Risk factors, interventions and therapeutic agents in the prevention of atherosclerosis-related ischaemic diseases.

Drugs 42 (Suppl. 5): 22-38. 1991 0012-6667/91/0500-0022/$8.50/0 © Adis International Limited. All rights reserved. DRSUP3273

Risk Factors, Interventions and Therapeutic Agents in the Prevention of Atherosclerosis-Related Ischaemic Diseases M. Verstraete Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium

Summary

Of the major risk factors for atherosclerosis, high factor VII and fibrinogen levels, genetic predisposition, gender and age cannot be influenced. Reduction of high blood pressure reduces the cerebral but not the coronary vascular risk and correction of dyslipidaemia correlates with cardiovascular risk. Other major risk factors (tobacco consumption, obesity, sedentary lifestyle and diabetes) can also be modified. Aspirin in doses of approximately 300 mg/day may be recommended for the primary prevention of myocardial infarction (MI), but only in those patients with a moderate to high risk of cardiovascular disease. Aspirin reduces the risk of fatal and nonfatal MI by about 50% and also decreases the overall mortality rate among patients with unstable angina. A lower dose of aspirin (150 mg/day) also reduces mortality by 23% in the acute phase of MI. In doses of 300 mg/day, aspirin is useful in the secondary prevention of MI and reduces the overall mortality rate by 15%. Various antiplatelet agents, including aspirin (alone or combined with dipyridamole) and ticlopidine, have proved useful in the prevention of thrombosis in aorto-coronary grafts, provided treatment begins at the latest 6 hours after surgery. The usefulness of anti platelet drugs has been well established in the prevention of immediate reocclusion following coronary angioplasty, but not in the prevention of late reocclusion. Aspirin and ticlopidine are also beneficial in extracorporeal circulation techniques. In patients with a synthetic cardiac valve prosthesis, antivitamin K-anticoagulants are still indispensable lifelong, but their anti thrombotic effect can be reinforced by dipyridamole or aspirin. Diuretics probably provide the best primary protection against cerebrovascular accidents, although medium doses of aspirin may be considered in elderly people at high risk of such accidents. Aspirin (alone or combined with dipyridamole) and ticlopidine may be recommended for the secondary prevention of cerebral ischaemic accidents. Aspirin (with or without dipyridamole) and tidopidine reinforce the treatment of obliterative arterial disease in the lower limbs.

Major risk factors for atherosclerosis are as follows: dyslipidaemia, high blood pressure, smoking, obesity, type II diabetes, a sedentary life style, high factor VII and fibrinogen levels, genetic predisposition, male gender and aging. The last 4 risk factors cannot be modified and a reduction in high

blood pressure reduces the cerebral but not the coronary vascular risk. While the correction of dyslipidaemia has been shown to correlate with cardiovascular risk, this is not the case when the diet is sllpplemented with w-3 polyunsaturated fatty acid.

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Atherosclerosis-Related Ischaemic Diseases

1. Primary Prevention 0/ Cardiovascular Risk 1.1 Apparently Healthy Subjects Only 2 randomised primary prevention trials have been published. In the United States Physicians' Health Study (Steering Committee of the Physicians' Health Research Study Group 1988), which included 22 071 male doctors who were followed up for 4.8 years, aspirin (acetylsalicylic acid) 325mg on alternate days significantly reduced the incidence of a first myocardial infarction (MI) by 44%, from about 0.44 to 0.24% per year (p < 0.00001). This effect was limited to individuals aged > 50 years. However, low dose aspirin did not alter the incidence or delay the onset of confirmed angina pectoris (positive diagnostic test or revascularisation procedure) [Manson et al. 1990]. Although aspirin clearly reduced the incidence of both fatal and nonfatal MI in this primary prevention trial, total cardiovascular deaths in the aspirin and placebo groups were identical as a result of increased stroke and 'sudden death' in the aspirin group. It seems likely that, in a population in which the risk of arterial thrombosis is low, the small risk of haemorrhagic stroke associated with aspirin intake may counteract the benefit. In the British Primary Prevention Trial conducted in 5139 male physicians (Peto et al. 1988), two-thirds were randomly assigned to aspirin 500mg daily, and one-third were instructed to avoid it (no placebo was used). A nonstatistically significant 10% reduction in mortality in the aspirin group was observed and the incidence of MI was similar in both groups. Even though the incidence of transient ischaemic attacks was lower in the aspirin group, that of disabling stroke was higher. It should be noted that mortality in the American study was only 12% of that expected on the basis of the demographic characteristics of the study population. Very clearly then, this trial was performed in a selected group of highly motivated, health conscious physicians, who had already eliminated as many risk factors as possible, undoubtedly with great success. When comparing the baseline characteristics of the 2 studies, it appears that

the American physicians were clearly younger and more likely to be nonsmoking and normotensive than their British counterparts. These characteristics are risk factors for MI and may be risk modifiers in the presence of aspirin (Mayo & Levy 1990). This renders direct comparison of the 2 trials hazardous but, when undertaken, analysis indicates that aspirin substantially reduces the rate of MI by 32% (p < 0.0001), and is associated with a nonsignificant (5%) reduction in cardiovascular death and a small increase (18%) in nonfatal stroke (Hennekens et al. 1988, 1989). A low dose of (enteric coated) aspirin is almost certainly warranted in individuals with a history of occlusive cardiovascular disease and in selected individuals without such a history but who are, for other reasons, at particularly high risk. In the absence of uncontrolled hypertension, the potential benefit may indeed outweigh the potential risk of cerebral bleeding. As in secondary prevention, an equally important risk reduction can probably be obtained by stopping smoking or by an adequate control of arterial hypertension when present. J3-Adrenergic receptor blockers may provide an equivalent risk reduction in survivors of MI, and there is encouraging evidence that the risk reductions achieved with various measures may be cumulative. 1.2 Patients with Mild or Moderate Arterial Hypertension Patients with hypertension, even when it is mild or borderline, cannot be considered to be healthy. McMahon et al. (1990) studied the association of diastolic blood pressure with stroke and coronary heart disease in 9 major prospective trials. The combined results demonstrate positive, continuous, and apparently independent associations, with no significant heterogeneity of effect between different studies. In 14 randomised trials of antihypertensive drugs (chiefly diuretics or J3-blockers) without confounding factors, pooling of results revealed a highly significant reduction in fatal and in nonfatal stroke (reduction in the odds of fatal or nonfatal stroke combined was 42%) [Collins et

Drugs 42 (Suppi. 5) 1991

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al. 1990]. However, the proportional reductions in nonfatal (14%) and fatal (11%) MI were much less and were only significant for nonfatal MI. Thus, antihypertensive treatment, particularly diuretics, appears to provide the best protection against stroke in patients with mild or moderate hypertension, but is considerably less effective in reducing MI incidence in the same time frame. The combination of low dose aspirin with antihypertensive drugs has been formally tested only in patients with moderate hypertension in the primary prevention of stroke and myocardial infarction.

2. Antithrombotic Prophylaxis in Patients with Angina 2.1 Stable Angina In a 5-year angiographic study, 370 patients with stable coronary heart disease were randomly allocated to aspirin 975 mg/day plus dipyridamole 225 mg/day or placebo and followed up for 5 years (Chesebro et al. 1989a). Treated patients had fewer infarcts (5.3 vs 12.1 %, p = 0.05) and a lower incidence of new coronary lesions at repeat angiography (23 vs 45%, p = 0.04). In the United States Physicians' Health Study, 22 071 male doctors were enrolled and randomly assigned to aspirin 325mg or placebo, taken every second day (Steering Committee of the Physicians' Health Study Research Group 1989). This study included 333 men with baseline chronic stable angina but without a previous history of MI. There was a significant (87%) reduction in the risk of first MI over a follow-up period of 60.2 months. This reduction in the risk of first MI was found in all patients with chronic stable angina including those with and without previous coronary revascularisation (Ridker et al. 1991). Given our current knowledge, aspirin is probably effective in the prevention of MI in patients with stable angina. 2.2 Unstable Angina Aspirin .therapy reduces the incidence of death and nonfatal MI by about 50% over a 3- to 24month period in patients with unstable angina. This

conclusion is based on the results of 4 trials using different doses of aspirin at different time intervals after staging of the disease. The first large prospective study compared aspirin (324 mg/day) administered from < 48 hours after admission with placebo in 1226 males with unstable angina; patients were followed up for 12 weeks (Lewis et al. 1983). The trial began in 1974 and was reported in 1983. The incidence of death or acute MI was 5% lower in the aspirin group than in the control group (10.1 and 5%, respectively). The frequency of new attacks of unstable angina was not significantly changed. In another double-blind trial, 555 men and women were randomly assigned to aspirin 325mg 4 times daily, sulfinpyrazone 325mg, their combination or placebo within 8 days of hospitalisation (Cairns et al. 1985). All patients were followed up for 18 months. Only in the intention-to-treat analysis was there with aspirin a (nonsignificant) reduction of 30% in the combined incidence of nonfatal MI and cardiac death; the 43% reduction in total death reached conventional levels of significance. A third study compared aspirin 325mg twice daily with heparin, their combination and placebo in 479 men and women who entered the trial at a mean of 7.9 hours after hospitalisation and were observed for 1 week (Theroux et al. 1988). There was a reduction in cardiac death or MI from 11.9% in the control group to 3.3% with aspirin and 1.6% when aspirin and heparin were combined. The differences between placebo and all treated groups were significant; mortality in this trial was very low (1.7% in the placebo group), but assessment was limited to the first 6 days. More recently, a double-blind Swedish trial in 796 males with unstable angina was reported; in this trial, a low dose of oral aspirin (75 mg/day), 5 days of intravenous heparin, their combination or neither treatment were given within 72 hours (mean 33 hours) of onset of clinical symptoms (RISC Group 1990). Aspirin was continued for 1 year and significantly reduced the incidence of nonfatal MI and death at 5 days, 1 month and 3 months, independently of concurrent drug therapy. Heparin limited to the 5 initial days had no significant in-

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fluence on the event rate. A slightly different trial was conducted in 399 patients with refractory unstable angina, who were randomised to receive aspirin 325 mg/day or intravenous heparin (continuous infusion or given intermittently) [Neri Semeri et al. 1990]. Heparin decreased the number of angina attacks and silent ischaemic episodes and was significantly more effective if given by continuous infusion than intermittently; aspirin was not effective. Also, ticlopidine 250mg twice daily was shown to be effective in 652 patients with unstable angina. Over a follow-up period of 6 months, ticlopidine reduced MI by 53% (p = 0.006), vascular mortality by 47% (p = 0.14) and total coronary events (vascular deaths and nonfatal MI combined) by 46% (p = 0.009) [Balsano et al. 1990]. Patients with unstable angina should be admitted to a coronary care unit and receive nitrates, either a ~-blocker or a calcium antagonist, and antithrombotic treatment with either aspirin 160 to 325 mg/day or ticlopidine 250mg twice daily. Heparin, administered for 7 days, is also effective and can be used concomitantly with aspirin; however, this combination may be safer with a reduced dose of aspirin of 75 mg/day. Thrombolytic treatment seems to offer only modest benefit.

3. Antithrombotic Prophylaxis after Myocardial Infarction 3.1 Immediately Postinfarction The ISIS-2 trial is a most important study, as much because of the high number of patients involved as from its therapeutic implications (ISIS2 Collaborative Group 1988). In total, 17 187 patients with suspected or evolving MI, from 417 hospitals, were randomised to receive streptokinase or placebo, and aspirin (160 mg/day for I month) or placebo. At week 5, vascular mortality was reduced from 11.8% (1016 patients) in the placebo group to 9.4% (804 patients) in the group receiving aspirin - a 23% reduction in favour of aspirin (p < 0.0001). This benefit was maintained over the following IS months. There was also a significant reduction in stroke (36%) and reinfarc-

tion (44%) during hospital stay in the aspirin-treated patients. As a last but unexplained bonus, nonvascular deaths were also less frequent in the aspirin group (25 vs 39). The various benefits were not counterbalanced by major bleeds or cerebral haemorrhage during aspirin treatment. Efficacy did not appear to be dependent on time: treatment was effective when given in the first 4 hours after MI (mortality reduction 25%), after the twelfth hour (mortality reduction 21%) or after 12 to 24 hours (mortality reduction 21 %). It should be noted that, in previous trials in patients with MI, aspirin was given in the first 7 days [half of the 1682 patients enrolled in the trial of Elwood and Sweetnam (1979)] or considerably later (from I month to 5 years in several other trials involving 10 700 patients and over 1000 deaths; de Gaetano et al. 1986). A meta-analysis of 6 trials revealed a decrease in total mortality of 20%, although each trial alone did not demonstrate a significant reduction (Hennekens et al. 1978, 1988, 1989). 3.2 Secondary Prevention 3.2.1 Oral Anticoagulants Numerous trials have been conducted to test the hypothesis that oral anticoagulation therapy prevents coronary rethrombosis, reinfarction and death, but have failed to demonstrate unequivocally that the potential benefit exceeds the risk of bleeding. In a reanalysis of acceptable short term randomised trials, a case-fatality rate of 15.4% for patients receiving anticoagulants and 20% for untreated patients (a 21 % reduction) did not convince the medical community (Chalmers et al. 1977). Reanalysis of the same data yielded a similar mortality reduction (Yusuf et al. 1988a). A revival of interest followed the Dutch Sixty Plus Study (Sixty Plus Reinfarction Study Group 1980), in which patients aged> 60 years receiving anticoagulants after a proven infarct at least 6 months previously were randomised to continue on anticoagulant tablets or to receive placebo. At 2 years of follow-up, mortality was 7.6% in the group maintained on anticoagulants and 13,4% in the placebo group (p =

26

0.017). The incidence of nonfatal reinfarction was 4.1 % vs 8.4% (p = 0.008). Major extracranial bleeding (p < 0.0001) and intracranial bleeding (p = 0.07) were more frequent in patients receiving anticoagulants. In a recent Norwegian trial, 1214 patients were randomised in a blinded fashion 27 days (mean) after MI to receive warfarin or placebo (Smith et al. 1990). With anticoagulation sustained in the range of an International normalised ratio {lNR) of 2.8 to 4.8, the risk reduction was 24% for total mortality (p = 0.027), 34% for nonfatal reinfarction (p = 0.007) and SS% for stroke (p = O.OOIS) after 37 months (mean). Serious bleeding occurred in 0.6% of the patients receiving anticoagulants per year compared with 0% in the placebo group. All studies with oral anticoagulants were aimed at an INR between 2.8 and 4.8. It is possible that less intensive anticoagulant therapy (e.g. an INR of I.S) would be sufficient in the secondary prevention of MI, either alone or combined with a low dose of aspirin (7Smg). This issue can be solved only by direct comparison of different treatment regimens. 3.2.2 Antiplatelet Drugs Several trials have been conducted, mainly with aspirin, in survivors of MI or stroke. No study individually reaches the conventional levels of statistical significance, probably because of the small number of patients included in each trial. In a metaanalysis pooling the results of 2S randomised trials involving a total of 29000 patients (two-thirds with a history of MI), there was a 32% reduction in nonfatal MI, a 27% decrease in cerebrovascular accidents and a IS% reduction in total mortality (Antiplatelet Trialists' Collaboration 1988; Hennekens et al. 1988). The benefit lasted for at least 2 years and was similar in patients with cardiac disease, in those with a history of cerebrovascular disease, and in both men and women. Over a 2-year period, the typical patient had a 7% risk of death from vascular disease and a further 7% risk of a major nonfatal MI or stroke. However, the pooling of results from different trials may arouse severe criticism.

Drugs 42 (Suppl. 5) 1991

In none of these studies was the combination of aspirin and dipyridamole significantly superior to aspirin alone. Moreover, there is no evidence that a high dose of aspirin (900 to IS00mg) is more efficacious than a low dose of 300mg (Fitzgerald 1987; Rowe & Folts 1990). While aspirin 40 to SOmg daily did not give optimal platelet inhibition in all patients, as measured by platelet aggregation (Boysen et al. 1984; Svensson & Samuelsson 1983), this was achieved with aspirin 7Smg daily over 24 months (Berglund & Wallentin 1991). The risks associated with aspirin administration in patients with vascular disease are small but real. There is a slight increase in the risk of haemorrhagic stroke (UK-TIA Study Group 1988) and, in the report of the United States Physicians' Health Study Research Group, total cardiovascular deaths in the aspirin and placebo groups were identical, partly as a result of increased stroke and 'sudden death' in the aspirin group. Gastrointestinal tolerance has been excellent with the low dose buffered aspirin (Steering Committee of the Physicians' Health Study Group 1988) or enteric-coated aspirin (UK-TIA Study Group 1988). The decrease in mortality with long term oral anticoagulation or aspirin therapy is similar (22% and 23%, respectively). However, the risk of bleeding is far greater with oral anticoagulants, while convenience, simplicity and lower cost all favour aspirin. 3.2.3 Heparin The long term effect of heparin after MI has been investigated in one trial (Neri Serneri et al. 1987). In total, 728 patients were recruited 6 to 18 months after MI and randomly assigned to a daily subcutaneous injection of 12 SOOIU unfractionated heparin for an average of 23 months, or no heparin. Age ranged from SO to 7S years. There were few withdrawals: 7.7% in the heparin group vs 6.3% of controls. Heparin treatment reduced the cumulative mortality rate by 34% on an intention-totreat basis (not significant), and by 48% on an 'ontreatment' basis (p < O.OS). The cumulated reinfarction rate (63%) was also significantly lower in the heparin group. About IS% of patients were tak-

27


ing {3-blockers. Moreover, > 30% of those assigned to heparin and> 40% of those allocated to the control group were taking antiplatelet agents concurrently. This study provides evidence of a benefit with heparin therapy after MI. However, the impact of concurrent antiplatelet medication may have been substantial and the inconvenience and cost of a daily subcutaneous injection is not to be underrated. 3.2.4 ;3-Blockers The effect of {3-blockade on the long term prognosis of patients surviving MI has been the subject of no less than 65 clinical trials in a total of 50000 patients (Yusuf et al. 1988a). On the basis of pooled data, {3-blockade results in a 25% relative reduction annually in mortality for years 1 to 3, and a 7% relative reduction for years 4 to 6, after MI. The reinfarction rate is also reduced by about 25%. It appears that drugs with appreciable intrinsic sympathomimetic activity may confer less benefit than those without, but the essential element appears to be {3-blockade. Whether immediate (intravenous) {3-blockade was superior to deferred (oral) {3-blockade at hospital discharge in patients with acute MI treated with a thrombolytic drug (alteplase) was studied in the TIMI-IIB trial (TIMI Study Group 1989). Immediate {3-blockade did not affect mortality or left ventricular function but reduced nonfatal reinfarction in the first 42 days from 6.1 % to 3.9% (p = 0.06). In about 20% of patients recovering from MI, {3-blockers are contraindicated. One-third of the remaining patients are at low risk, mortality being approximately 2% in the year following MI. {3Blockade is indicated in all other patients, particularly those with arrhythmias and mechanical complications of infarction, who seem to derive the greatest benefit. The mechanism by which {3-blockers have a favourable impact on survival, particularly with regard to sudden death, remains speculative. An additive effect of aspirin and {3-blockers could be envisaged only if their mechanisms were mutually exclusive. It is therefore logical to use {3-

blockers in addition to aspirin only in high risk MI patients with hypertension and angina (Hampson et al. 1991). The benefits of aspirin or {3-blockers are approximately equal in terms of major outcome, so the choice depends on contraindications and tolerability. Furthermore, prophylaxis with either agent is considered cost-effective (Goldman et al. 1988b; Olsson et al. 1987). 3.2.5 Calcium Antagonists Diltiazem (Multicenter Diltiazem Postinfarction Trial Research Group 1988) or verapamil (Danish Study Group on Verapamil in Myocardial Infarction 1990) administered after MI decreased the subsequent 2- to 3-year mortality in patients with reasonably good left ventricular function, but they were associated with a higher mortality in those with poor left ventricular function. In an overview of these studies and 5 others with calcium antagonists (lidoflazine, nifedipine, diltiazem, verapamil), Held et al. (1989) concluded that calcium antagonists cannot be recommended in patients with acute MI or unstable angina. 3.2.6 Captopril The remodelling process that occurs in the heart after acute MI may act to preserve stroke volume, but may also have long term detrimental consequences. Judicious use of acute intravenous nitrate therapy can prevent myocardial dilatation, but the effects of this approach on survival are unknown (Jugdatt & Warnica 1988). Furthermore, experimental and clinical investigations demonstrate a similar beneficial effect on ventricular dimensions with the chronic use of captopril after acute MI (Pfeffer et al. 1988). However, prospective controlled clinical trials are required to ascertain the effect of these drugs on survival and the development of congestive heart failure. 3.2.7 Other Interventions

Current Recommendations for Lowering the Cholesterol Level to Prevent Reinfarction Currently, many patients with MI receive {3blocking agents or aspirin. Even allowing for the 22 to 25% reduction in mortality expected with the

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use of these agents (Yusuf et al. 1985, 1988b), the reinfarction rate was still 13% in the first year and 5% in the second year in the placebo group of a recent trial, although about 0.5% of patients were taking ,B-blocking agents and 33% were on aspirin (Multicenter Diltiazem Postinfarction Trial Research Group 1988). While indicators of the extent of myocardial damage rank higher than serum cholesterol levels as predictors of reinfarction (Schlant et al. 1982; Secondary Prevention of Coronary Disease with Lipid Lowering Drugs 1989), particularly during the first few months (Moss & Benhorin 1990), over the long term, serum cholesterol levels and dyslipidaemia continue to influence outcome (Rossouw et al. 1990). The secondary prevention trials have demonstrated that a 10% reduction in cholesterol can be expected to reduce the rate of reinfarction by 19% and of fatal reinfarction by 12% (Rossouw et al. 1990). With vigorous diet control and the use of cholesterol-lowering drugs, either alone or in combination, substantial lowering oflipid levels is feasible. It is to be remembered that saturated fatty acids are also linked with thrombosis and that fish oil has been reported to lower plasma fibrinogen (H6stmark et al. 1988). Current recommendations are that, in survivors of MI, low density lipoprotein-cholesterol (LDL-C) should be reduced below 3.36 or even 2.58 mmoljL and serum cholesterol below 5.17 mmoljL (Report of the National Cholesterol Education Program Expert Panel 1988). It should be stated, however, that studies so far have only shown a correlation between elevated serum cholesterol and the incidence of nonfatal reinfarction; direct evidence for the therapeutic proposition is lacking. As recently stated, although the benefits of reduced cardiac morbidity outweigh putative noncardiac risks in patients with severe dyslipidaemia, general exhortations for everyone to reduce their serum cholesterol levels may be premature (Oliver 1991). Smoking Cessation As a result of government regulations prohibiting smoking in public places, the proportion of adult cigarette smokers has declined by roughly


30%. The social attitude towards smoking has undergone a dramatic change from tolerance to stigmatisation. Although the proportion of smokers in the general population has decreased, that of addicted smokers has increased. Psychologically based treatment approaches for these nicotine-dependent smokers are often not adequate, as the long term success rates do not exceed 30% (Jarvik & Schneider 1984). For these smokers to stop, nicotine chewing-gum or transdermal nicotine patches may be necessary, as nicotine relieves many withdrawal symptoms and reduces the weight gain that curtails many attempts to stop smoking (Fagerstrom 1983). Clonidine, in addition to behavioural counselling, may increase the cessation rates to around 60%. There are some indications that antidepressants and anxiolytics (buspirone, alprazolam) may also help. The effects of smoking cessation are impressive in survivors of MI. Over a 5-year follow-up period, there was an 87% survival rate amongst ex-smokers compared with only 72% in those who continued to smoke (Daly et al. 1985). In the foregoing trials of ,B-blockers, at 3 years, survival was 90% in ex-smokers compared with 85% in smokers (Aberg et al. 1983).

4. Antithrombotic Prophylaxis in Other Cardiac Indications 4.1 Reduced Left Ventricular Function Stroke attributable to cerebral embolism occurs in 1 to 3% of all patients with acute MI, including 2 to 6% of those with anterior infarction and 10 to 20% of those with extensive anteroseptal infarction (Visser et al. 1984). Clinical evidence of cerebral embolism is found in about 10% of acute MI patients with echocardiographically evident mural thrombi, and the risk continues well beyond the acute phase. Numerous studies have been conducted with heparin followed by oral anticoagulation and, in general, thrombus formation detected by echocardiography was reduced by more than 50% with anticoagulation, which also reduced the incidence of cerebral embolism from 3 to 1% compared with controls (Halperin & Petersen 1991).

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The subcutaneous dose of standard heparin should be 12 500IU every 12 hours during the first 10 days (Turpie et al. 1989). In patients at a higher risk of embolism, e.g. those with a large akinetic zone, oral anticoagulation should be maintained for 1 to 3 months or longer (Halperin & Petersen 1991). 4.2 Prevention of Acute Occlusions and Recurrent Stenosis in Percutaneous Transluminal Coronary Angioplasty Acute occlusions occur in 4 to 10% of patients after percutaneous transluminal coronary angioplasty (PTCA) and recurrent stenosis in 30 to 40% of patients within 6 months (Badimon et al. 1990; Popma & Dehmer 1989). In well conducted studies, ticlopidine 250mg twice daily, or aspirin alone (330mg 3 times daily) or in association with dipyridamole would prevent early reocclusion after PTCA (Bamathan et al. 1987; Bertrand et al. 1990; Chesebro et al. 1989b; Limbo et al. 1988; Schwartz et al. 1988a; White et al. 1987). The incidence of Q-wave MI was 1.6% in treated patients in the first week after PTCA compared with 6.9% in the placebo group (Schwartz et al. 1988b). In a further study, ticlopidine 250mg 3 times daily and aspirin 325mg twice daily combined with dipyridamole (75mg 3 times daily) were compared with placebo. Ischaemic complications occurred in 1.8, 5.4 and 13.6% of patients, respectively (White et al. 1987). Numerous drugs, including oral anticoagulants (Thorton et al. 1984; Urban et al. 1988), short term heparin (Ellis et al. 1989), aspirin plus dipyridamole (Chesebro et al. 1989b; Limbo et al. 1989; Schwartz et al. 1988b; White et al. 1987), nifedipine (Whiteworth et al. 1986), diltiazem (Corcos et al. 1985; O'Keefe et al. 1991a), ticlopidine (Bertrand et al. 1990; White et al. 1987), a thromboxane receptor blocker (Finci et al. 1989) and colchicine (O'Keefe et al. 1991b) were ineffective in reducing the rate of restenosis in patients after coronary angioplasty. While w-3 fatty acid begun the night before PTCA did not reduce the risk of restenosis (assessed angiographically), dietary supplementation for 1 week before angioplasty low-

ered the risk from 36 to 16% (Dehmer et al. 1988; Milner et al. 1989). However, the results of subsequent trials of w-3 fatty acid, which also relied on angiographic follow-up, were negative (Grigg et al. 1989; Reis et al. 1989). The potential role of angiopeptin, a somatostatin analogue (Lundergan et al. 1991), and of long term local drug delivery at the site of arterial dilation, is the focus of intense research; also under investigation are synergistic drug combinations aimed at inhibiting intimal proliferation (low dose antimitogenic treatment combined with a growth factor antagonist or with an inhibitor of collagen formation) [Muller et al. 1991]. More recently, lovastatin was found to significantly reduce the incidence of restenosis when patients were evaluated by coronary angiography at a mean interval of 4 months (Sahni et al. 1991). It should be recognised that, except for diabetes, none of the patient-related risk factors (gender, family history, elevated cholesterol, smoking) have been found to be consistently related to the risk of restenosis. 4.3 Prevention of Graft Occlusion after Aortocoronary Bypass Surgery Occlusion of a coronary bypass in the first few postoperative days is most often related to the level of blood flow through the bypass, which in tum depends mainly upon the size of the anastomosis and distal run-off. Activation of platelets and vascular injury of the bypass are also implicated in the pathogenesis of early graft occlusion. Late occlusion is usually related to progression of the basic disease, in which platelet adherence to the graft wall could be an important factor. The occlusion rate of vein grafts has been shown to be 10% within 1 month of surgery (Chesebro et al. 1982), 15% within 2 months (Goldman et al. 1988a) and up to 25% within 12 months (Chesebro et al. 1984). The effect of oral anticoagulants on aortocoronary graft closure has been studied in at least 3 randomised trials. Unfortunately, the outcome event was assessed at different time intervals and results are inconclusive (Verstraete et al. 1986). Furthermore, surgeons are reluctant to start anticoagula-

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tion preoperatively, and oral anticoagulants have no effect on platelet deposition (Harker & Slichter 1972). The inconclusive study results, together with the problems of regulating anticoagulant therapy and the fear of bleeding in the postoperative period, have prompted most physicians to abandon the use of oral anticoagulants after aortocoronary bypass grafting. In several older studies, antiaggregating agents were started 24 hours or more after aortocoronary bypass surgery, which may explain the deceptive results (Verstraete et al. 1986). Provided prophylaxis is commenced before or at the most 6 hours after surgery, the combined use of aspirin 1000 mg/ day and dipyridamole 225 mg/day reduces graft occlusion rates from 25 to 11% (p < 0.0001); 42% of control patients vs 20% of treated patients had I or more occluded grafts. This benefit is maintained in the first year (Chesebro et al. 1982, 1984; Goldman et al. 1988a). Aspirin alone, at a daily dose of 100mg (Lorenz et al. 1984), 150mg (Sanz et al. 1990), 324mg (Gavaghan et al. 1990, 1991) or 1000mg (Brown et al. 1985), and ticlopidine alone (500mg per day) [Chevigne et al. 1984; Limet et al. 1987) significantly increase graft patency, provided these drugs are started before or at surgery. In a prospective randomised trial, 4 antithrombotic treatments were compared: aspirin 325mg as a single daily dose; aspirin in 3 daily doses each of 325mg; the combination of aspirin 325mg and dipyridamole 75mg; sulfinpyrazone 267mg 3 times daily or placebo (Goldman 1988a, 1989). Antiplatelet treatment was commenced 12 to 48 hours before surgery. The angiographic patency rate in the first 60 postoperative days was higher in those patients taking aspirin compared with the placebo group, with no difference between the lower (325mg) or higher (975mg) daily aspirin dose. It should be noted that aspirin administered 12 hours before surgery was associated with a greater blood loss and a higher number of early reoperations. A prospective trial is presently investigating the benefit and risks of preoperative vs very early postoperative administration of aspirin (Sethi et al. 1990).


A direct comparison of oral anticoagulation vs a low dose of aspirin (50mg) combined with dipyridamole (400mg) [the latter was started before surgery] revealed that 7% of grafts were thrombosed after I week in the 2 treatment groups (Pfisterer et al. 1989). After 1 year, repeat angiography revealed that 5% of the distal anastomoses were open in the group receiving anticoagulants compared with 6% in the group receiving aspirin and dipyridamole. As both treatment regimens seem to be similarly effective, although bleeding occurred more often in the patients receiving anticoagulants, antiplatelet treatment seems to be safer and is easier. A similar comparison between oral anticoagulation and ticlopidine (500 mg/day) leads to the same conclusion (Rothlin et al. 1985). It thus appears that platelet inhibitor therapy is mandatory for prevention of early vein graft occlusion. Preoperative aspirin increases intraoperative bleeding and does not appear to be more beneficial than aspirin started within a few hours of surgery. Therefore, for elective surgical cases, aspirin therapy (160 to 325mg) should begin only after surgery. Preoperative dipyridamole does not increase intraoperative bleeding but its advantage over postoperative aspirin has not been investigated. Ticlopidine also appears to be very effective; however, its relative benefit compared with aspirin after coronary bypass still needs to be assessed. The appropriate duration of therapy after surgery is still controversial. Because some studies suggest that prolonged antithrombotic therapy reduces late graft occlusion, and because of the beneficial effects of aspirin in the secondary prevention of coronary disease, aspirin can be continued indefinitely in these patients. The use of internal thoracic artery, whenever possible, and the control of risk factors remain essential. It is possible that, after the first postoperative year, vein graft atherosclerosis is influenced by risk factors similar to those predisposing to native coronary disease. 4.4 Heart Valve Replacement The main long term complications of heart valve replacement are valve failure, MI, prosthetic endocarditis and thromboembolism. The latter problem


exists for all older and newer synthetic heart valves and bioprosthetic valves, but to different degrees (Molitch 1991). It should be recognised that platelets and fibrin are already deposited during surgery on the damaged perivalvular tissue. Both mechanical and bioprosthetic valves contain a dacron sewing ring, which may induce platelet activation and set the coagulation process into motion. Recent improvement in prosthetic valve technology resulted in increased durability, which is excellent with all mechanical prosthetic valves, but failed to completely resolve the thromboembolic problem, despite the use of less thrombogenic material. Even if this were the case, stasis and decreased blood flow, as in the left atrium during atrial fibrillation and during low cardiac output states with left ventricular dysfunction, might promote fibrin formation. As the latter conditions are independent of the prosthetic valve, they would still require anti thrombotic prophylaxis. There are indeed well recognised patient-dependent factors also contributing to the thromboembolic risk, e.g. patients with an aortic valve replacement have a much lower thromboembolic risk than those with mitral valve replacement, while patients with mitral and aortic valve replacement carry the highest risk, not only because ofthe greater surface area of the prosthetic material but also because of more advanced heart disease with a greater potential for mechanical and electrical left ventricular dysfunction. As platelets are deposited particularly in the area of the endocardium-suture-prosthetic valve and damaged perivalvular tissue, an inhibitor of platelet function could be useful. There are no published reports on the use of antiaggregating agents alone in patients with mechanical heart valves, most probably because timid attempts have failed. Patients with mechanical heart valves, including the newer ones, are at such a high thromboembolic risk that oral anticoagulation remains mandatory. The present recommendation for patients with mechanical heart valves is to start with intravenous heparin (about 600 IV/h) 4 to 6 hours after surgery, adjusting the dose to maintain partial thromboplastin time at the upper limit of normal.

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The infusion is continued until chest tubes are removed and then subcutaneous unfractionated heparin (12 500IV twice daily) is substituted, this dose being adjusted to increase the partial thromboplastin time to 1.5 to 2 times the normal level. After a few days, oral anticoagulation is started and maintained at a prothrombin time corresponding with an INR between 3.0 and 4.5. No trial has been conducted in patients with mechanical heart valves to determine whether a lower level of anticoagulation (e.g. INR 2.5 to 3.5) would be as effective as, but reduce the bleeding incidence observed with the more intensive anticoagulation corresponding to the presently recommended INR range of 3.0 to 4.5. A step in the right direction comes from Argentina, where patients with mechanical prosthetic valves were randomised to receive oral anticoagulation at an INR of either 2.0 to 3.0 or 3.0 to 4.5. Protection from embolism was equal in the 2 treatment groups, but more bleeding occurred with the higher dose range (Altman et al. 1991). However, it is important to note that both groups of patients also received a combination of aspirin and dipyridamole in addition to the oral anticoagulant. The inhibition of platelet function does indeed potentiate the anti thrombotic effect of coumarin drugs, as was already shown for dipyridamole (Groupe de Recherche PACTE 1978; Kasahara 1977; Rajah et al. 1980), sulfinpyrazone (Steele et al. 1979) and aspirin (Altman et al. 1976; Dale et al. 1977). The present recommendation is that patients with newer bioprosthetic valves in a mitral position be treated for the first 3 months after valve insertion with oral anticoagulants at an INR of 2.0 to 3.0. The lower level of anticoagulation is based on a randomised study of patients with a bioprosthetic valve in the mitral position, which showed that less intensive oral anticoagulation (INR 2.0 to 3.0) gave the same protection from thromboembolism (1.2% incidence) as more intensive anticoagulation (INR 3.0 to 4.5) but with significantly less bleeding (5.7% vs 20.6%) [Turpie et al. 1988]. However, after 3 months, these patients can discontinue coumarin drugs and switch to aspirin (80 mg/day), but only in the absence of atrial

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fibrillation, a large left atrium or a history of previous systemic thromboembolism. 4.5 Atrial Fibrillation 4.5.1 Valvular Atrial Fibrillation In patients with valvular disease, atrial fibrillation is nearly always associated with mitral valve disease. Thromboembolism often occurs soon after the onset of atrial fibrillation. In 1 study, 33% of thromboemboli occurred within the first month and 66% within 12 months of the onset of atrial fibrillation (Szekely 1964). Recurrent thromboemboli in patients with valvular heart disease occur at approximately 10%/year and in 30 to 75% of patients with most occurring within the first 6 months after the initial event (Chesebro et al. 1990). Mortality from recurrent emboli in patients with mitral stenosis may be as high as 42%. Thus, therapy in such high risk patients should be designed for a higher level of anticoagulation (lNR 3.0 to 4.5). Long term oral anticoagulation can reduce the thromboembolic risk to less than 1%/year. The therapeutic range for oral anticoagulation differs depending upon the thromboembolic risk. Thus, patients at high risk with valvular heart disease (those with previous thromboembolism) should have the prothrombin time prolonged to an INR of 3.0 to 4.5. For all other patients with valvular heart disease and atrial fibrillation, who are at medium risk, an INR between 2.0 and 3.0 will suffice (Sackett 1986). 4.5.2 Nonvalvular Atrial Fibrillation Among patients with nonvalvular atrial fibrillation, the risk of embolism is around 5 to 10%/ year, and appears greatest when stroke or systemic embolism has occurred within the previous 2 years. This incidence is about 5 to 7 times that in a general population of comparable age and gender. The superiority of oral anticoagulation (INR 1.5 to 4.5) over placebo was shown in 6 recent prospective trials in patients with non valvular atrial fibrillation, reducing stroke by about 3%/year (Petersen 1990). Aspirin is also effective, but less so in patients over 75 years of age.

5. Antiaggregating Agents in Extracorporeal Circuits Despite anticoagulation, platelets interact with foreign surfaces during haemodialysis and cardiopulmonary bypass surgery and can cause platelet microembolism. Thrombocytopenia due to platelet destruction also increases the bleeding risk. Ticlopidine can reduce thrombocytopenia due to extracorporeal circuits. Moreover, ticlopidine administered in a daily dose of 200 to 500mg reduces the incidence of thrombotic occlusion of arteriovenous shunts and external synthetic shunts in patients on chronic haemodialysis (Grontoft et al. 1985; Kobayashi et al. 1980). A similar benefit can also be obtained with sulfinpyrazone (Adrassy et al. 1974) or aspirin (Harter et al. 1979). Ticlopidine (500mg) used during cardiopulmonary bypass operations reduced platelet destruction without augmenting the bleeding risk in 2 placebo-controlled studies (Limet et al. 1987; Installe et al. 1981).

6. Secondary Prevention 0/ Cerebral Ischaemia 6.1 Transient Ischaemic Attacks The efficacy of antiplatelet agents (aspirin, sulfinpyrazone or dipyridamole), alone or in combination in the secondary prevention of a transient ischaemic attack, is still open to question. A trend to a reduction in strokes (mainly in men) with any regimen containing aspirin was observed in several trials, supporting the use of only 1 anti platelet agent, aspirin, in cerebral ischaemia. In a meta-analysis of 7 controlled studies in patients with transient ischaemic attacks, a significant risk reduction of 40 to 90% in recurrent transient ischaemic attacks, stroke or death was obtained (Sherman et al. 1986). In 2 of these trials, the combination of dipyridamole and aspirin was not superior to aspirin alone. A much broader meta-analysis of 31 randomised clinical trials in 29000 survivors of a transient ischaemic attack, stroke, unstable angina or MI found anti platelet prophylaxis reduced the incidence of nonfatal, cerebral or cardiac vascular events by 30%,


and of fatal vascular events by 15% (Antiplatelet Trialists' Collaboration 1988). A trial comparing ticlopidine 500mg daily with aspirin 1300mg daily in 3069 patients with transient ischaemic attack or very minor and rapidly regressive stroke has been conducted in the United States and Canada (Hass et al. 1989). The 3-year risk reduction in fatal and nonfatal stroke for ticlopidine compared with aspirin was 21% (p = 0.024), demonstrating the former drug's superiority. The cumulative incidence of nonfatal stroke and total mortality was 17% in ticlopidine-treated patients and 19% in aspirin-treated patients, a risk reduction of 12% (p = 0.048). The survival curves diverge very early in the treatment period and remain parallel between the sixth and the twelfth month, and up to the end of the 3-year follow-up. No differences between the 2 treatment groups were noted in total mortality, cardiovascular mortality and fatal MI. Diarrhoea and cutaneous eruptions were twice as frequent in the ticlopidine group, but the incidence of minor bleeding was the same in both groups (10%). Adverse effects due to either drug were minor and divided equally between the 2 patient groups. In conclusion, aspirin and ticlopidine appear efficacious in reducing fatal and nonfatal stroke in patients who have had a transient ischaemic attack. In a direct comparison, ticlopidine was more effective and apart from reversible severe neutropenia in 0.86% of patients, was associated with relatively benign adverse effects.

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in the aspirin and placebo groups (Swedish Cooperative Study Group 1987). In a larger double-blind trial, 1072 patients who had had a thromboembolic stroke between 1 week and 4 months before selection were randomly allocated to ticlopidine 250mg twice daily or placebo (Gent et al. 1989). The patients were observed for up to 3 years (mean 24 months). Analysis by 'intention-to-treat' gave a risk reduction of 24% (p = 0.020) for stroke, MI or vascular death. In the efficacy analysis, the event rate for stroke, MI or vascular death, considered together, was 15.3% in the placebo group and 10.8% in the ticlopidine group, representing a relative risk reduction with ticlopidine of 30% (p = 0.006), occurring in both men and women. In a subgroup of patients pertaining to this trial, serial measures of cognition were maintained during treatment in both groups; while the efficacy of aspirin was similar to that of ticlopidine in sustaining cerebral perfusion among men and women, ticlopidine increased the rate of change in cerebral perfusion among male, but decreased it in female, patients (Mortel et al. 1991). For patients with completed stroke, treatment with aspirin, aspirin plus dipyridamole, or ticlopidine is effective for prevention of death, stroke and, in some studies, MI. The usefulness of anticoagulant therapy in atherothrombotic stroke remains questionable and is only recommended for patients with embolic stroke from a cardiac source.

7. Antithrombotic Prophylaxis in Patients with Obliterative Disease in Limb Arteries

6.2 Ischaemic Stroke It is highly desirable to prevent major vascular events in survivors of thromboembolic stroke, since they have a 25% risk of recurrence of stroke, MI, or vascular death over the ensuing 2 years (Gent et al. 1985). To extrapolate the beneficial effect of aspirin in patients with transient ischaemic attacks and mild stroke to these more severely affected patients may not be appropriate. In the 1 randomised study of aspirin restricted to patients with a completed thromboembolic stroke, the observed incidence of stroke recurrence or death was similar

The most common cause of obliterative disease in the legs is slowly progressive atherosclerosis, which is eventually superimposed by thrombosis. The danger of the condition is the underlying disease, as most patients die from a cardiac or cerebral complication of atherosclerosis. The increased mortality in patients with intermittent claudication corresponds approximately to the mortality rate one would expect in a general population 10 years older. The message is therefore very clear. A patient with claudication is to be treated first for the underlying illness and medical risk factors, and not for the pre-

34

senting symptoms. Abstinence from smoking, appropriate diet and physical exercise are therefore the first treatment guidelines, while percutaneous transluminal dilatation and reconstructive surgery often relieve the most severe cases. Since thrombosis of atherosclerotic arteries is only the final step in a long process, long term oral anticoagulation is rather unlikely to represent a serious advance in the pharmacological prevention of the progression of peripheral arterial occlusive disease. A few early trials have shown a favourable trend with oral anticoagulants, but their design and size do not allow a definite conclusion. There are 2 prospective studies on the value of oral anticoagulants in patients with intermittent claudication. In the first, all included patients initially received oral anticoagulant therapy for at least 6 months and were then randomly assigned to receive placebo or to continue oral anticoagulation. This trial was interrupted prematurely because of a significant surplus of deaths in the placebo group (Hamming et al. 1965). In the second (de Smit & van Urk 1987) trial, no benefit of anticoagulants with regard to total mortality was found, although there was a lower incidence of vascular events (peripheral, cerebrovascular, cardiovascular) in patients receiving anticoagulants. In addition, the progression of the leg arterial disease appeared to be delayed as evidenced by a slow decrease in the ankle pressure index in patients treated with anticoagulants. To examine whether oral anticoagulants given after autologous saphenous vein bypass surgery in the femoropopliteal region influenced patient survival, 199 patients were recruited for a controlled randomised clinical trial. The 2 groups differed significantly in probability of survival after a median follow-up of at least 5 years: 10 patients died in the anticoagulant group vs 20 in the control group. This difference remained significant when patients with an occluded bypass were excluded from analysis (Kretschmer et al. 1988). However, even when considered together, these data still do not convince most clinicians that long term oral anticoagulation is worthwhile in patients with peripheral arterial obstructive disease. Large randomised trials with anti platelet agents


in patients with intermittent claudication are not available. The anti serotonin agent ketanserin did not reduce cardiovascular mortality nor the incidence of nonfatal vascular events in the doubleblind, placebo-controlled PACK trial, the largest controlled study ever published on pharmacological intervention in claudication patients [Prevention of Atherosclerotic Complications with Ketanserin (PACK) Trial Group 1989]. On the other hand, the Antiplatelet Trialists' Collaboration (1988), in a meta-analysis of 31 randomised trials of anti platelet therapy involving over 29 000 patients with clinical symptoms of cardiovascular and cerebrovascular disease, calculated that antiplatelet treatment reduced vascular death by 15%, and nonfatal MI and stroke by 30% (p < 0.0003 and p < 0.0001, respectively). It appears logical to expect a similar effect in individuals with intermittent claudication, in view of the epidemiological evidence that these patients have coronary and cerebral artery disease as well and that they have a 2- to 3-fold increase in cardiovascular mortality on long term follow-up in comparison with an agematched healthy control group. Further support for a beneficial effect of antiplatelet drugs comes from another, still unpublished, meta-analysis of 14 smaller trials involving patients with peripheral vascular disease, many of whom had undergone surgery. The total number of patients included was 2724 and 539 vascular events occurred; antiplatelet agents reduced the odds of suffering a vascular event by 41 ± 8% (Anti platelet Trialists' Collaboration 1991). The local progression of atherosclerotic disease in the legs may also be influenced by anti platelet agents. There is evidence that aspirin and ticlopidine retard the progression of atherosclerosis and the occurrence of its thrombotic complications in legs of patients with obstructive arterial disease. Schoop et al. (1983) randomised 300 patients with a stenosis of the femoral artery in 1 leg (and an occlusion in the contralateral leg) to receive daily either aspirin Ig, aspirin Ig combined with dipyridamole 225mg, or placebo. After 4 years offollowup, the occlusion rate was lower in the 2 groups receiving active treatment, but the combination was


not superior to the administration of aspirin alone. In addition, antiplatelet therapy did not prevent femoral artery thrombosis in diabetic and hypertensive patients. Hess et al. (1985) reported a placebo-controlled double-blind trial in 199 patients with angiographically studied evolution of peripheral atherosclerosis over a 2-year period. Disease progression was most pronounced in the placebo group, less so in the aspirin-treated group (lg daily) and least in the aspirin (lg daily) plus dipyridamole (225mg daily)-treated group. In contrast to the previous study, patients who continued to smoke and those with hypertension benefited most from active treatment. A similar placebo-controlled randomised trial was conducted with ticlopidine in 114 patients; control angiograms repeated after 1 year of treatment showed that ticlopidine significantly reduced progression of the disease (Stiegler et al. 1984). Boissel et al. (1989) published a meta-analysis of 4 placebo-controlled trials with ticlopidine in peripheral vascular disease (Arcan et al. 1988; Cloarec et al. 1988; Ellis & Eckhoff 1988; Stiegler et al. 1984). They found not only a decreased incidence of vascular events with the active substance, but also an improvement in walking distance. Since claudication distance may be influenced by factors other than blood flow, it is uncertain whether this improvement can be taken as proof of a better local evolution of atherosclerotic disease. More recently, a placebo-controlled, double-blind Scandinavian trial in 687 patients with intermittent claudication reported decreased mortality and cardiovascular complications in patients treated with ticlopidine (Janzon et al. 1990).

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