journal o/ lnternal Medicine 1 9 9 0 ; 2 2 7 : 301-308
Prevention of myocardial infarction and stroke in patients with intermittent claudication ; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study L. J A N Z O N , D. BERGQVIST, J. BOBERG§, M. B O B E R G I , 1. ERIKSSONS, F. LINDGARDE* & G. PERSSONt From the Department oJ Surgery and the * Department oJ Internal Medicine. Malmo General Hospital. the Department of Internal Medicine, University OJ Lund. Malmii. the $Department oJ Surgery and the 5 Department oJ lnternal Medicine. Academic Hospital. and the [: Department oJ Geriatrics. Kungsgiirdets Hospital. University of Uppsala, Uppsala. Sweden
Abstract. Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G (Department of Surgery and Department of Internal Medicine, Malmo General Hospital. Department of Internal Medicine, University of Lund, Malmo, Department of Surgery and Department of Internal Medicine, Academic Hospital, and Department of Geriatrics, Kungsgardets Hospital, University of Uppsala, Uppsala, Sweden). Prevention of myocardial infarction and stroke in patients with intermittent claudication : effects of ticlopidine. Results from STIMS. the Swedish Ticlopidine Multicentre Study. journal of Internal Medicine 1 9 9 0 ; 2 2 7 : 301-308. The Swedish Ticlopidine Multicentre Study (STIMS)was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until a n end-point was reached. The number of end points (99 vs. 89). analysed according to the intention-to-treat principle, was 11.4%lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1 % lower in the ticlopidine group (64 vs. 89, P = 0.015): this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine.
Keywords : intermittent claudication. myocardial infarction, prevention, ticlopidine.
Introduction Intermittent claudication is not only a symptom of leg artery occlusive disease: it is also an indicator of generalized atherosclerosis, associated with a greatly increased cardio- and cerebrovascular morbidity and mortality rate 11, 21. During the last two decades there has been growing evidence from both experimental research and clinical studies that the risk of myocardial
infarction and stroke can be reduced by means of drugs that inhibit platelet aggregation [3-lo]. The Swedish Ticlopidine Multicentre Study (STIMS) was designed to assess whether the incidence of myocardial infarction, stroke and transitory ischaemic attacks (TIA) in patients with intermittent claudication can be reduced with ticlopidine, a platelet anti-aggregatory agent [ l 11known to inhibit the formation of arterial thrombi 1121.
The study medication (Ticlid". ticlopidine hydrochloride, 2 50 rng) was supplied by Sanoli UK Ltd.
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Table 1 Characteristics of the study population
Characteristic Number of patients randomized Sex Male Female Mean agekSD (years) Smoking habits Non-smoker Ex-smoker Current smoker Systolic blood pressure > 1 6 0 mmHg Diastolic blood pressure > 100 mmHg Cholesterol concentration > 6.2 mmol I-' Triglyceride concentration > 1.6 mmol I-'
341
346
260 (76.2) 81 (23.8) 60.2 6.9
265 (76.6) 81 (23.4) 60.5 & 6.0
12 (3.5) 99 (29.0) 229 (67.2) 101 (29.6) 11 (3.2) 184 (54.0) 171 (50.1)
17 (4.9) 9 6 (27.7) 233 (67.3) 105 (30.3) 8 (2.3) 196 (56.6) 176 (50.9)
Patients and methods
Table 2. Medical history of study population
Patient selection
Medical history
Placebo group (%)
Ticlopidine group (%)
Number of patients randomized Duration of peripheral arterial disease (PAD)
341
346
49 (14.4) 110 (32.3) 181 (53.0) 105 (30.8) 77 (22.6) 6 7 (19.0) 1 1 (3.2) 2 4 (7.0)
52 97 196 109 96 56 9 22
All patients included in the study had a history of intermittent claudication as defined by the WHO classification [13], i.e. effort-induced pain which forced the patient to stop walking, but which disappeared within 10 min of rest. The presence of leg artery occlusive disease was confirmed by an abnormal systolic pressure gradient between upper arm and ankle [14]. For the purpose of this study, an abnormal pressure gradient was a difference of 5 or 10 mmHg, with upper arm pressure above or below 150 mmHg, respectively. Patients who had undergone reconstructive vascular surgery to relieve the symptoms of intermittent claudication, or amputation, were also eligible for inclusion in the study. The following patients were excluded from the study: patients aged > 70 years: pregnant and fertile women ; patients receiving treatment known to affect platelet function or anticoagulant drugs : patients who had a platelet count below 100 x lo9 I-' : patients receiving lipid-lowering drugs other than clofibrate; patients who had suffered a myocardial infarction within the last 3 months or who had undergone major surgery within the last month: diabetic patients who were treated with insulin or who showed evidence of advanced proliferative retinopathy or renal failure : patients with chronic diseases such as malignancy, signs of polyneuritis of obscure origin, uncontrolled hypertension (blood pressure > 190/ 110 mmHg), rheumatic valvular disease with atrial fibrillation, previous bleeding peptic ulcer, or a stroke which prevented them from
-=
1 year 1-3 years > 3 years Previous surgery for PAD Evidence of angina Previous myocardial infarction Previous stroke Diabetes mellitus type I1
(15.0) (28.0) (56.6) (31.5) (27.7) (16.2) (2.6) (6.4)
walking to the extent that claudication could not be experienced : patients with renal dysfunction (serum creatinine > 150 mmol I-'), or liver dysfunction (aspartate aminotransferase > 2 pkat* I-', alanine aminotransferase > 2 pkat I-', gamma-glutamyltransferase > 3 pkat I-'). Each patient gave his/her informed oral consent to participate in the study, which was approved by the Ethical Committee of the Medical Faculty, University of Lund.
Study population A total of 687 patients was entered by six clinical centres based in three Swedish cities. The first patient started treatment in November 1980. The numbers of patients entered by each centre were as follows: *One microkatal (pkat) = 1 micromole of reaction product per second.
SWEDISH TICLOPIDINE MULTICENTRE STUDY
Uppsala Medical, 7 ; Uppsala Geriatric, 4 4 ; Uppsala Surgical, 61 ; Lund Medical, 101: Malmo Medical, 204; Malmo Surgical, 270. Of the patients entered, 418 individuals were regularly attending the participating clinics for control of peripheral arterial disease. A further 1 2 1 patients were actively recruited by seeking referrals from general practitioners in the surrounding areas. The remaining 148 patients were entered following the offer of active screening (history and ankle/arm blood pressure measurements) to individuals who had experienced leg pain on walking. The trial population is described in Tables 1 and 2.
Study organization The STIMS organization comprised the six clinical centres, a Policy Committee, an Adjudication Committee, an independent statistician, and a study monitoring centre. The Policy Committee comprised senior personnel independent of the study investigators, and its function was to resolve any ethical or procedural problems. The Chairman of the Policy Committee was also responsible for monitoring serious or unexpected adverse events, and advised on the notification of the Swedish Health Board regarding such events. The Adjudication Committee consisted of an independent cardiologist and a neurologist, and was responsible both for the validation of end points and for the review and classification of deaths. The role of the study statistician was to prepare the randomization procedure, to design the case record forms, to maintain the database and to assist in analysis of the study.
Randomization A minimization procedure [15] was used to balance the placebo and ticlopidine treatment groups for important risk factors (Tables 1 and 2 ) .
Study medication Ticlopidine-5-(2-chlorobenzyl)-4,5,6, 7-tetrahydrothieno-( 3,2-c)-pyridine hydrochloride was supplied as coated 2 50-mg tablets enclosed in protective strips, each pack containing 100 tablets. Placebo tablets were identical in appearance and packing, and contained denatonium benzoate to match the bitter taste of ticlopidine. The treatment regimen consisted of one tablet administered twice daily.
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Other interventions All patients were monitored for known cardiovascular risk factors, and received other interventions if necessary. Hypertension (blood pressure > 160/ 100 mmHg) was controlled with beta blockers, calcium antagonists and/or diuretics. Hyperlipidaemia was controlled by diet and, where necessary, clofibrate therapy. High blood glucose levels were also controlled by dietary advice and, when appropriate, with oral hypoglycaemic agents. The effect of cigarette smoking on the progress of atherosclerosis was explained, and all patients were encouraged to abstain from smoking. Patients were advised not to use acetylsalicylic acid-containing medications, and were informed as to which analgesics they should use.
Follow-up assessments The progress of patients was reviewed 1 month after entry and at 3-month intervals thereafter. Blood samples were analysed at each visit.
End points and mortality Acute myocardial infarction was diagnosed on the basis of clinical symptoms, abnormal ECG findings and enzyme changes. Fatal cases required the postmortem demonstration of a myocardial infarction with evidence of histological changes in the myocardium and/or occlusion of a coronary artery with a fresh thrombus. Stroke was diagnosed on the basis of unequivocal signs of focal or global neurological deficits of sudden onset, with a duration of at least 24 h, judged clinically to be of vascular origin. A TIA was defined as the occurrence of a disturbed motor or sensory function of duration < 24 h. Two ischaemic attacks were required to be counted as an end point if the first episode did not lead to treatment. The immediate and underlying causes of death were established from the hospital records, death certificates and, in 57% of cases, from autopsy. The underlying cause of death was classified according to the ICD-code 8th revised version [ t6].
Statis tics The study was designed to have 90% power, at 5% significance levels, to detect a 50% reduction of
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primary end points. The anticipated incidence in the control group was 20%. The predetermined end of the trial was 31st December 1987. No interim analyses were performed. The following factors were compared between treatment groups. (a) Protocol end points: (i) intention to treat ’ analysis-all end points and all patients were included ; (ii) ‘on treatment ’ analysis-patients who never received medication (seven out of 687 individuals) and end points which occurred more than 1 5 d after treatment was first discontinued (65 of 188 individuals) were excluded. (b) Deaths: ‘ intention to treat’ analysis, including all patients and all deaths recorded up to the end of the study. All comparisons of end points were made using the log-rank test (two-sided).
Results The minimization procedure yielded two groups which were well matched for all baseline characteristics and cardiovascular risk factors (Tables 1 and 2). All patients were identified for evaluation of status at the end of the trial. The median duration of observation from entry to final evaluation, or to an end point and/or death if earlier, was 5.6 years. One hundred and forty-six patients in the placebo group and 1 2 0 patients in the ticlopidine group completed the study (Table 3). At the end of the study, 238 patients (34.6 %) were still taking medication (ticlopidine in 1 0 7 cases, placebo in 1 3 1 cases).
Table 3. Patient status at end of trial Placebo group (%)
Outcome Protocol end point Death other than study end point Withdrawal from study Adverse events Intercurrent disease Dropped out Other reason Sub-total Number of patients who completed study Total number of subjects
99 (29.0) 37 (10.9)
8 9 (25.7) 31 (8.9)
26 (7.6) 13 (3.8) 10 (2.9) 1 0 (2.9) 195 146 (42.8)
73 (21.1) 7 (2.0) 12 (3.5) 14 (4.0) 226 1 2 0 (34.7)
341
346
End points Eighty-nine (2 5.7%) patients in the ticlopidine group and 99 (29.0%) patients in the placebo group had suffered an end point by the time the study had ended. This 11.4% lower incidence of primary end points in the ticlopidine group was not statistically significant (Table 4). Sixty-eight (68.7%) of the primary end points in the placebo group and GO (67.4 %) of those in the ticlopidine group fulfilled the study criteria for acute myocardial infarction. With the on-treatment evaluation, the incidence of primary end points in the ticlopidine group ( n = 4 7 : 13.8%). was 38.4% lower than in the placebo group ( n = 7 6 ; 22.4%) (P = 0.017) as shown in Table 4 and Fig. 1. When the time of observation in the two groups was taken into account, the corresponding risk ratio was 0.66 (95% confidence interval, 0.45-0.9 6).
Table 4. Incidence of myocardial infarction, stroke and TIA Intention to treat
On treatment
End point
Placebo group (n = 341) (%)
Ticlopidine group (n = 346) (%I
Placebo group (n = 339) (%)
Fatal myocardial infarction Non-fatal myocardial infarction Fatal stroke Non-fatal stroke TIA Sum of all primary end points
26 (7.6) 42 (12.3) 3 (0.9) 19 (5.6) 9 (2.6) 99* (29.0)
15 (4.3) 45 (1 3.0) 1 (0.3) 18 (5.2) 10 (2.9) 89* (25.7)
18 (5.3) 35 (10.3) 1 (0.3) 14 (4.1) 8 (2.4) 7 6 t (22.4)
~
*Statistically significant at P = 0.24. t Statistically significant at P = 0.01 7.
Ticlopidine group (%I
Ticlopidine group (n = 341) (%) ~~~
6 (1.8) 26 (7.6) 0 (0) 10 (2.9) 5 (1.5) 4 7 t ( I 3.8)
SWEDISH TICLOPIDINE MULTICENTRE STUDY
305
I.o
>
0.8
+ ..-
32
2
0.6
!.
0.4
g -
Fig. 1 . STIMS on-treatment analysis of end points, i.e. acute myocardial infarction, stroke and TIA. Log-rank test for treatment difference: P = 0.01 7, (----) = ticlopidine. (-) = placebo.
L
3
m
0.2
0
I
2
3
4
5
6
7
5
6
7
Year of study
1.0
0.8
L
a
._ ? 0.4
z
Fig. 2. Intention-to-treat analysis of total mortality, including all deaths up until the end of the trial. Log-rank test for treatment difference: P = 0.01 5. (---) = ticlopidine. (-) = placebo.
m
0.2
0
lschaemic heart disease
Placebo
Ticlopidine
( n = 341)
( n = 346)
n
%
n
54 (12)t
15.8
31 ( 9 ) t
9.0
4 (1)
1.2
5 (3)
1.4
I 7 (3) 1 1 (2) 64$ (1 7)
4.9 3.2 18.5
%
410-414
Cerebro-vascular disease 430-438 Cancer 140-239
Other Total
15 (1) 16 (9) 89$ (23)
2
3
4
Year of study
Table 5. Comparison of total and cause-specific mortality Underlying cause of death'
I
4.4 4.7 26.1
*According to ICD code 8th revised version. tFigures in parentheses denote deaths which occurred following a non-fatal end point. $Statistically significant at P = 0.015.
from ischaemic heart disease. Other causes of death were similar in the two groups. Twenty-six patients in the placebo group and fifteen in the ticlopidine group died from acute myocardial infarction (ICD-code 8th revised version 410.0410.9). A further 1 4 deaths in the placebo group and 7 deaths in the ticlopidine group were classified by the Adjudication Committee as cardiovascular deaths on the basis of information obtained from hospital records and findings at autopsy. These patients died suddenly, or were found after death at home. The underlying cause of death recorded on the death certificate was in each case chronic ischaemic heart disease (ICD-code 412.0-412.9). A total of 4 0 deaths ( 2 3 in the placebo group and 1 7 in the ticlopidine group) followed non-fatal end points.
Mortality
Risk variables
The total mortality in the ticlopidine group ( n = 64) was 29.1 % lower than that in the placebo group ( n = 89) (P = 0.015), as shown in Table 5 and Fig 2. This differencewas explained by the lower mortality
Nineteen per cent of subjects in the placebo group and 10% of those in the ticlopidine group stopped smoking. The mean cholesterol level for patients in the ticlopidine group increased by 0.21 mmol I-'
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L. J A N Z O N et al.
Table 6. Frequency of side-effects
Side-effect Thrombocytopenia Thrombocytopenia + leucopenia Leucopenia Pancytopenia Diarrhoea Other gastro-intestinal symptoms Skin rash Other dermatological symptoms Hepatic symptoms Other side-effects*
Placebo group (n = 341) (%) 0 0 0 0 30 (8.8) 35 (10.3)
Ticlopidine group (n = 346) (%) 3 (0.9) 1 (0.3) 2 (0.6) 1 (0.3) 75 (21.7) 57 (16.5)
6 (1.8) 8 (2.3)
12 (3.5) 12 (3.5)
6 (1.8) 28 (8.2)
6 (1.7) 37 (10.7)
*Including haemorrhagic adverse events. Patients reporting the same adverse event on more than one occasion are cited only once. Patients who reported more than one type of event are cited once for each event.
(range - 2.6- + 4.7 mmol I-'). The mean cholesterol concentration in the placebo group decreased by 0.09 mmol I-' (range - 3.4-+ 3.6 mmol I-'). The mean blood pressure remained unchanged in the two groups. Side-eflects and toxicity
The frequency of side-effects was greater in the ticlopidine group (T) than in the placebo group (P), as shown in Table 6, and more patients on ticlopidine had treatment permanently withdrawn because of side-effects (26P: 73T), as shown in Table 3. The most frequently recorded side-effect was diarrhoea, reported by 75 patients (22 %) on ticlopidine and 30 patients (9%) on placebo. Haematological events were recorded for seven patients (2%) in the ticlopidine group, but not for any patients in the placebo group. One case of pancytopenia occurred after more than 2 years of treatment, and was reversed on cessation of treatment. Malignant lymphoma was diagnosed 2 months later. Two cases of leucopenia were considered unlikely to be related to therapy : one was registered after treatment for 5 months, and normalized with continued therapy: the other, recorded after 11 months of treatment and later associated with a relative thrombocytopenia which remained within normal limits, was still unchanged after withdrawal from therapy and also when rechallenged. The third
case of leucopenia was asymptomatic, but the leucocyte count remained low for several years after withdrawal from therapy. This case did not occur until 2.5 years after initiation of therapy. Examination of the routine laboratory data revealed 11 unreported cases of a patient (3P:ST) with a white cell count of < 3.5 x lo8I-' on at least one occasion. Most of these deficits were marginal, and the lowest recorded value was 2.2 x lo9I-'. These events had no clinical correlate, they did not lead to withdrawal of medication, and all remained stable or reverted spontaneously to normal. Three cases of absolute thrombocytopenia were reported as adverse events in the ticlopidine group. In addition, examination of the laboratory data revealed six further cases (5P: 1T) with a platelet count below 100 x 10' I-' on at least one occasion. These cases were not associated with clinical symptoms at the time of examination or in the subsequent clinical course, and specifically were not associated with bleeding. The three reported cases had been taking study medication for at least 4 years : the medication was discontinued, but in each case the platelet count declined further over a period of several months (minimum recorded value: 20 x 10yl-') before recovering to sustained marginally subnormal levels. In 10 patients a haemoglobin concentration of < 100 g 1-' was recorded on at least one occasion during the study (7P :3T) ; this was never associated with bleeding, recovery was spontaneous with continued treatment, and no adverse events were reported. Bleeding episodes or effects were reported in 25 patients (9P: 16T). six of whom (1P: 5T) had study medication withdrawn.
Discussion The main objective of the present study was to determine the effect of long-term antiplatelet therapy with ticlopidine on the reduction of the risk of myocardial infarction and stroke in patients with intermittent claudication. The incidence of primary end points was similar in the two groups. The number of cases with fatal myocardial infarction (15 vs. 26) was. however, 43% lower in the ticlopidine group. The 29% lower mortality in the ticlopidine group (64 vs. 89) at the end of the study was explained by the lower mortality from ischaemic heart disease (ICD 4 1 0 .0 4 1 4 .9 ) in
SWEDISH TICLOPIDINE MULTICENTRE STUDY
the ticlopidine group. A higher proportion of individuals gave up smoking in the placebo group than in the ticlopidine group. The mean cholesterol concentration increased by 0.21 mmol I-' in the ticlopidine group, but not in the placebo group and, if anything, these changes would reduce the potential benefits associated with ticlopidine treatment. The case-fatality rate among patients who suffered a cardiovascular event, i.e. acute myocardial infarction (ICD 410 .0 4 1 0 .9 ) or death due to chronic ischaemic heart disease (ICD 4 1 2 .0 4 1 2 .9 ) was 22/67 (32.8%) in the ticlopidine group and 40/82 (48.8%) in the placebo group. These results suggest that ticlopidine improves the survival rate in patients suffering a cardiovascular event. The incidence of side-effects in the ticlopidine group was higher than expected. At the end of the study, a greater proportion of patients were still receiving medication in the placebo group than in the ticlopidine group. Many of the patients who had treatment withdrawn because of side-effects stopped their medication early. From a clinical perspective it is rational to include in the analysis a comparison of the effect in patients who actually took the medication. The on-treatment analysis showed a greater preventive effect associated with ticlopidine treatment, and indicates that ticlopidine not only improves survival among patients suffering a vascular event, but in fact reduces the risk of myocardial infarction and stroke. The beneficial effects associated with long-term ticlopidine treatment observed in STMS further extend the results obtained by the CanadianAmerican Ticlopidine Study (CATS) and the Ticlopidine-Aspirin Stroke Study (TASS) in North America. Not only was there a decrease in the number of studied end points, but a reduction in total mortality was also observed. In TASS, the incidence of stroke among patients with previous cerebrovascular disease was 2 1% lower in the ticlopidine group than in the aspirin group [17]. In CATS, a placebo controlled trial, the incidence of new vascular events in patients who had experienced recent thromboembolic stroke was 30% lower in the ticlopidine group [18]. The results of these three studies support the conclusion recently drawn in a review on secondary prevention of vascular disease [191 that antiplatelet treatment improves the prognosis for patients with symptomatic atherosclerotic disease. We consider that tidopidine is a powerful drug 22
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which is, however, associated with a fairly high incidence of side-effects. It should be noted that many of the side-effects reported in the ticlopidine group were also observed in the placebo group. Side-effects tended to occur at an early stage, i.e. within 6 months of treatment. The clinical course was nonserious in all cases. We conclude that, in claudicants who tolerate the drug, treatment with ticlopidine is associated with a reduction in cardio- and cerebrovascular morbidity and mortality rate.
Acknowledgements We should like to thank the following for their assistance in this study: B. Fagher, MD, H. Larsson, MD, and L. Norgren, MD, from the Department of Internal Medicine, University of Lund ; G. Adielsson, MD, and T. Kjellstrom, MD, from the Department of Internal Medicine, Malmo General Hospital ; R. Takolander, MD, B. F. Ericsson, MD, and H. H. Persson, MD, from the Department of Surgery, Malmo General Hospital; B. Almgren, MD, from the Department of Surgery, Academic Hospital, University of Uppsala. The members of the Policy Committee were S.-E. Bergentz, MD, A. Gustafsson, MD, B. Hood, MD, S.-E. Lindell, MD, and S. Persson, MD. The following served on the Adjudication Committee : S. Persson, MD, from the Department of Cardiology, University of Lund, and B. Hindfeldt, MD, from the Department of Neurology, University of Lund. The study statistician was Dr A. Oden, of the University of Goteborg. The study was co-ordinated by S. Bews, MD, and Dr J. Dickinson of Sanofi UK, Manchester, UK, and L. Hermann, MD, and A. Wagner, MD, of Meda AB, Goteborg.
References 1 Kannel WB. ShurtleffD. The natural history of arteriosclerosis obliterans. Cardiovasc Clin 1971: 3 : 37-52. 2 Criqui M. Coughlin S, Fronek A. Non-invasive diagnosed peripheral arterial disease as a predictor of mortality: results from a prospective study. Circulation 1985; 4 : 768-73. 3 Ross R. Glomset JA. The pathogenesis of atherosclerosis. N Engl] Med 1976: 295: 369-77. 4 Bowie EJW.Fuster V. Resistance to atherosclerosis in pigs with Willebrand's disease. Acta Med Scand 1980: 642 (Suppl.): 121-30. 5 Moore S et al. Inhibition of injury induced thrornbo-atherosclerotic lesions by anti-platelet serum in rabbits. Thrornb Haeniost 19 76 : 3 5 : 70-8 I . IMB 227
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6 Mustard JF et al. Platelets. thrombosis and atherosclerosis. Prog Biochern Phnrmacol 19 77 : 14 : 3 12-2 5. 7 Ward AS et al. Platelet aggregation in patients with peripheral vascular disease. Atherosclerosis 1978: 2 9 : 63-8. 8 Hess H. Mietaschk A. Deichsel G. Drug-induced inhibition of platelet functional delays progression of peripheral occlusive arterial disease. Lancct 1985 : 8 4 2 6 : 41 5-9. 9 UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial. Br Med / 1988: 2 9 6 : 316-20. 10 ISIS-2 (Second International Study of Infarct Survival). Collaborative Group. Randomized trial of intravenous streptokinase. oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction. J A m Coll Cardiol 1 9 8 8 : 6 (Suppl. A): 3A-13A. 1 1 Panak E. Maffrand JP. Picard-Fraire C. Vallee E. Blanchard J, Ronucci R. Ticlopidine, a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 1 9 8 3 : 13 (SUPPI.):1-54. 12 Saltiel E. Ward A. Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in platelet dependent disease states. Drugs 1987: 34: 222-62. 13 Rose GA. Blackburn H. Gillum RF. Prineas RJ. Cardiovascular Survey Methods. Geneva World Health Organisation, 1982. 14 Carter SA. Clinical measurements of systolic pressures in limbs
with arterial occlusive disease in the lower extremities. Circulatioti 1968 : 38 : 624-37. 15 Pocock SI. Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Bionietrics 1975: 3 1 : 103-15. 16 World Health Organization. Manual of the International Statistical Classification of Diseases. lrijuries and Causes of Death : Based on the Recommendations of the 8th Revision Conference 1965 and Adopted by the 19th World Health Assembly. Geneva: WHO, 1969. 17 Hass WK. Easton JD. Adams HP Jr et al. A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N Erigl/ Med 1989: 3 2 1 : 501-7. 18 Gent M. Blakely JA. Easton J D et a!. Canadian American Ticlopidine Study in Thromboembolic Stroke. lrrncet 1989 : i : 121 5-20. 19 Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Hr Med / 1 9 8 8 : 2 9 6 : 320-31. Received 2 November 1989. accepted 2 0 December 19x9.
Correspondence: L. Janzon. MD. Department of Community Health Sciences, Malmo General Hospital, Malmo, Sweden.
Prevention of myocardial infarction and stroke in patients with intermittent claudication ; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study L. J A N Z O N , D. BERGQVIST, J. BOBERG§, M. B O B E R G I , 1. ERIKSSONS, F. LINDGARDE* & G. PERSSONt From the Department oJ Surgery and the * Department oJ Internal Medicine. Malmo General Hospital. the Department of Internal Medicine, University OJ Lund. Malmii. the $Department oJ Surgery and the 5 Department oJ lnternal Medicine. Academic Hospital. and the [: Department oJ Geriatrics. Kungsgiirdets Hospital. University of Uppsala, Uppsala. Sweden
Abstract. Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G (Department of Surgery and Department of Internal Medicine, Malmo General Hospital. Department of Internal Medicine, University of Lund, Malmo, Department of Surgery and Department of Internal Medicine, Academic Hospital, and Department of Geriatrics, Kungsgardets Hospital, University of Uppsala, Uppsala, Sweden). Prevention of myocardial infarction and stroke in patients with intermittent claudication : effects of ticlopidine. Results from STIMS. the Swedish Ticlopidine Multicentre Study. journal of Internal Medicine 1 9 9 0 ; 2 2 7 : 301-308. The Swedish Ticlopidine Multicentre Study (STIMS)was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until a n end-point was reached. The number of end points (99 vs. 89). analysed according to the intention-to-treat principle, was 11.4%lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1 % lower in the ticlopidine group (64 vs. 89, P = 0.015): this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine.
Keywords : intermittent claudication. myocardial infarction, prevention, ticlopidine.
Introduction Intermittent claudication is not only a symptom of leg artery occlusive disease: it is also an indicator of generalized atherosclerosis, associated with a greatly increased cardio- and cerebrovascular morbidity and mortality rate 11, 21. During the last two decades there has been growing evidence from both experimental research and clinical studies that the risk of myocardial
infarction and stroke can be reduced by means of drugs that inhibit platelet aggregation [3-lo]. The Swedish Ticlopidine Multicentre Study (STIMS) was designed to assess whether the incidence of myocardial infarction, stroke and transitory ischaemic attacks (TIA) in patients with intermittent claudication can be reduced with ticlopidine, a platelet anti-aggregatory agent [ l 11known to inhibit the formation of arterial thrombi 1121.
The study medication (Ticlid". ticlopidine hydrochloride, 2 50 rng) was supplied by Sanoli UK Ltd.
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Table 1 Characteristics of the study population
Characteristic Number of patients randomized Sex Male Female Mean agekSD (years) Smoking habits Non-smoker Ex-smoker Current smoker Systolic blood pressure > 1 6 0 mmHg Diastolic blood pressure > 100 mmHg Cholesterol concentration > 6.2 mmol I-' Triglyceride concentration > 1.6 mmol I-'
341
346
260 (76.2) 81 (23.8) 60.2 6.9
265 (76.6) 81 (23.4) 60.5 & 6.0
12 (3.5) 99 (29.0) 229 (67.2) 101 (29.6) 11 (3.2) 184 (54.0) 171 (50.1)
17 (4.9) 9 6 (27.7) 233 (67.3) 105 (30.3) 8 (2.3) 196 (56.6) 176 (50.9)
Patients and methods
Table 2. Medical history of study population
Patient selection
Medical history
Placebo group (%)
Ticlopidine group (%)
Number of patients randomized Duration of peripheral arterial disease (PAD)
341
346
49 (14.4) 110 (32.3) 181 (53.0) 105 (30.8) 77 (22.6) 6 7 (19.0) 1 1 (3.2) 2 4 (7.0)
52 97 196 109 96 56 9 22
All patients included in the study had a history of intermittent claudication as defined by the WHO classification [13], i.e. effort-induced pain which forced the patient to stop walking, but which disappeared within 10 min of rest. The presence of leg artery occlusive disease was confirmed by an abnormal systolic pressure gradient between upper arm and ankle [14]. For the purpose of this study, an abnormal pressure gradient was a difference of 5 or 10 mmHg, with upper arm pressure above or below 150 mmHg, respectively. Patients who had undergone reconstructive vascular surgery to relieve the symptoms of intermittent claudication, or amputation, were also eligible for inclusion in the study. The following patients were excluded from the study: patients aged > 70 years: pregnant and fertile women ; patients receiving treatment known to affect platelet function or anticoagulant drugs : patients who had a platelet count below 100 x lo9 I-' : patients receiving lipid-lowering drugs other than clofibrate; patients who had suffered a myocardial infarction within the last 3 months or who had undergone major surgery within the last month: diabetic patients who were treated with insulin or who showed evidence of advanced proliferative retinopathy or renal failure : patients with chronic diseases such as malignancy, signs of polyneuritis of obscure origin, uncontrolled hypertension (blood pressure > 190/ 110 mmHg), rheumatic valvular disease with atrial fibrillation, previous bleeding peptic ulcer, or a stroke which prevented them from
-=
1 year 1-3 years > 3 years Previous surgery for PAD Evidence of angina Previous myocardial infarction Previous stroke Diabetes mellitus type I1
(15.0) (28.0) (56.6) (31.5) (27.7) (16.2) (2.6) (6.4)
walking to the extent that claudication could not be experienced : patients with renal dysfunction (serum creatinine > 150 mmol I-'), or liver dysfunction (aspartate aminotransferase > 2 pkat* I-', alanine aminotransferase > 2 pkat I-', gamma-glutamyltransferase > 3 pkat I-'). Each patient gave his/her informed oral consent to participate in the study, which was approved by the Ethical Committee of the Medical Faculty, University of Lund.
Study population A total of 687 patients was entered by six clinical centres based in three Swedish cities. The first patient started treatment in November 1980. The numbers of patients entered by each centre were as follows: *One microkatal (pkat) = 1 micromole of reaction product per second.
SWEDISH TICLOPIDINE MULTICENTRE STUDY
Uppsala Medical, 7 ; Uppsala Geriatric, 4 4 ; Uppsala Surgical, 61 ; Lund Medical, 101: Malmo Medical, 204; Malmo Surgical, 270. Of the patients entered, 418 individuals were regularly attending the participating clinics for control of peripheral arterial disease. A further 1 2 1 patients were actively recruited by seeking referrals from general practitioners in the surrounding areas. The remaining 148 patients were entered following the offer of active screening (history and ankle/arm blood pressure measurements) to individuals who had experienced leg pain on walking. The trial population is described in Tables 1 and 2.
Study organization The STIMS organization comprised the six clinical centres, a Policy Committee, an Adjudication Committee, an independent statistician, and a study monitoring centre. The Policy Committee comprised senior personnel independent of the study investigators, and its function was to resolve any ethical or procedural problems. The Chairman of the Policy Committee was also responsible for monitoring serious or unexpected adverse events, and advised on the notification of the Swedish Health Board regarding such events. The Adjudication Committee consisted of an independent cardiologist and a neurologist, and was responsible both for the validation of end points and for the review and classification of deaths. The role of the study statistician was to prepare the randomization procedure, to design the case record forms, to maintain the database and to assist in analysis of the study.
Randomization A minimization procedure [15] was used to balance the placebo and ticlopidine treatment groups for important risk factors (Tables 1 and 2 ) .
Study medication Ticlopidine-5-(2-chlorobenzyl)-4,5,6, 7-tetrahydrothieno-( 3,2-c)-pyridine hydrochloride was supplied as coated 2 50-mg tablets enclosed in protective strips, each pack containing 100 tablets. Placebo tablets were identical in appearance and packing, and contained denatonium benzoate to match the bitter taste of ticlopidine. The treatment regimen consisted of one tablet administered twice daily.
303
Other interventions All patients were monitored for known cardiovascular risk factors, and received other interventions if necessary. Hypertension (blood pressure > 160/ 100 mmHg) was controlled with beta blockers, calcium antagonists and/or diuretics. Hyperlipidaemia was controlled by diet and, where necessary, clofibrate therapy. High blood glucose levels were also controlled by dietary advice and, when appropriate, with oral hypoglycaemic agents. The effect of cigarette smoking on the progress of atherosclerosis was explained, and all patients were encouraged to abstain from smoking. Patients were advised not to use acetylsalicylic acid-containing medications, and were informed as to which analgesics they should use.
Follow-up assessments The progress of patients was reviewed 1 month after entry and at 3-month intervals thereafter. Blood samples were analysed at each visit.
End points and mortality Acute myocardial infarction was diagnosed on the basis of clinical symptoms, abnormal ECG findings and enzyme changes. Fatal cases required the postmortem demonstration of a myocardial infarction with evidence of histological changes in the myocardium and/or occlusion of a coronary artery with a fresh thrombus. Stroke was diagnosed on the basis of unequivocal signs of focal or global neurological deficits of sudden onset, with a duration of at least 24 h, judged clinically to be of vascular origin. A TIA was defined as the occurrence of a disturbed motor or sensory function of duration < 24 h. Two ischaemic attacks were required to be counted as an end point if the first episode did not lead to treatment. The immediate and underlying causes of death were established from the hospital records, death certificates and, in 57% of cases, from autopsy. The underlying cause of death was classified according to the ICD-code 8th revised version [ t6].
Statis tics The study was designed to have 90% power, at 5% significance levels, to detect a 50% reduction of
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primary end points. The anticipated incidence in the control group was 20%. The predetermined end of the trial was 31st December 1987. No interim analyses were performed. The following factors were compared between treatment groups. (a) Protocol end points: (i) intention to treat ’ analysis-all end points and all patients were included ; (ii) ‘on treatment ’ analysis-patients who never received medication (seven out of 687 individuals) and end points which occurred more than 1 5 d after treatment was first discontinued (65 of 188 individuals) were excluded. (b) Deaths: ‘ intention to treat’ analysis, including all patients and all deaths recorded up to the end of the study. All comparisons of end points were made using the log-rank test (two-sided).
Results The minimization procedure yielded two groups which were well matched for all baseline characteristics and cardiovascular risk factors (Tables 1 and 2). All patients were identified for evaluation of status at the end of the trial. The median duration of observation from entry to final evaluation, or to an end point and/or death if earlier, was 5.6 years. One hundred and forty-six patients in the placebo group and 1 2 0 patients in the ticlopidine group completed the study (Table 3). At the end of the study, 238 patients (34.6 %) were still taking medication (ticlopidine in 1 0 7 cases, placebo in 1 3 1 cases).
Table 3. Patient status at end of trial Placebo group (%)
Outcome Protocol end point Death other than study end point Withdrawal from study Adverse events Intercurrent disease Dropped out Other reason Sub-total Number of patients who completed study Total number of subjects
99 (29.0) 37 (10.9)
8 9 (25.7) 31 (8.9)
26 (7.6) 13 (3.8) 10 (2.9) 1 0 (2.9) 195 146 (42.8)
73 (21.1) 7 (2.0) 12 (3.5) 14 (4.0) 226 1 2 0 (34.7)
341
346
End points Eighty-nine (2 5.7%) patients in the ticlopidine group and 99 (29.0%) patients in the placebo group had suffered an end point by the time the study had ended. This 11.4% lower incidence of primary end points in the ticlopidine group was not statistically significant (Table 4). Sixty-eight (68.7%) of the primary end points in the placebo group and GO (67.4 %) of those in the ticlopidine group fulfilled the study criteria for acute myocardial infarction. With the on-treatment evaluation, the incidence of primary end points in the ticlopidine group ( n = 4 7 : 13.8%). was 38.4% lower than in the placebo group ( n = 7 6 ; 22.4%) (P = 0.017) as shown in Table 4 and Fig. 1. When the time of observation in the two groups was taken into account, the corresponding risk ratio was 0.66 (95% confidence interval, 0.45-0.9 6).
Table 4. Incidence of myocardial infarction, stroke and TIA Intention to treat
On treatment
End point
Placebo group (n = 341) (%)
Ticlopidine group (n = 346) (%I
Placebo group (n = 339) (%)
Fatal myocardial infarction Non-fatal myocardial infarction Fatal stroke Non-fatal stroke TIA Sum of all primary end points
26 (7.6) 42 (12.3) 3 (0.9) 19 (5.6) 9 (2.6) 99* (29.0)
15 (4.3) 45 (1 3.0) 1 (0.3) 18 (5.2) 10 (2.9) 89* (25.7)
18 (5.3) 35 (10.3) 1 (0.3) 14 (4.1) 8 (2.4) 7 6 t (22.4)
~
*Statistically significant at P = 0.24. t Statistically significant at P = 0.01 7.
Ticlopidine group (%I
Ticlopidine group (n = 341) (%) ~~~
6 (1.8) 26 (7.6) 0 (0) 10 (2.9) 5 (1.5) 4 7 t ( I 3.8)
SWEDISH TICLOPIDINE MULTICENTRE STUDY
305
I.o
>
0.8
+ ..-
32
2
0.6
!.
0.4
g -
Fig. 1 . STIMS on-treatment analysis of end points, i.e. acute myocardial infarction, stroke and TIA. Log-rank test for treatment difference: P = 0.01 7, (----) = ticlopidine. (-) = placebo.
L
3
m
0.2
0
I
2
3
4
5
6
7
5
6
7
Year of study
1.0
0.8
L
a
._ ? 0.4
z
Fig. 2. Intention-to-treat analysis of total mortality, including all deaths up until the end of the trial. Log-rank test for treatment difference: P = 0.01 5. (---) = ticlopidine. (-) = placebo.
m
0.2
0
lschaemic heart disease
Placebo
Ticlopidine
( n = 341)
( n = 346)
n
%
n
54 (12)t
15.8
31 ( 9 ) t
9.0
4 (1)
1.2
5 (3)
1.4
I 7 (3) 1 1 (2) 64$ (1 7)
4.9 3.2 18.5
%
410-414
Cerebro-vascular disease 430-438 Cancer 140-239
Other Total
15 (1) 16 (9) 89$ (23)
2
3
4
Year of study
Table 5. Comparison of total and cause-specific mortality Underlying cause of death'
I
4.4 4.7 26.1
*According to ICD code 8th revised version. tFigures in parentheses denote deaths which occurred following a non-fatal end point. $Statistically significant at P = 0.015.
from ischaemic heart disease. Other causes of death were similar in the two groups. Twenty-six patients in the placebo group and fifteen in the ticlopidine group died from acute myocardial infarction (ICD-code 8th revised version 410.0410.9). A further 1 4 deaths in the placebo group and 7 deaths in the ticlopidine group were classified by the Adjudication Committee as cardiovascular deaths on the basis of information obtained from hospital records and findings at autopsy. These patients died suddenly, or were found after death at home. The underlying cause of death recorded on the death certificate was in each case chronic ischaemic heart disease (ICD-code 412.0-412.9). A total of 4 0 deaths ( 2 3 in the placebo group and 1 7 in the ticlopidine group) followed non-fatal end points.
Mortality
Risk variables
The total mortality in the ticlopidine group ( n = 64) was 29.1 % lower than that in the placebo group ( n = 89) (P = 0.015), as shown in Table 5 and Fig 2. This differencewas explained by the lower mortality
Nineteen per cent of subjects in the placebo group and 10% of those in the ticlopidine group stopped smoking. The mean cholesterol level for patients in the ticlopidine group increased by 0.21 mmol I-'
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L. J A N Z O N et al.
Table 6. Frequency of side-effects
Side-effect Thrombocytopenia Thrombocytopenia + leucopenia Leucopenia Pancytopenia Diarrhoea Other gastro-intestinal symptoms Skin rash Other dermatological symptoms Hepatic symptoms Other side-effects*
Placebo group (n = 341) (%) 0 0 0 0 30 (8.8) 35 (10.3)
Ticlopidine group (n = 346) (%) 3 (0.9) 1 (0.3) 2 (0.6) 1 (0.3) 75 (21.7) 57 (16.5)
6 (1.8) 8 (2.3)
12 (3.5) 12 (3.5)
6 (1.8) 28 (8.2)
6 (1.7) 37 (10.7)
*Including haemorrhagic adverse events. Patients reporting the same adverse event on more than one occasion are cited only once. Patients who reported more than one type of event are cited once for each event.
(range - 2.6- + 4.7 mmol I-'). The mean cholesterol concentration in the placebo group decreased by 0.09 mmol I-' (range - 3.4-+ 3.6 mmol I-'). The mean blood pressure remained unchanged in the two groups. Side-eflects and toxicity
The frequency of side-effects was greater in the ticlopidine group (T) than in the placebo group (P), as shown in Table 6, and more patients on ticlopidine had treatment permanently withdrawn because of side-effects (26P: 73T), as shown in Table 3. The most frequently recorded side-effect was diarrhoea, reported by 75 patients (22 %) on ticlopidine and 30 patients (9%) on placebo. Haematological events were recorded for seven patients (2%) in the ticlopidine group, but not for any patients in the placebo group. One case of pancytopenia occurred after more than 2 years of treatment, and was reversed on cessation of treatment. Malignant lymphoma was diagnosed 2 months later. Two cases of leucopenia were considered unlikely to be related to therapy : one was registered after treatment for 5 months, and normalized with continued therapy: the other, recorded after 11 months of treatment and later associated with a relative thrombocytopenia which remained within normal limits, was still unchanged after withdrawal from therapy and also when rechallenged. The third
case of leucopenia was asymptomatic, but the leucocyte count remained low for several years after withdrawal from therapy. This case did not occur until 2.5 years after initiation of therapy. Examination of the routine laboratory data revealed 11 unreported cases of a patient (3P:ST) with a white cell count of < 3.5 x lo8I-' on at least one occasion. Most of these deficits were marginal, and the lowest recorded value was 2.2 x lo9I-'. These events had no clinical correlate, they did not lead to withdrawal of medication, and all remained stable or reverted spontaneously to normal. Three cases of absolute thrombocytopenia were reported as adverse events in the ticlopidine group. In addition, examination of the laboratory data revealed six further cases (5P: 1T) with a platelet count below 100 x 10' I-' on at least one occasion. These cases were not associated with clinical symptoms at the time of examination or in the subsequent clinical course, and specifically were not associated with bleeding. The three reported cases had been taking study medication for at least 4 years : the medication was discontinued, but in each case the platelet count declined further over a period of several months (minimum recorded value: 20 x 10yl-') before recovering to sustained marginally subnormal levels. In 10 patients a haemoglobin concentration of < 100 g 1-' was recorded on at least one occasion during the study (7P :3T) ; this was never associated with bleeding, recovery was spontaneous with continued treatment, and no adverse events were reported. Bleeding episodes or effects were reported in 25 patients (9P: 16T). six of whom (1P: 5T) had study medication withdrawn.
Discussion The main objective of the present study was to determine the effect of long-term antiplatelet therapy with ticlopidine on the reduction of the risk of myocardial infarction and stroke in patients with intermittent claudication. The incidence of primary end points was similar in the two groups. The number of cases with fatal myocardial infarction (15 vs. 26) was. however, 43% lower in the ticlopidine group. The 29% lower mortality in the ticlopidine group (64 vs. 89) at the end of the study was explained by the lower mortality from ischaemic heart disease (ICD 4 1 0 .0 4 1 4 .9 ) in
SWEDISH TICLOPIDINE MULTICENTRE STUDY
the ticlopidine group. A higher proportion of individuals gave up smoking in the placebo group than in the ticlopidine group. The mean cholesterol concentration increased by 0.21 mmol I-' in the ticlopidine group, but not in the placebo group and, if anything, these changes would reduce the potential benefits associated with ticlopidine treatment. The case-fatality rate among patients who suffered a cardiovascular event, i.e. acute myocardial infarction (ICD 410 .0 4 1 0 .9 ) or death due to chronic ischaemic heart disease (ICD 4 1 2 .0 4 1 2 .9 ) was 22/67 (32.8%) in the ticlopidine group and 40/82 (48.8%) in the placebo group. These results suggest that ticlopidine improves the survival rate in patients suffering a cardiovascular event. The incidence of side-effects in the ticlopidine group was higher than expected. At the end of the study, a greater proportion of patients were still receiving medication in the placebo group than in the ticlopidine group. Many of the patients who had treatment withdrawn because of side-effects stopped their medication early. From a clinical perspective it is rational to include in the analysis a comparison of the effect in patients who actually took the medication. The on-treatment analysis showed a greater preventive effect associated with ticlopidine treatment, and indicates that ticlopidine not only improves survival among patients suffering a vascular event, but in fact reduces the risk of myocardial infarction and stroke. The beneficial effects associated with long-term ticlopidine treatment observed in STMS further extend the results obtained by the CanadianAmerican Ticlopidine Study (CATS) and the Ticlopidine-Aspirin Stroke Study (TASS) in North America. Not only was there a decrease in the number of studied end points, but a reduction in total mortality was also observed. In TASS, the incidence of stroke among patients with previous cerebrovascular disease was 2 1% lower in the ticlopidine group than in the aspirin group [17]. In CATS, a placebo controlled trial, the incidence of new vascular events in patients who had experienced recent thromboembolic stroke was 30% lower in the ticlopidine group [18]. The results of these three studies support the conclusion recently drawn in a review on secondary prevention of vascular disease [191 that antiplatelet treatment improves the prognosis for patients with symptomatic atherosclerotic disease. We consider that tidopidine is a powerful drug 22
307
which is, however, associated with a fairly high incidence of side-effects. It should be noted that many of the side-effects reported in the ticlopidine group were also observed in the placebo group. Side-effects tended to occur at an early stage, i.e. within 6 months of treatment. The clinical course was nonserious in all cases. We conclude that, in claudicants who tolerate the drug, treatment with ticlopidine is associated with a reduction in cardio- and cerebrovascular morbidity and mortality rate.
Acknowledgements We should like to thank the following for their assistance in this study: B. Fagher, MD, H. Larsson, MD, and L. Norgren, MD, from the Department of Internal Medicine, University of Lund ; G. Adielsson, MD, and T. Kjellstrom, MD, from the Department of Internal Medicine, Malmo General Hospital ; R. Takolander, MD, B. F. Ericsson, MD, and H. H. Persson, MD, from the Department of Surgery, Malmo General Hospital; B. Almgren, MD, from the Department of Surgery, Academic Hospital, University of Uppsala. The members of the Policy Committee were S.-E. Bergentz, MD, A. Gustafsson, MD, B. Hood, MD, S.-E. Lindell, MD, and S. Persson, MD. The following served on the Adjudication Committee : S. Persson, MD, from the Department of Cardiology, University of Lund, and B. Hindfeldt, MD, from the Department of Neurology, University of Lund. The study statistician was Dr A. Oden, of the University of Goteborg. The study was co-ordinated by S. Bews, MD, and Dr J. Dickinson of Sanofi UK, Manchester, UK, and L. Hermann, MD, and A. Wagner, MD, of Meda AB, Goteborg.
References 1 Kannel WB. ShurtleffD. The natural history of arteriosclerosis obliterans. Cardiovasc Clin 1971: 3 : 37-52. 2 Criqui M. Coughlin S, Fronek A. Non-invasive diagnosed peripheral arterial disease as a predictor of mortality: results from a prospective study. Circulation 1985; 4 : 768-73. 3 Ross R. Glomset JA. The pathogenesis of atherosclerosis. N Engl] Med 1976: 295: 369-77. 4 Bowie EJW.Fuster V. Resistance to atherosclerosis in pigs with Willebrand's disease. Acta Med Scand 1980: 642 (Suppl.): 121-30. 5 Moore S et al. Inhibition of injury induced thrornbo-atherosclerotic lesions by anti-platelet serum in rabbits. Thrornb Haeniost 19 76 : 3 5 : 70-8 I . IMB 227
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6 Mustard JF et al. Platelets. thrombosis and atherosclerosis. Prog Biochern Phnrmacol 19 77 : 14 : 3 12-2 5. 7 Ward AS et al. Platelet aggregation in patients with peripheral vascular disease. Atherosclerosis 1978: 2 9 : 63-8. 8 Hess H. Mietaschk A. Deichsel G. Drug-induced inhibition of platelet functional delays progression of peripheral occlusive arterial disease. Lancct 1985 : 8 4 2 6 : 41 5-9. 9 UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial. Br Med / 1988: 2 9 6 : 316-20. 10 ISIS-2 (Second International Study of Infarct Survival). Collaborative Group. Randomized trial of intravenous streptokinase. oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction. J A m Coll Cardiol 1 9 8 8 : 6 (Suppl. A): 3A-13A. 1 1 Panak E. Maffrand JP. Picard-Fraire C. Vallee E. Blanchard J, Ronucci R. Ticlopidine, a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 1 9 8 3 : 13 (SUPPI.):1-54. 12 Saltiel E. Ward A. Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in platelet dependent disease states. Drugs 1987: 34: 222-62. 13 Rose GA. Blackburn H. Gillum RF. Prineas RJ. Cardiovascular Survey Methods. Geneva World Health Organisation, 1982. 14 Carter SA. Clinical measurements of systolic pressures in limbs
with arterial occlusive disease in the lower extremities. Circulatioti 1968 : 38 : 624-37. 15 Pocock SI. Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Bionietrics 1975: 3 1 : 103-15. 16 World Health Organization. Manual of the International Statistical Classification of Diseases. lrijuries and Causes of Death : Based on the Recommendations of the 8th Revision Conference 1965 and Adopted by the 19th World Health Assembly. Geneva: WHO, 1969. 17 Hass WK. Easton JD. Adams HP Jr et al. A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N Erigl/ Med 1989: 3 2 1 : 501-7. 18 Gent M. Blakely JA. Easton J D et a!. Canadian American Ticlopidine Study in Thromboembolic Stroke. lrrncet 1989 : i : 121 5-20. 19 Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Hr Med / 1 9 8 8 : 2 9 6 : 320-31. Received 2 November 1989. accepted 2 0 December 19x9.
Correspondence: L. Janzon. MD. Department of Community Health Sciences, Malmo General Hospital, Malmo, Sweden.
