Ticlopidine versus oral
anticoagulation for coronary stenting
B Cosmi, A Rubboli, C Castelvetri,
M Milandri.
DOI: 10.1002/14651858.CD002133
David K. Cundiff, MD
Date received: September 12, 2007
In this meta-analysis of noninferiority RCTs, the control group, ASA + a vitamin k inhibitor, has never been shown to improve clinical outcomes for people with coronary stenting. Therefore, this meta-analysis cannot determine the effectiveness and safety of the use of ticlopidine plus aspirin after coronary stenting.
ASA + warfarin may well do clinical harm due to rebound hypercoagulability,1-4 bleeding (3% rate of major haemorrhage the first month falling to 0.3% per month after the first year),5 and hypercoagulability associated with initiation of vitamin k inhibition of vitamin k inhibition. A study from Italian anticoagulation clinics showed that, in 2111 patient-years on vitamin k inhibitors, 34/70 thromboses occurred within the first 90 days of treatment (OR of < or =90 days versus >90 = 20.6, CI 12.7-33.5; p <0.0001). These investigators found that the risk of thrombotic events when the INR is less than 1.5 is 7.6 times the risk when the INR is 2.0-2.99 in patients taking warfarin for various indications.6
The most relevant comparison would be between ASA and ASA + ticlopidine. In this regard, Hall and colleagues published an informative RCT of ASA alone versus ASA + ticlopidine after stent placement, concluding, “At 1 month, there was no difference in the incidence of stent thrombosis or other clinical end points between the two poststent antiplatelet regimens.”7 Without evidence of efficacy of combination antiplatelet therapy over ASA alone, the 2-2.5% incidence of idiopathic bone marrow suppression and 0.8% incidence of severe neutropenia requiring prolonged hospitalization and antibiotics7, 8 make ticlopidine an unlikely candidate as part of the standard of care.
Since the safety of ticlopidine, regarding bone marrow suppression, is a major consideration in the overall risk/benefit ratio of ASA + ticlopidine, large retrospective or prospective observational studies should have been included.
This
Cochrane review references a 1998 RCT by Leon and colleagues justifying
combination ASA + ticlopidine thromboprophylaxis: “This regimen, now
representing the gold standard after coronary stenting, is considered to be
effective in reducing both the thrombotic occlusion of the stented vessel (and
the associated clinical events) and the hemorrhagic and peripheral vascular
complications.”9 The
Consequently, the conclusion of
this Cochrane review, “Ticlopidine plus aspirin after coronary stenting is
effective in reducing the risk of the revascularization, non fatal myocardial
infarction and bleeding complications when compared with oral anticoagulants”
is not justified.
The review should be updated to reflect
the late thrombosis risks of drug eluting stents10 and that electively done percutaneous coronary
interventions (angioplasties with or without stents) are
evidence based not to improve clinical outcomes.11 In this regard, it is notable that all deaths in the ASA +
ticlopidine group of this review (6/1223) were procedure complication related.
It should be stated whether or not the funding
sources for the review, (1)
1. Cundiff DK. Commentary - Insufficient Evidence Supporting Low-Intensity Warfarin for Venous Thromboembolism (VTE) Prophylaxis. Medscape General Medicine™. 07/02/2003;http://www.medscape.com/viewarticle/457570.
2. Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994;72(2):222-226.
3. Ascani A, Iorio A, Agnelli G. Withdrawal of warfarin after deep vein thrombosis: effects of a low fixed dose on rebound thrombin generation. Blood Coagul Fibrinolysis. 1999;10(5):291-295.
4. Grip L, Blomback M, Schulman S. Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients. Eur Heart J. January 1, 1991;12(11):1225-1233.
5. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. American Journal of Medicine. 1989;87(2):144-152.
6. Palareti G, Manotti C, DAngelo A, et al. Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy). Thromb Haemost. 1997;78(6):1438-1443.
7. Hall P, Nakamura S, Maiello L, et al. A Randomized Comparison of Combined Ticlopidine and Aspirin Therapy Versus Aspirin Therapy Alone After Successful Intravascular Ultrasound–Guided Stent Implantation. Circulation. January 15, 1996;93(2):215-222.
8. Hass W, Easton J, Adams H, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med. August 24, 1989;321(8):501-507.
9. Leon MB, Baim DS, Popma JJ, et al. A Clinical Trial Comparing Three Antithrombotic-Drug Regimens after Coronary-Artery Stenting 10.1056/NEJM199812033392303. N Engl J Med. December 3, 1998;339(23):1665-1671.
10. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late Thrombosis of Drug-Eluting Stents: A Meta-Analysis of Randomized Clinical Trials. The American Journal of Medicine. 2006;119(12):1056-1061.
11. Boden WE, O'Rourke RA, Teo KK, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. 10.1056/NEJMoa070829. N Engl J Med. March 26, 2007:NEJMoa070829.
The aim of the review was to compare ASA plus ticlopidine versus ASA plus vitamin K antagonists after coronary stenting and not the efficacy and safety of ASA plus ticlopidine per se. The review included trials performed mostly in the 1990s with bare metal stents and mostly after elective stents. Dual antiplatelet treatment seemed at least as effective as ASA plus vitamin K antagonists. Since then dual antiplatelet treatment with ASA plus ticlopidine or clopidogrel has become the standard treatment after coronary stenting. The comparison of ASA alone versus dual antiplatelet agents would entail an entirely different and new meta-analysis.
The meta-analysis of ASA plus ticlopidine versus ASA plus vitamin K antagonists should probably be considered historical as nowadays the relevant comparison would be the effectiveness and safety of ASA plus ticlopidine versus ASA plus clopidogrel after coronary stenting and thus, again, an entirely different question. Moreover nowadays drug-eluting stents should be considered as well primary angioplasty with stenting and therefore a different and new meta-analysis would be required. The original authorship team is no longer active and consequently not currently in a position to plan new meta-analyses.
David Cundiff
Benilde Cosmi