Background information of the condition:
Drug Eluting Stents (DES) Implantation DES were invented to reduce restenosis compared to bare metal stents (8% vs. 25%1,2 respectively). The process responsible for stent stenosis is delayed with drugs (sirolimus [rapamycin] and paclitaxel); however this benefit is offset by harm due to stent thrombosis (0.2-1.1%). Dual antiplatelet therapy is recommended to decrease the rate of stent thrombosis.
Drug (Product Monograph3)
Category Clopidogrel is categorized as platelet aggregation inhibitor.
Mechanism of action: Clopidogrel selectively inhibits the binding of ADP to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein IIb-IIIa complex, thereby inhibiting platelet aggregation.
Indication: Clopidogrel is indicated for the secondary prevention of atherothrombotic events (myocardial infarction, stroke and vascular death) in patients with atherosclerosis documented by stroke, myocardial infarction (MI), or established peripheral arterial disease, as well as in patients with acute coronary syndromes – without ST segment elevation (i.e. unstable angina or non-Q-wave myocardial infarction).
These benefits of clopidogrel have been shown only when these patients were concomitantly treated with acetyl salicylic acid (ASA) in addition to other standard therapies. These benefits were also seen in patients who were managed medically and those who were managed with percutaneous coronary intervention (PCI, with or without stent) or coronary artery bypass graft (CABG)
Note: The product monograph does not state specific indication for use of clopidogrel with bare metal stent or drug eluting stents.
Dose MI, Stroke or Established Peripheral Arterial Disease: 75 mg once daily long term with or without food.
Acute Coronary Syndrome (includes percutaneous coronary intervention): 300 mg loading dose, maintenance (long term) at 75 mg once a day with ASA (80 mg-325 mg daily).
Duration: long-term duration (not specified in the product monograph)
Methodology of Systematic review
- In RCTs (double blind, single blind or open label), does [clopidogrel + ASA] combination therapy provides a therapeutic advantage over ASA alone or in combination with other platelets drugs, in patients after drug-eluting stent implantation?
- In RCTs (double blind, single blind or open label), does [clopidogrel + ASA] combination therapy for more than 6 months provides a therapeutic advantage over shorter duration of therapy, in patients after drug-eluting stent implantation?
Assessment principles: RCTs (double blind, single blind or open label) in patients with drug eluting stent implantation (sirolimus or paclitaxel) comparing [clopidogrel + ASA] combination therapy with appropriate comparators will be critically appraised. Benefit and harm will be assessed according to the following hierarchy of health outcomes – all cause mortality, non-fatal serious adverse events (MI, unstable angina, stroke and bleeding), angiographically proven stent thrombosis, WDAE’s and total adverse events. Other antiplatelets used following DES include tirofiban HCl (Aggrastat®), eptifibatide (Integrilin®), ticlopidine HCl (Apo®-Ticlopidine Gen-Ticlopidine, Novo-Ticlopidine, Nu-Ticlopidine, Sandoz® Ticlopidine, Ticlid®), and dipyridamole (Persantine).
Search strategy: Databases searched include – Medline (1966-May 2007), Embase (1988-May 2007), and the Cochrane database. Key search words included: “drug eluting stent”, paclitaxel eluting stent”, “sirolimus eluting stent”, Clopidogrel, RCT, randomised or randomized clinical trials.
Search findings: No RCTs met the inclusion criteria.
No RCTs were identified comparing dual antiplatelet therapy [clopidogrel +ASA] vs. ASA alone or in combination with other anti-platelet medications in patients with drug-eluting stent implantation.
Critical appraisal issues:
- There are no RCTs (vs. placebo or other anti-platelets) in patients after drug-eluting stent implantation to support the recommendations provided in the guidelines.
No RCTs were identified, therefore there is no evidence from RCTs that combination antiplatelet therapy with clopidogrel and ASA has a clinical therapeutic advantage vs. ASA alone or other combination therapies in prevention of major events after implantation of drug-eluting stent, and no evidence regarding the duration of the therapy.
Clopidogrel plus ASA is used routinely, but not studied, in RCTs involving drug eluting stents. One RCT compared sirolimus eluting stent to bare-metal stent in patients who underwent sirolimus eluting stents implantation1 and received oral ASA (325 mg daily) plus oral clopidogrel (a loading dose of 300 to 375 mg 24 hours before the procedure and then 75 mg daily for three months). A second RCT compared paclitaxel eluting stent to bare metal stent in patients who underwent paclitaxel-eluting stent implantation2 and received oral ASA (325 mg daily) indefinitely plus oral clopidogrel (loading dose of 300 mg before the procedure and than 75 mg daily for six months).
Clopidogreal was studied in two trials in patients undergoing bare-metal stent implantation: the PCI-CURE study4 (an observational sub-study of the CURE trial.) and the CREDO Trial5 (DB-RCT). The CURE trial included 12,562 patients hospitalized within 24 hours after the onset of symptoms of acute coronary syndrome without ST segment elevation and compared combination of [clopidrogel + ASA] to ASA monotherapy for mean duration of 9 months of treatment. 2,658 of these patients who underwent a PCI were included in the PCI-CURE sub-study. The CREDO trial included 2116 patients undergoing PCI, comparing combination of [clopidogrel + ASA] to ASA monotherapy with a follow-up duration of 12 months. Neither trial demonstrated a significant difference in total or cardiovascular mortality, myocardial infarction, stroke, revascularization procedures and major or minor bleeding at the end of the trial (9 months and 12 months respectively).
The guidelines are based on several observational studies6,8–14 showing that combination therapy with clopidogrel has a therapeutic advantage vs. no treatment. However, selection bias rules out drawing any scientifically valid conclusions from these observational studies.
- Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003 Oct 2;349(14):1315-23.
- Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004 Jan 15;350(3):221-31.
- Clopidogrel (Plavix) product monograph in eCPS
- Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001 Aug 18;358(9281):527-33.
- Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. Erratum in: JAMA. 2003 Feb 26;289(8):987.
- Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007 Jan 10;297(2):159-68.
- FDA Clinical Overview for Panel Packet, DES Thrombosis Panel, December 7-8, 2006 in http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4253b1_01.pdf
- Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A: IIncidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005 May 4;293(17):2126-30.
- Jeremias A, Sylvia B, Bridges J, et al. Stent thrombosis after successful sirolimus – eluting stent implantation. Circulation. 2004;109:1930-1932.
- Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation. 2006 Feb 28;113(8):1108-13
- Park DW, Park SW, Park KH, Lee BK, Kim YH, Lee CW, Hong MK, Kim JJ, Park SJ. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol. 2006 Aug 1;98(3):352-6.
- Park SJ, Shim WH, Ho DS, Raizner AE, Park SW, Hong MK, Lee CW, Choi D, Jang Y, Lam R, Weissman NJ, Mintz GS. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003 Apr 17;348(16):1537-45.
- Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C; BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006 Dec 19;48(12):2584-91.
- Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ: Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006 Jun 20;113(24):2803-9.