Clopidogrel with Aspirin Is the Optimal Antiplatelet Regimen for Intracoronary Stenting

Transcription

1 Clopidogrel Aspirin Steinhubl for and Stenting Topol Journal of Thrombosis and Thrombolysis 1999;7: Kluwer Academic Publishers. Boston. Printed in the Netherlands. Clopidogrel with Aspirin Is the Optimal Antiplatelet Regimen for Intracoronary Stenting Steven R. Steinhubl 1 and Eric J. Topol 2 1 Department of Cardiology, Wilford Hall Medical Center, Lackland AFB, Texas; 2 Department of Cardiology and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA It is anticipated that nearly 700,000 percutaneous coronary interventions will be performed in the United States alone in 1998 [1]. A substantial majority of these procedures will include the placement of a stent, with elective stenting making up over 70% of procedures at many institutions. The prominent role of stenting in coronary interventions today is due in no small part to the effectiveness and safety of combined antiplatelet therapy with ticlopidine and aspirin for stent thrombosis prophylaxis. Following the initial description of intracoronary stenting just over 10 years ago, subacute stent thrombosis was recognized as a common and often lifethreatening complication of the procedure [2]. In spite of the use of intense antighrombotic regimens, including aspirin, dipyridamole, dextran, and prolonged heparin followed by coumadin, subacute stent thrombosis still occurred in nearly 5% of patients. Also, this aggressive anticoagulation was associated with substantial hemorrhagic complications and the need for protracted hospitalizations. Although stenting was shown to improve procedural success and long-term outcomes when compared with balloon angioplasty alone [3,4], these limitations hampered its early widespread utilization. However, with the change to combined antiplatelet therapy with ticlopidine and aspirin in late 1994 and early 1995, the incidence of stent thrombosis has decreased to 2%, without the hemorrhagic risk or prolonged hospital stays associated with earlier regimens [5]. The generalized application of this dual antiplatelet regimen has contributed to a tripling of the number of patients treated with stents from 1995 to 1998 [1]. In spite of the proven bene~t of ticlopidine as part of a antiplatelet regimen with stenting, increasing experience has lead to a greater awareness of its limitations, primarily related to its delayed onset of action and multiple adverse effects. Another thienopyridine, clopidogrel, structurally similar to ticlopidine except for the addition of a carboxymethyl side group (Figure 1), has recently been commercially released. The available data suggest that clopidogrel offers all of the bene~ts of ticlopidine without its limitations, making it the optimal agent to use in conjunction with aspirin in coronary stenting. Antiplatelet Effects Clopidogrel, like ticlopidine, irreversibly inhibits ADPinduced platelet aggregation and ADP-mediated ampli~cation of other platelet agonists by selectively binding to adenylate cyclase coupled ADP receptors on the platelet surface [6]. Although on a molar basis clopidogrel has a greater platelet inhibitory effect than ticlopidine, standard dosing of 75 mg daily was determined based on equivalency with the platelet inhibitory effects of chronic daily therapy with 500 mg of ticlopidine [7]. Ticlopidine and clopidogrel are prodrugs that require metabolism in the liver for the development of antiplatelet effects via an unknown metabolite. When ticlopidine is give as a 500 mg loading dose followed by 250 mg twice daily, as is standard following stenting, maximal platelet inhibition does not occur for at least 7 days, and 3 4 days of therapy are necessary to achieve 75% of its maximal effect [8] (Figure 2). Since the modal presentation of subacute stent thrombosis is 5 6 days following stenting [9], adequate antiplatelet protection can be achieved with ticlopidine to prevent a large number of these events. However, the majority of all major adverse cardiac events (death, myocardial infarction, and urgent revascularization, MACE) following stenting occur within the ~rst 3 days, during the period in which ticlopidine is only beginning to develop its platelet inhibitory effects (Figure 3). A retrospective analysis of nearly 3000 stent procedures over a 5-year period demonstrated that a postprocedure regimen without ticlopidine was an independent risk factor for the development of MACE [10]. However, consistent with ticlopidine s delayed onset of action, no protective effect of ticlopidine was identi~ed before the third day following the procedure (Figure 4). Address for correspondence: Steven R. Steinhubl, M.D., Department of Cardiology, Wilford Hall Medical Center, 2200 Bergquist Dr., Lackland AFB, TX , USA steinhubl@whmc.af.mil Received and accepted for publication 22 September,

2 228 Steinhubl and Topol Fig. 1. Chemical structure of clopidogrel and ticlopidine, which differ only by a substitution at the benzyl carbon. Fig. 3. Cumulative incidence of major adverse cardiac events (death, MI, or target lesion revascularization) following stenting. (Modi~ed from Schulen et al. [10], with permission.) The importance of adequate platelet inhibition early following stenting has been highlighted by the recently reported results of the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial [11]. In this trial, stented patients were randomized to receive either the platelet glycoprotein IIb/IIIa receptor antagonist abciximab or placebo. All stented patients were also treated with ticlopidine and aspirin. Those patients who received additional antiplatelet protection with abciximab during and following the stent procedure experienced a greater than 50% decrease in MACE compared with placebo-treated stented patients (10.8% vs. 5.3%, P 0.001). Interestingly, of the over 800 patients randomized to the placebo arm in this trial, almost 60% began ticlopidine along with aspirin prior to undergoing stenting. Compared with those patients that did not start ticlopidine until the time of the procedure, pretreated patients experienced a 33% decrease in the incidence of MACE (13.4% vs. 8.9%, P 0.033) [12]. These results emphasize the importance of platelet inhibition at the time of stenting and early thereafter for the prevention of adverse events, and demonstrate that at least some degree of protection can be achieved with the combination of aspirin and thienopyridines Fig. 2. Inhibition of ADP-induced platelet aggregation as a function of time by clopidogrel after a 375 mg loading dose followed by 75 mg daily (modi~ed from Bachman et al. [15], with permission.) and ticlopidine after a 500 mg load followed by 250 mg twice daily (modi~ed from Di Perri et al. [8], with permission). Fig. 4. Hazard ratio of a postprocedure regimen without ticlopidine as a function of time following stenting. (Modi~ed from Schulen et al. [10], with permission.)

3 Clopidogrel Aspirin for Stenting 229 alone. A recent retrospective analysis of stented patients who were started on ticlopidine prior to their procedure support these results and underscore the importance of an adequate duration of pretreatment by the thienopyridine for the development of suf~cient platelet inhibition [13]. In this study, patients who received ticlopidine and aspirin for at least 3 days prior to the procedure had a non Q-wave MI (any abnormal CK with positive MB fraction) rate of only 5%, compared with 14% for those treated for only 1 2 days prior, and 29% in patients not receiving ticlopidine until the day of the procedure. As encouraging as these results are, it is clinically impractical to treat patients with at least 3 full days of ticlopidine prior to a potential coronary intervention. Like ticlopidine, the platelet inhibitory effects of clopidogrel are time and dose dependent. Without a loading dose, a steady state of inhibition is attained following 4 7 days of therapy [14]. However, the use of an oral loading dose dramatically increases the rapidity of achieving maximal inhibition. In one study employing a 375 mg loading dose followed by 75 mg daily, near maximal platelet inhibition to 5 lm ADP was seen after only 2 hours, with steady-state levels by 5 hours (see Figure 2) [15]. This pharmacodynamic advantage of clopidogrel over ticlopidine allows for the development of greater platelet inhibition immediately following stenting, even when it is started at the time of the procedure. Beginning therapy only 6 12 hours prior to a procedure in order to develop maximal antiplatelet protection provides enhanced protection from the early clustering of MACE. This strategy is clinically much more feasible than the 3 or more days required for ticlopidine. Adverse Effects In large clinical trials including just over 2000 patients treated with ticlopidine, adverse events lead to the discontinuation of its use in approximately 20% of patients [16,17]. Most commonly discontinuation was due to nuisance events. Gastrointestinal symptoms, primarily diarrhea, occurred in 30% of patients, and lead to 12% of patients stopping therapy. Rash was the next most common complaint, and was seen in 5% of patients. In general, these events occurred early in the course of therapy. Although they are not life-threatening themselves, these adverse events can force the premature termination of therapy. Early discontinuation of ticlopidine after stenting would increase the risk of stent thrombosis. Of even greater concern, however, are the blood dyscrasias associated with ticlopidine. Neutropenia (absolute neutrophil count 1200/virgule mm 3 ) has been reported in 2.4% of patients, and was severe ( 450/virgule mm 3 ) in 0.8%. Aplastic anemia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP) have also all been associated with ticlopidine treatment [18]. The median onset of these events ranged from 30 to 45 days after starting therapy [18]. TTP is of particular concern due to its associated mortality rate of up to 50% and its greater than previously appreciated incidence, estimated to be as high as one in every patients (Ticlid Package Insert). The majority of TTP cases present within the ~rst 4 weeks of therapy, and can be seen within the initial 2 weeks [19]. Because of the possibility of these potentially life-threatening complications, a complete blood count is necessary in all treated patients at 2-week intervals for the ~rst 3 months [18]. Clinical safety data for clopidogrel comes primarily from the 19,185 patient CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial. This was a randomized, double-blinded trial that compared clopidogrel 75 mg daily with aspirin 325 mg daily for the prevention of ischemic events in patients with atherosclerotic vascular disease [20]. The mean duration of follow-up was almost 2 years. Overall, the incidence of adverse events was similar in the two treatment groups. Clopidogrel was stopped in 5.3% of patients due to adverse events, and in 6.0% of aspirintreated patients. Although diarrhea was more common in clopidogrel-treated patients (4.5% vs. 3.4%), the overall incidence of gastrointestinal symptoms was higher in those receiving aspirin. Importantly, there was no excess incidence of neutropenia in clopidogrel treated patients compared with those receiving aspirin (0.10% vs. 0.17%). No cases of TTP were reported in this trial, or have since surfaced after broad clopidogrel administration since its release in March This lack of blood dyscrasias eliminates the need for frequent blood monitoring, and the overall better tolerance of clopidogrel allows for better compliance and longer duration of therapy. With nearly 400,000 patients receiving stents in the United States this year, if all patients were treated with clopidogrel instead of ticlopidine, over 9000 case of neutropenia and 100 cases of TTP would be expected to be prevented. Clinical Trials Although the results of prospective randomized trials of clopidogrel in stenting are presently lacking, data will soon be forthcoming. The Clopidogrel Aspirin Stent International Co-operative Study (CLASSICS) trial is currently enrolling patients in Europe. It is comparing ticlopidine along with aspirin with two regimens of clopidogrel and aspirin in patients following a successful percutaneous coronary intervention with a stent (Figure 5). Patients randomized to ticlopidine are being given 250 mg twice daily and then continued for 30 days. The two clopidogrel arms are 300 mg at the time of stenting followed by 75 mg daily for 30 days, or 75 mg at the time of stenting followed by 75 mg daily for 30 days. Three-hundred and thirty-~ve patients will

4 230 Steinhubl and Topol Compared with previous antithrombotic regimens utilized in stenting, dual antiplatelet therapy with aspirin and the thienopyridine ticlopidine has proven to be safer and more effective in the prevention of subacute stent thrombosis. Although there have been a number of recognized problems with ticlopidine, until recently this combination was the optimal therapy available for patients receiving stents. However, a new thienopyridine, clopidogrel, is now available that provides a superior alternative to ticlopidine. Published data con~rm clopidogrel s ef~cacy and improved pharmacodynamics compared with ticlopidine. Likewise, there is overwhelming evidence supporting its increased safety and tolerance. All of this compelling data led The Medical Letter to recommend that clopidogrel replace ticlopidine [21] Furthermore, with the additional cost of over $1000 related to stenting [22], the reduced cost of clopidogrel ( 25%) compared with ticlopidine is an important additional bene~t. Replacing ticlopidine with clopidogrel as part of an antiplatelet regimen following stenting should help prevent deaths as well as other major adverse cardiac and noncardiac events. The results of ongoing randomized trials will clarify the degree of this bene~t and the optimal duration of therapy. References Fig. 5. Study design of the CLASSICS (Clopidogrel Aspirin Stent International Co-operative Study) trial. be randomized into each arm, and enrollment is expected to be completed in late A second study, Clopidogrel for Reduction of Events During extended Observation (CREDO), is also planned and will compare preloaded clopidogrel, a minimum of 375 mg total beginning at least 12 hours prior to planned stenting, with 75 mg of clopidogrel begun at the time of the procedure. Both groups will receive daily aspirin. Those randomized to the preload arm will continue aspirin and 75 mg of clopidogrel daily for 1 year. The non-preload arm will be treated for 1 month with dual therapy and then continue on aspirin alone. This trial will involve approximately 2000 patients. Conclusions 1. Malone AP. Salmon Smith Barney Equity Research: Medical supplies and technology, April 3, 1998, Company Analysis. Guidant Corporation. 2. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary artery stent. N Engl J Med 1991;324: Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331: Serruys PW, DeJaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl JMed1994;331: Schomig A, Neumann F-J, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334: Mills DCB, Puri R, Hu C-J, et al. Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arterioscler Thromb 1992;12: Boneu B, Destelle G, on behalf of the study group. Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients. Thromb Haemost 1996;76: Di Perri T, Pasini FL, Frigerio C, et al. Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration. Eur J Clin Pharmacol 1991;41: Mak KH, Belli G, Ellis SG, Moliterno DJ. Subacute stent thrombosis: Evolving issues and current concepts. J Ame Coll Cardiol 1996;27: Schulen H, Kastrati A, Dirschinger J, et al. Intracoronary stenting and risk for major adverse cardiac events during the ~rst month. Circulation 1998;98: The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein- IIb/IIIa blockade. Lancet 1998;352: Steinhubl SR, Balog C, Topol EJ. Pretreatment with ticlopidine prior to stenting is associated with a substantial decrease in complications. Data from the EPISTENT trial (abstr) Circulation Steinhubl SR, Lauer MS, Mukherjee DP, et al. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-q-wave myocardial infarctions. J Am Coll Cardiol 1998, in press.

5 Clopidogrel Aspirin for Stenting Caplain H, Kieffer G, Thiercelin JF, Thebault JJ. Tolerance and clinical pharmacology of repeated administration of clopidogrel (SR C) a new antiplatelet agent, at three dose levels in normal healthy volunteers (abstr). Thromb Haemost 1989;62: Bachman F, Savcic M, Hauert J, Geudelin B, Kieffer G, Cariou R. Rapid onset of inhibition of ADP-induced platelet aggregation by a loading dose of clopidogrel (abstr). Eur Heart J 1996;17: Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1: Hass WK, Easton JD, Adams HP, Jr. et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N Engl J Med 1989;321: Wysowksi DK, Bacsanyi J. Blood dyscrasias and hematologic reactions in ticlopidine users. JAMA 1996;276: Bennet CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med 1998;128: CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996;348: Anonymous. Clopidogrel for reduction of atherosclerotic events. Medical Letter 1998;40: Serruys PW, van Hout B, Bonnier H, et al. Randomised trial of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet 1998;352:

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