Ticlopidine
Ticlopidine and clopidogrel inhibit platelet function by selectively blocking ADP-induced platelet aggregation. Both require hepatic transformation to an active metabolite. The action of ticlopidine (as well as clopidogrel) appears to be permanent in that there is still antiplatelet activity for seven to ten days after the medications have been stopped. Ticlopidine requires 4 to 7 days to achieve full platelet inactivation. Adverse reactions to ticlopidine include rash, gastrointestinal side effects, neutropenia (2.4 %), thrombocytopenia, aplastic anemia, and thrombotic thrombocytopenic purpura (TTP)1.
Secondary Prevention
High-Risk Patients. Ticlopidine has been studied in several groups of patients presenting with cardiovascular events. CATS 2 (The Canadian American Ticlopidine Study) randomized approximately 1100 patients who had suffered a CVA into ticlopidine and placebo arms. A combined endpoint of CVA, MI and vascular death was analyzed over a three-year period. An analysis revealed a significant 15.3 % vs. 10.8 % benefit, mainly in the reduction of CVA rate for those taking ticlopidine. There were no significant differences in MI. An intention to treat analysis was still significant, but slightly less favorable. STIMS 3 (Swedish Ticlopidine Multicentre Study) was a smaller but similar study performed in patients with peripheral vascular disease. Only the "on-drug" analysis reached statistical significance.
Unstable Angina. To date there has been one randomized clinical trial looking at the use of ticlopidine in patients with unstable angina. The endpoints were non-fatal and fatal myocardial infarction and any cause of cardiovascular death. Overall there was a significant reduction in events at six months (13.6 % placebo, 7.3% ticlopidine) with a noted trend toward mortality benefit as well (4.7 vs. 2.5 %, p = 0.14) 4. There have been no direct comparisons of aspirin (ASA) and ticlopidine for the treatment of unstable angina. For those patients intolerant of ASA, ticlopidine is recommended in unstable angina by the ACCP 5.
Interventional Cardiology
White et al.6 randomized 333 patients to ASA, ticlopidine, or placebo prior to stand-alone angioplasty. The event (abrupt occlusion, thrombosis, major dissection) rate in the ticlopidine arm was significantly less than that in the placebo arm, but not significantly different than the ASA arm (14 % placebo, 5 % ASA and persantine, 2 % ticlopidine). In patients with an ASA-sensitivity or in cases which appear to be angiographically unfavorable and not amenable to stenting, ticlopidine is an acceptable pre- and post-procedural antiplatelet agent.
The advent of coronary stenting has revolutionized percutaneous coronary revascularization; however, the early days of stenting were notable for a relatively high (5%) subacute closure rate, usually due to thrombus. Unfortunately, subacute stent thrombosis tended to occur after patients had been discharged from the hospital and carried a significant risk of mortality. Aggressive anticoagulation regiments and typically longer hospital stays were implemented. As stenting techniques improved the anticoagulation regiment moved toward the use of ASA and ticlopidine with marked results. Specifically, Columbo et al.7 showed that patients with stent implantation guided by intravascular ultrasound (IVUS) had a very low subacute thrombosis rate. His group further demonstrated that patients with optimized stent implantation could be treated with a much simpler antiplatelet regiment. Patients were given ticlopidine for one month, the first three to five days of which they also received ASA in order to provide double antiplatelet coverage while waiting for ticlopidine to achieve its full effect. He also compared the ticlopidine/ASA combination therapy to a smaller group of ASA-only patients. He found no difference between the groups in the already very low rate of subacute stent thrombosis. Over the coarse of this study the added incremental benefit of IVUS-guided stenting decreased as operators learned how to better deploy stents. Schömig et al.8 randomized patients post-stent deployment to ticlopidine and ASA vs. warfarin and ASA. A combined endpoint analysis was performed which included not only cardiovascular events, but also bleeding and vascular endpoints. The ticlopidine arm had a combined endpoint of 2.7 % vs. 16.5 % in the warfarin arm. More recently, STARS (Stent Anticoagulation Restenosis Study) demonstrated that patients treated with ASA and ticlopidine for one month had a better outcome than patients treated with ASA alone or ASA and warfarin (ticlopidine + ASA 0.5 % event rate, ASA 2.7 %, and ASA + warfarin 3.6 %) 9.
CABG. Two trials have demonstrated an improvement in graft patency with the use of ticlopidine. The benefit of ticlopidine in maintaining graft patency at 10 days was similar to that of ASA (13 % occlusion rate with placebo vs. 7 % ticlopidine). Ticlopidine, however, appeared to have a more significant late term effect on graft patency as compared to ASA (ASA does not appear to effect the rate of graft occlusion after the initial 10 day period whereas ticlopidine continued to improve graft patency over the first-year post bypass 26.1 % occlusion rate with placebo vs. 15 % occlusion rate with ticlopidine) 10,11. To date, there have been no direct comparisons of ticlopidine to ASA; however, ticlopidine may be used for those patients unable to tolerate ASA during the first-year post-bypass surgery.
References
1. Bennett CL, Kiss JE, Weinberg PD, Pinevich AJ, Green D, Kwaan HC and MD Feldman (1998). Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 352: 1036-7
.2. Gent M, Blakely JA, Easton JD, et al (1989). The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1:1215-1220
.3. Janzon L, Bergqvist D, Boberg J, et al (1990). Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine: results from STIMS, the Swedish Ticlopidine Multicentere Study. J Int Med 227:301-8.
4. Balsano F, Rizzon P, Violo F, et al (1990). Antiplatelet treatment with ticlopidine in unstable angina:a controlled multicenter clinical trial. Circulation 82:17-26
5. Fifth ACCP Consensus Conference on Antithrombotic Therapy (1998). Chest 114(5):626-8S.
6. White CW, Chaitman B, Lassar TA, et al (1987). Antiplatelet agents are effective in reducing the immediate complications of PTCA: results from the ticlopidine multicenter trial (abstract). Circulation 76:400.
7. Colombo A, Hall P, Nakamura S, et al (1995). Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 91:1676-88.
8. Schömig A, Neumann FJ, Kastrati A, et al (1996). A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary artery stents. NEJM 334:1084-9.
9. Leon MB, Baim DS, Popma JJ, et al (1998). A randomized trial comparing three drug regimens to prevent thrombosis following elective coronary stenting. NEJM 339:1665-71.
10. Limet R, David JL, Magotteaux P, et al (1987). Prevention of aortocoronary bypass graft occlusion; beneficial effect of ticlopidine on early and late patency rate of venous coronary bypass grafts: a double-blind study. J Thorac Cardiovasc Surg 94:773-83.
11. Chevigne M, David J-L, Rigo P, et al (1984). Effect of ticlopidine on saphenous vein bypass patency rates: a double blind study. Ann Thoracic Surg 37:371-8.
Steven D. Filardo, M.D., M.P.H.