Stroke ticlopidine

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Ticlopidine is slightly more beneficial in stroke prevention than aspirin in both men and women.31,32 The usual recommended dosage is 250 mg orally twice daily. Ticlopidine is costly, and side effects include bone marrow suppression, rash, diarrhea, and an increased cholesterol level. Neutropenia is seen in approximately 2% of patients. Thrombotic thrombocytopenic... 

A 65-year-old male with a previous history of a stroke is treated with ticlopidine as prophylaxis for preventing further stroke. What is the mechanism of action of ticlopidine ... 

Ticlopidine can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and thrombotic thrombocytopenic purpura (TTP). Neutropenia/agranulocytosis Neutropenia defined as an absolute neutrophil count (ANC) less than 1,200 neutrophils/mm occurred in 50 of 2048 (2.4%) stroke patients who received ticlopidine in clinical trials. Neutropenia is calculated as follows ANC = WBC x % neutrophils. In 17 patients (0.8%) the neutrophil count was less than 450/mm. ... 

Activation of platelets is considered an essential process for arterial thrombosis. Thus, treatment with platelet-inhibiting drugs such as aspirin and ticlopidine or clopidogrel is indicated in patients with transient ischemic attacks and strokes or unstable angina and acute myocardial infarction. In angina and infarction, these drugs are often used in conjunction with -blockers, calcium channel blockers, and fibrinolytic drugs. 

Antagonists of the ADP P2Y, 2 receptor, ticlopidine and its safer successor clopidogrel, are also potent inhibitors of platelet aggregation and have demonstrated their efficacy alone and on top of ASA in numerous in clinical studies. The results of the CAPRIE study, a large study involving 19,185 patients with recent Ml, stroke, or established peripheral arterial disease (PAD) demonstrated an 8.7% overall risk reduction versus ASA in the combined endpoints of the first occurrence of Ml, stroke, or other vascular death (30). 

Currently, the two antiplatelet agents with proven efficacy are aspirin, which inhibits cyclooxygenase -dependent synthesis of thromboxane Aj (TXj ), and ticlopidine, wdrich blocks the ability of ADP to inhibit stimulated adenyl cyclase. Bodi of these drags have proven prophylactic uses in reducing the risk of thrombo -occlusive and thromboembolic complications for all major arterial beds in individuals with a previous history of such episodes. Controlled trials show that both aspirin and ticlopidine are indicated in the secondary prevention of stroke, myocardial induction and peripheral vascular occlusion. However, there are limitations to their efficacy. No net changes in vascular events are seen with primary prevention. Moreover, antiplatelet drugs do not alter thrombocytopenia or impairment... 

In a randomized trial comparing ticlopidine (500 mg/ day) with aspirin (1300 mg/day) for the prevention of stroke in high-risk patients, the incidence of bleeding was similar in both groups, although more patients treated with aspirin developed peptic ulceration or gastrointestinal hemorrhage (52). 

Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. 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 1989 321(8) 501-7. 

Ticlopidine is a thienopyridine derivative with potent antiplatelet activity associated with inhibition of ADP-induced platelet aggregation. It was first used in Europe in 1978 in the secondary prevention of stroke and coronary events, the treatment of peripheral vascular disease, and after vascular stent placement. However, the use of ticlopidine has been progressively restricted in some countries because of its serious adverse effects. It has largely been superseded by clopidogrel. 

Ellie E, Durrieu C, Besse P, Julien J, Gbipki-Benissan G. Thrombotic thrombocytopenic purpura associated with ticlopidine. Stroke 1992 23(6) 922-3. 

Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AG. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989 l(8649) 1215-20. 

Ticlopidine can be useful clinically. It inhibits expression of the platelet GPIlb/lIIa receptors into the high-afflnity ligand-binding state, a process that takes some days to become fully effective. Although it may be as effective as aspirin in reducing stroke, this delay (and greater side-effects) limits usefulness. 

Ischemic stroke TPA, heparin, ASA, clopidogrel, ticlopidine, dipyridamole and aspirin, warfarin, surgery Neurological worsening, bieeding, PT/APTT, INR, CBC... 

Hass, W.K. Easton, J.D. Adams, H.P Pryse-Phillips, W. Molony, B.A. Anderson, S. Kamm, B. A Randomized Trial Comparing Ticlopidine Hydrochloride with Aspirin for tlie Prevention of Stroke in High Risk Patients, ... 

The efficacy of clopidogrel as an antiplatelet agent in atherothrombotic disorders was demonstrated in the CAPRIE trial. In this study of more than 19,000 patients with a history of either myocardial infarction (MI), stroke, or peripheral arterial disease (PAD), clopidogrel 75 mg/day was compared with aspirin 325 mg/day for its ability to decrease MI, stroke, or cardiovascular death. In the final analysis, clopidogrel was slightly (8% relative risk reduction [RRR]) more effective than aspirin (p =. 043) and had a similar incidence of adverse effects. It is not associated with the blood dyscrasias (neutropenia) common with its congener, ticlopidine, and is used widely in patients with atherosclerosis. 

Ticlopidine is a thienopyridine antiplatelet agent, similar in structure and mechanism of action to clopidogrel. It has been shown to reduce the risk of stroke by 30% compared with placebo and by 21% compared with aspirin 325 mg/day inpatients at risk. The use of ticlopidine has been severely restricted by its side-effect profile, however. It causes bone marrow suppression, rash, diarrhea, and elevation of the serum cholesterol concentration. Neutropenia occurs in up to 2% of patients and generally is reversible. More problematic, however, is the increased risk of aplastic anemia and thrombotic thrombocytopenic purpura. Ticlopidine 250 mg twice daily is stiU available as an alternative in patients who fail or are intolerant of other therapies but is rarely needed. 

Bennett CL, Davidson CJ, Raisch DW, et al. Thrombotic thrombocytopenic purpura associated wifii ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999 159 2524-2528. 

Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Int Med 1990 227 301-308. 

---