The Canadian American Ticlopidine Study is a randomized, placebo-controlled, double-blind, multicenter study to assess the efficacy and safety of ticlopidine hydrochloride in patients who have suffered a thromboembolic stroke no less than 1 week and no more than 4 months before entry into the study. The primary assessment of efficacy will be based on the cluster of outcome events recurrent stroke, myocardial infarction, or vascular death. Twenty-five clinical centers, 12 in Canada and 13 in the United States, entered a total of 1,072 patients during a 3-year recruitment period; these patients were randomly allocated to receive either 250 mg ticlopidine or identical-appearing placebo tablets twice daily for up to 3 years. Patient recruitment was completed in December 1986. Patients were followed for a maximum of 3 years or until the close of the study in December 1987; at that time an average follow-up of 25 months had been achieved. We summarize the protocol and organization of the study and document the methods of execution and analysis, with corresponding criteria, before disclosure of the treatment code to any of the study investigators. We also provide a clinical description of the patients at entry into the study.

Four hundred and thirty-eight patients who had suffered a thromboembolic stroke not less than two weeks or more than four months previously, were entered into a placebo-controlled randomized clinical trial to determine whether suloctidil (200 mg t.i.d.) would influence the subsequent recurrence of stroke, the occurrence of myocardial infarction, or cardiovascular death. The two treatment groups were comparable at baseline with respect to important prognostic variables and there was good adherence to the study protocol during an average follow-up of 20 months. Significantly more patients complained of side-effects in the suloctidil group and more hepatotoxicity was also reported in the suloctidil group. Four cases of clinical hepatitis were suspected to be due to suloctidil, each of which was reversible on termination of study treatment; relative increases in SGOT and SGPT at three months in the suloctidil group were found to be mild and transient. The primary analysis of efficacy was based on the incidence of the first event of stroke, myocardial infarction or cardiovascular death, but excluding events that occurred more than 28 days after complete withdrawal from study medication for whatever reason. Thus, the primary analysis included 38 events in the suloctidil group and 47 in the placebo group (p = 0.17) representing a risk reduction of 24%. If total mortality is substituted for cardiovascular death, the corresponding figures are 47 in the suloctidil group and 58 in the placebo group (p = 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Approximately 1000 patients who have suffered a well-documented thromboembolic stroke within two weeks to four months of study entry will be enrolled in this double-blind, randomized, placebo controlled, parallel group trial. Five Canadian and five United States study centers will participate. The enrollment period will be two and one half years, and follow-up will run for an additional six months to a common termination point at three years. Ticlopidine hydrochloride, administered as two 125 mg tablets b.i.d. (500 mg/day total dose) will be compared with placebo for efficacy in the prevention of recurrent stroke, myocardial infarction, cardiovascular death, and overall mortality. Inclusion and exclusion criteria will be the minimum necessary to provide safety and scientific validity. After a screening visit, qualifying patients will be randomly assigned to ticlopidine or placebo. Follow-up laboratory studies for monitoring complete blood and platelet counts will be made at weeks 2, 4, 6, 8, 10 and 12, and then months 4, 5, 6, 8 and then every 4 months thereafter. Follow-up clinic visits will be made at 1 month, 4 months, and then every four months thereafter for clinical evaluation and for dispensing test medication. Study outcome events will be appropriately documented on case report forms. The statistical analysis will evaluate the initial comparability of the two treatment groups, and the principal outcomes of the two groups will be compared by using the Mantel-Haenszel life table analysis.

* Presented at the VIth International Congress on Thrombosis and Haemostasis, Philadelphia, Pa., June 27, 1977

The observation by Didisheim of platelet-fibrin hemostatic plugs occluding puncture sites in teflon AV shunts prompted an attempt to produce similar plugs in vitro using a pump to circulate shed blood. Various anticoagulants, tubing types, flow rates, pressures and methods of producing suitable holes have been investigated. Satisfactory results have been obtained with drilled holes 0.013 - 0.018” diameter in tygon or teflon tubing using heparinized or native, but not EDTA or citrated whole blood. Holes are occluded by platelet fibrin thrombus. Red cells are necessary for plugs to form but are not a component of the plug. Time required for plugs to form correlate with the template bleeding time and are prolonged by thrombocytopenia, aspirin administration, and Von Willebrand’s disease. Possible applications are being explored.

169 patients were randomly allocated to Sulfinpyrazone or placebo after peripheral vascular surgical procedures. Randomization was stratified for surgeon and type of operation (endarterectomy, vein graft, or prosthesis) and aorto-iliac or femoral popliteal site. Treatment was begun with Sulfinpyrazone 200 mgs. t.i.d. or equivalent placebo. Platelet tests were performed at intervals and patients with active collagen aggregation were given increments to 1200 mgs. daily or equilivent placebo. Patients were followed for up to 3 years. Claudication distances, peripheral pulses, readmissions, and returns to surgeon were documented at intervals. Three endpoints were assessed without knowledge of treatment category; occlusion at operated site, occlusion in same leg, and all peripheral vascular events, as well as other episodes of vascular disease. 137 patients had femoral popliteal and 27 had aortoiliac surgery. There was no evidence of benefit in either group with respect to any of the endpoints. There was 1 death in the treated group and 2 deaths in the control group. Suspect drug toxicity was similar in treatment and control groups (22 vs. 19) although more patients were withdrawn from the treatment group as a result (11 vs. 50, mostly because of rash, dyspepsia, and nausea. This study suggests that Sulfinpyrazone does not prolong patency after peripheral vascular surgery.

Arterial disease is a severe test of clinical trials methodology. Results to date have defined areas for further study, but clinical indications are not established. Dipyridamole reduces emboli from prosthetic heart valves but applicability to less thrombogenic valves is uncertain. Transient cerebral ischemic attacks are physiologically appropriate and there is preliminary evidence of reduced attacks with Sulfinpyrazone, none with Dipyridamole, and favorable case reports with Aspirin. Effects on stroke and death in patients presenting with TIA or stroke are under study. Sulfinpyrazone has failed to prolong patency time after peripheral vascular surgery. Administration of aspirin and of Sulfinpyrazone to elderly populations has shown no detectable benefit from Aspirin, and has suggested that Sulfinpyrazone should be further studied in patients recovered from thrombotic stroke. The greatest potential benefit may be secondary prevention of myocardial infarct, but to date efficacy has neither been demonstrated nor excluded. Studies in progress include: ASA and/or Sulfinpyrazone and TIA, stroke and death in patients with TIA; ASA with and without Dipyridamole in patients with TIA: Sulfinpyrazone and survival after recovery from thrombotic stroke; Secondary prevention of myocardial infarct with ASA, ASA or ASA + Dipyridamole, Sulfinpyrazone, and Clofibrate; Sulfinpyrazone, ASA, and ASA with anticoagulants and emboli from prosthetic valves. Platelet survival studies may permit selection of populations likely to benefit and assessment of adequacy of therapy. Hypotheses tested by clinical trial must be distinguished from hypotheses formulated from retrospective analysis, and methods must permit effects of treatment to be distinguished from differences in risk.