatment strategy was used for some years.
In the CLASSICS study the combination of aspirin and clopidogrel was found to be as effective as aspirin plus ticlopidine (4). Like ticlopidine, clopidogrel inhibits the platelet ADP-receptor, but clopidogrel has few side effects compared to ticlopidine.
The combination of low dose aspirin and clopidogrel is now standard therapy after coronary stenting.
Patients should be pre-treated with aspirin. If this is not the case, aspirin 250-500 mg should be given orally or intravenously on the table. After stenting aspirin 75-150 mg should be given life-long.
Strongly consider a glucoprotein IIb/IIIa inhibitor during and 12-18 hours after the procedure. Clopidogrel should be used life-long in these patients. In selected cases, where a high risk of stent thrombosis is suspected, a low molecular weight heparin or even oral anti-coagulation could be considered.
If the patient develops a skin rash or experiences other intolerable side effects to clopidogrel, we would recommend to treat the patient with ticlopidine 250 mg bid in combination with aspirin. Ticlopidine therapy should be monitored (leucocyte and plaletet count every second week) and the duration of this therapy should be shorter than when clopidogrel is used (4 weeks with bare metal stents and 3-6 months with drug-eluting stents).
The PCI- CURE (5) and the CREDO study (6) strongly suggest that pre-treatment with clopidogrel at least 6 hours prior to intervention is of benefit. Also in the CLARITY-PCI study pre-treatment with clopidogtrel was associated with a better outcome (7). The loading dose of clopidogrel in these studies was 300 mg. However, the use of a higher loading dose of 600 mg is an interesting option. This dose was used in the ISAR-REACT study showing pre-treatment with clopidogrel may make the use of abciximab unnecessary in low-risk PCI patients (8). The major advantage of using a higher loading dose is that inhibition of the platelet ADP-receptor occurs faster. The ISAR-CHOICE and the ALBION study presented at the TCT meeting October 2005 confirmed, that a quicker platelet inhibition occurs after a bolus of 600 mg clopidogrel compared to a bolus of 300 mg.
The PCI-CURE (5) and the CREDO study (6) both suggest that patients undergoing stenting benefit from prolonged combination therapy with aspirin and clopidogrel. In PCI-CURE, the patients all suffered from an acute coronary syndrome and combination therapy for 3-12 months (average 9 months) was associated with a better outcome than one month of combination therapy. In CREDO approximately half of the patients were unstable/NSTEMI. Also in this study an extended treatment period of 12 months of the combination of aspirin plus clopidogrel was better than 1 month of combination therapy.
Although there are reasons to believe that the risk of stent-thrombosis is higher with drug-eluting stents than with conventional stents, this dogma has not been investigated in properly designed clinical trials. In the randomised trials where drug-eluting stents have been compared to conventional stents, pre-treatment with the combination therapy aspirin plus clopidogrel has been used and the duration of therapy has been 2-9 months.
The importance of resistance to aspirin or clopidogrel is undergoing intensive investigation and may in the future lead to a more individualised therapy based on measurement of the intensity of platelet inhibition. However, at the present time there is no consensus on how platelet function/inhibition should be assessed.
Prasugrel is an interesting new platelet ADP-receptor blocker that is currently being evaluated against clopidogrel in the TIMI 38 trial. Cangrelor is an ADP-receptor blockers for intravenous use that is currently being tested in phase 2 and 3 trials.
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.
The combination of low-dose aspirin and clopigrel is recommended after coronary stenting. Aspirin should be used life-long. Clopidogrel should not be used life-long and the duration of therapy is debatable – we use 12 months of therapy after implantation of both conventional and drug-eluting stents. Pretreatment with aspirin and clopidogrel prior to stenting is recommended. In acute cases a loading dose of 600 mg of clopidogrel seems logical.
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8. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2005; 25: 1903-10. 9. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005; 111: 2099-106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15750189&query_hl=4&itool=pubmed_docsum 10. Kastrati A, Mehilli J, Schuhlen H et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pre-treatment with clopidogrel. N Engl J Med 2004; 350: 232-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14724302&query_hl=6&itool=pubmed_DocSum 11. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 High Oral Doses for Immidiate Clopidogrel Effect) Trial. Circulation 2005; 112: 2946-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16260639&query_hl=10&itool=pubmed_docsum 12. Zimarino M, Renda G, De Caterina R: Optimal duration of antiplatelet therapy in recipients of coronary drug-eluting stents. Drugs 2005; 65(6): 725-732. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15819586&query_hl=8&itool=pubmed_docsum
Dr. S.D. Kristensen*, Dr F. Andreotti, Prof. K. Huber, Prof. R. De Caterina. *Aarhus, Denmark Chairperson of the Working Group on Thrombosis
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