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Antiplatelet agents: a review' Michael L Gantmacher MD2 Geigy Pharmaceuticals, Macclesfield, Cheshire
The socioeconomic importance of cardiovascular and cerebrovascular arterial diseases is very well documented and need not be stressed here. Despite the progress accomplished in their understanding, treatment and prevention, they still hold the dubious honour of being the primary cause of death. Anticoagulants have for many years been the main or only therapy, one that has always been instituted too late (after the primary vascular event) and which has proven too often to be ineffective in preventing secondary episodes or death. The concept of antiplatelet agents (or platelet 'modulators') arose as a new approach to antithrombotic therapy and is gaining increasing support as the role of platelets in thrombus formation is recognized as a basic aetiopathological process of arterial thromboembolism. In the past decade, expansion of research in the field of thromboembolism has been considerable and a clinical review of the more important drugs which have been and are currently studied in man, is presented here. Clofibrate, dipyridamole, aspirin and sulphinpyrazone are still under extensive investigation, though not all four look as promising as a few years ago; continuing clinical research has failed to confirm earlier hypotheses, and new and more sophisticated experimental models and ex-vivo tests did not substantiate optimistic expectations. Only the outstanding clinical studies which have been carried out with these drugs and which cast some light on a rapidly developing field of research are mentioned here.
Clofibrate Cerebrovascular disease Only one study (Acheson & Hutchinson 1972) was published in this indication. Clofibrate was compared against placebo in patients grouped according to their clinical condition: single stroke, multiple stroke and transient cerebral ischaemia. All patients had a minimal serum cholesterol of 250 mg/ 100 ml. The end points (recurrence of stroke, death and further episodes of cerebral ischaemia) were not affected by the drug. A reduction of cholesterol levels was observed in all patients, but the mean proportional fall was significantly greater (as would be expected) on clofibrate in all clinical categories. The lack of clinical efficacy suggests that the lowering of serum cholesterol per se is of no benefit in respect of the natural history of cerebrovascular disease. Because of the low number ofpatients (95) this study is not conclusive. Ischaemic heart disease A total of 497 patients with symptoms of angina, myocardial infarction or both, were treated with clofibrate or placebo and observed over a period of five years (Newcastle upon Tyne Region Physicians 1971). Patients with a history of angina or both angina and myocardial infarction were protected by the drug against sudden death and nonfatal infarcts, but the drug was not effective in reducing the risk of fatal reinfarctions. The reduction in the number of deaths and infarcts is independent of the degree by which the cholesterol serum levels were reduced. In the study conducted by a research committee of the Scottish Society of Physicians (1971), 717 patients were grouped according to diagnosis of angina, myocardial infarct or both. Randomization flaws occurred: a significant difference in the initial serum cholesterol levels 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 11 April 1978. Accepted 28 April 1978 2 Present address: CIBA-GEIGY Limited, CH-4002 Basel, Switzerland
0 1 41-0768/79/070513-07/$Ol
-
00/0
'."
1979 The Royal Society of Medicine
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Journal of the Royal Society of Medicine Volume 72 July 1979
and systolic blood pressures, both higher in men in the placebo group. The end-points (sudden death, fatal and nonfatal myocardial infarction) were significantly reduced by the drug in patients with both angina and infarction; a similar trend was observed in the angina group. Patients with only myocardial infarction did not benefit, those on clofibrate being affected by a higher rate of fatal infarcts. These findings are contradictory and the trial is inconclusive. Likewise, no relationship between beneficial effects and lowering of serum cholesterol may be inferred from it. The Coronary Drug Project is a national collaborative study to assess long-term therapies which influence lipid metabolism. It is conducted on a sample population of men, aged 30-64 years who have recovered from one or more myocardial infarcts. In such a study, 3908 patients were treated with either clofibrate, nicotinic acid or placebo, and followed for approximately eight years. Total and cause-specific mortalities were not affected by clofibrate. There was a statistically significant excess of angina pectoris, cardiac arrhythmias, intermittent claudication and nonfatal cardiovascular events in the drug group as compared with the placebo one. The research group concluded that there is no evidence that justifies recommending the use of clofibrate in the treatment of coronary heart disease (Coronary Drug Project Research Group 1975). The results of an important international trial in the primary prevention of ischaemic heart disease are now available. The study is based on 15 745 men studied for an average period of 5.3 years (Committee of Principal Investigators 1978). All the statistical difference between the treated and the control high-cholesterol groups is accounted for by the difference in the incidence of nonfatal myocardial infarctions, which was significantly lower in the clofibratetreated group. No differences were found between both groups regarding fatal infarctions, sudden death or incidence of angina pectoris. An adverse important finding was that there were significantly more deaths from noncardiovascular diseases (liver, gallbladder, small and large intestines) in the clofibrate group than in the control group; there is no clear explanation for this finding which remains a reason for concern.
Dipyridamole Cerebrovascular disease A controlled study was conducted by Acheson et al. (1969) on 169 patients classified in the same diagnostic groups as for their clofibrate study: transient ischaemic attacks, single stroke and multiple strokes. A first treatment period with 400 mg a day lasted 14 months, after which the patients remaining in the study (14 died and 16 had been eliminated because of noncompliance) were followed for a further 11 months on 800 mg daily. The incidence of ischaemic attacks and recurrence of stroke was not affected by the drug nor was any difference detected between both dosage regimes. The natural history of the disease remained unchanged through the study. Ischaemic heart disease Similar deceptive results (Gent et al. 1968) were obtained in 103 patients with acute myocardial infarction. After a treatment period of 4 weeks (400 mg daily) the recorded mortality in the dipyridamole group was 15.7% (8 patients) and 5.8% (3 patients) in the control group. Though the higher mortality in the dipyridamole group could be influenced by the fact that more patients received the drug within the first 48 hours after infarction, as 74.8% of all patients (41 drug-treated, 36 placebo-treated) were admitted within the first three days after infarction it is unlikely that this would have influenced the final negative results. Prosthetic heart valves The value of the drug combined with anticoagulants in preventing thromboembolic events in 39 patients who had undergone successful insertions of mitral or aortic valve prostheses was evaluated against a retrospective assessment of 29 patients exclusively on anticoagulants (Arrants & Hairston 1972). Results suggest that the combination was more effective in preventing arterial emboli and death than anticoagulants alone. Unfortunately changes in the
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design of the valves which bias the results in favour of dipyridamole were introduced during the study. The control group studied retrospectively is also unsatisfactory and the results may not be accepted as conclusive. A similar study with a placebo group (Sullivan et al. 1971) included 163 patients (all on anticoagulants) controlled during 12 months following valve replacement. Emboli developed in 14% of the placebo-treated subjects but only in 1.3% of the dipyridamole group. Moreover, none of the patients on the drug died of embolic accidents, whilst two deaths were recorded in those on placebo. The results of this well-conducted trial are conclusive as far as the antithrombotic effect of the drug combined with anticoagulants is concerned, but no conclusion may be drawn regarding the antithrombotic effects of dipyridamole alone.
Aspirin Cerebrovascular disease The first report on the possible beneficial effects of aspirin on transient ischaemic attacks (Harrison et al. 1971) referred to two patients with amaurosis fugax in which 600 mg a day effectively reduced the number of attacks. A retrospective study on the differences in the number of carotid transient ischaemic attacks associated with antiplatelet therapy strongly suggested that aspirin could be of value in preventing these type of attacks (Dyken et al. 1973). The histories of 117 patients admitted during the previous 31 years with a diagnosis of transient ischaemic attacks were reviewed. After rigorous criteria were established for the selection of true transient ischaemic episodes, only 26 patients (22%) remained in the study, of which 15 had been treated with 600 mg a day of aspirin. Whilst 9 out of the 11 patients not receiving the drug had an additional attack, only 2 out of the 15 on the drug suffered from a further episode. There was no difference in the number of recorded deaths and infarctions. Two flaws reduce the reliability of this study: it is retrospective and the average follow-up period for the patients receiving aspirin was 14 months as against 29 months for those not on the drug. This large difference may have reduced the number of attacks recorded in the aspirin group compared with the non-treated group. The results of an excellent prospective controlled study (against placebo) were recently published (Fields et al. 1977). The objectives were to determine whether treatment with aspirin would reduce or prevent transient ischaemic attacks (including amaurosis fugax) and result in a reduction in the incidence of mortality and cerebral and retinal infarctions. The analysis of the sample as a whole (178 patients) at the end of the study did not reveal a significant difference between both treatments. The data were then stratified for two variables: (1) history of transient ischaemic attacks (single versus multiple episodes); (2) presence or absence of anatomic lesions appropriate to the presenting clinical picture (complete occlusion of the carotid artery was defined as a nonappropriate lesion). The data from patients with multiple episodes and from those with anatomic lesions appropriate to their symptomatology revealed statistical significance for the absolute end-points in favour of aspirin. An analysis of the cumulative probabilities of death or nonfatal cerebral or retinal infarction showed that patients with multiple ischaemic attacks are at a significantly higher risk than those with single attacks. These results stress the importance of making a clinical distinction between single and multiple attacks, let alone of a correct diagnosis of the causative lesion. A careful patient selection is essential before deciding upon antiplatelet therapy. The Canadian co-operative trial of platelet-suppressing drugs in transient cerebral ischaemia partly confirmed the above-mentioned results (Canadian Co-operative Study Group 1978). Patients who had experienced at least one episode of transient ischaemia in the three months prior to entry were admitted into one of four therapeutic groups: aspirin (1300 mg); sulphinpyrazone (800 mg); both drugs; placebo; and they were followed for at least one year. Follow-up data from 585 patients were examined for three events: number of transient ischaemic attacks, stroke, and death. The overall preliminary analysis showed that aspirin significantly reduced the risk of the three events, whilst sulphinpyrazone was of no benefit. The
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effect on stroke and death was positive for both drugs, though significant only for aspirin. Both were effective (not significantly) on single transient ischaemic attacks; aspirin benefited the patients with multiple attacks, reducing the risk of stroke or death by one third. These positive findings for aspirin apply only to normotensive men, as the drug was apparently ineffective among women and hypertensive patients. Both these findings need to be further clarified before any conclusion can be drawn in respect of high-risk patients and high responders to therapy. Deep venous thrombosis The effectiveness of aspirin in the prophylaxis of venous thromboembolism was studied in patients undergoing total hip replacement (Harris et al. 1977). Before operation, 95 patients were assigned to treatment with aspirin (1200 mg) or placebo. Thromboembolism developed in 45%O of the non-treated but only in 25% of those on the drug. This protection was limited to men-a difference between sexes similar to that observed by the Canadian Co-operative Study Group (1978). Most female patients in the study were postmenopausal and none were on contraceptive medications; hence, the interpretation of this different response is even more difficult. These results in venous thrombosis should be treated with caution and not extended to other types of venous diseases; as the authors rightly stress, hip surgery involves direct trauma to veins which may exaggerate the contribution of platelets to venous thrombosis. Cardiovascular disease Two large independent survey studies (Boston Collaborative Drug Surveillance Group 1974) in which information was obtained on regular drug intake before admission and on discharge diagnoses, involved 776 patients (treated in hospital and discharged as acute myocardial infarction) and almost 14 000 controls. A negative association between regular aspirin intake and nonfatal myocardial infarction was shown for patients with a first infarct as well as for those with a recurrent episode. In the field of secondary prevention of mortality from myocardial infarction, a study based on 1126 patients followed for 2 years (Elwood et al. 1974) showed that the mortality rate in the placebo group was always higher than in the aspirin group (though not reaching statistical significance). This study, however, suffers from a number of flaws: halfway through, the code was broken and the results disclosed; the age restriction of 65 years was removed; the interval between infarction and admission was changed from less than four weeks to six months or more; the group admitted earlier in the study consisted disproportionately of men from one specific area (a 'geographical' effect may hence not be discarded); the compliance is unknown, and it could be that the dose of aspirin (300 mg a day) was too low. In the Coronary Drug Project aspirin study, with results based on 1529 patients with a prior history of myocardial infarction, followed for an average of 22 months, the overall mortality was 5.8% in the aspirin group and 8.3% in the placebo group (Coronary Drug Project Research Group 1976). This difference of 30% is only suggestive and not large enough to be conclusive. Furthermore, only men with a prior history of oestrogen or dextrothyroxine therapy were included in this study, which precludes from extending these findings to other populations.
Sulphinpyrazone Cerebrovascular disease The study on patients with amaurosis fugax (Evans 1972), though well controlled is not conclusive. Twenty patients were randomly allocated to start treatment on either sulphinpyrazone (800 mg) or placebo, and then crossed over to the other therapeutic group, each treatment period lasting six weeks. Baseline numbers of attacks were similar for both groups. Subjects first treated with placebo showed no change from these, but when crossed over to sulphinpyrazone the incidence of attacks fell. The group first treated with the drug showed a reduction of the number of attacks, which rose when they received placebo. Thirteen subjects improved on the drug who did not improve whilst on placebo; all subjects who had improved on placebo also improved on sulphinpyrazone.
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Though these results are statistically highly significant, no short-term trial in a clinical condition which is itself so variable may be regarded as conclusive. Doubts were also raised regarding the correct diagnosis and selection of patients: this is not an easy condition to identify and the 20 patients were recruited in a short time by a single centre. General arterial disease The longevity study by Blakely & Gent (1975) showed that the survival of elderly male patients with a history of myocardial infarction, stroke and/or peripheral arterial disease could be prolonged by sulphinpyrazone. Out of 291 patients closely monitored for 4 years, 166 had a previous history of arterial disease. Sulphinpyrazone (600 mg) significantly reduced the total mortality in this group, remaining without effect in the patients without arterial disease. The benefit was even more striking when only deaths from vascular causes were taken into consideration. Unfortunately the cause of death was not accurately determined in all cases. These results may be applied only to a similar high risk group but should not be extended to the general population.
Platelet survival In clinical conditions such as transient cerebral ischaemic attacks (Steele et al. 1977), rheumatic heart disease (Steele et al. 1974), hypoxaemia and pulmonary hypertension (Steele et al. 1977), substitute heart valves (Steele et al. 1975), recurrent venous thrombosis (Steele et al. 1973) and coronary artery disease (Steele et al. 1975), platelet survival time was consistently shortened and significantly increased after treatment with 800 mg of sulphinpyrazone for periods ranging from 5 weeks to 38 months. Steele and his colleagues obtained dramatic clinical improvement in 7 patients with recurrent venous and arterial thrombosis, despite that platelet survival was normalized in only two. These authors also treated 19 patients with transient cerebral ischaemia for an average period of 30 months (six patients served as controls). The drug significantly increased platelet survival and a marked beneficial effect on the frequency of ischaemic attacks was observed in 10 patients, whilst a further 6 had a reduction of attacks by at least one half of pre-treatment levels (Steele et al. 1977).
Arteriovenous-shunt thrombosis In patients on renal dialysis (Kaegi et al. 1975) 600 mg a day of sulphinpyrazone significantly reduced the number of thrombi per patient-month. Significance was reached for male patients, whilst only a trend in favour of the drug was recorded in females. Similar results were confirmed by Michie & Wombolt (1977), who also found this therapeutic difference (which remains unexplained) between males and females. Cardiovascular disease It is perhaps in this field that the most exciting progress has been made. The initial results of a study in the prevention of cardiac mortality after a first myocardial infarct (Anturane Reinfarction Trial Research Group 1978) represent data accumulated on 1475 eligible patients entered at 25-35 days after myocardial infarction. There were 69 deaths of which 68 were of cardiac nature and 1 was cerebrovascular. For cardiac deaths the annual death rate was 9.5% in the placebo group and 4.9% in the sulphinpyrazone group; this represents a reduction of 48.5%. When the annual sudden cardiac death rate is analysed (sudden death being defined as that occurring within 60 minutes of the onset of symptoms) this rate was of 6.3% for the placebo group and 2.7% for the sulphinpyrazone one, representing a reduction of 57.2%. Discussion The only study in cerebrovascular disease with clofibrate did not produce evidence as to the effectiveness of the drug and it is difficult to assume that patients without hypercholesterolaemia would have benefited from treatment. Despite the claimed beneficial effect of the drug in coronary disease, this was not confirmed by the well conducted study by the Coronary
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Drug Project Research Group (1975). The results of the international trial in coronary ischaemic disease (Committee of Principal Investigators 1978) confirmed the basic hypothesis that reduction of high serum cholesterol can reduce the incidence of ischaemic heart disease, though the validity of this affirmation seems to be restricted to nonfatal infarctions. The results of this study are basically in agreement with the negative findings of the Coronary Drug Project, and clofibrate may not be recommended as a lipid-lowering drug for the primary prevention of coronary heart disease. Regarding dipyridamole, the total absence of effect on major end-points in cerebrovascular disease is disheartening, and inadequate designs of other trials preclude from drawing valid conclusions in this field. It has been proven effective when combined with anticoagulants in preventing thromboembolic accidents after cardiac valve replacements. The usefulness of the drug in improving the prognosis in ischaemic heart disease is unknown and the results of the Persantin-Aspirin Reinfarction Study should be awaited before trying to answer this question. The evidence that aspirin is helpful and beneficial in thromboembolic diseases is growing, but further results where major end points are unequivocally affected are required in ischaemic heart disease. Evidence is good regarding its effectiveness in transient ischaemia and deep venous thrombosis; in the field of coronary disease, results of ongoing studies such as the Aspirin Myocardial Infarction Study (USA) and a one-year study under the supervision of the Medical Research Council (UK) should be available in the course of the next two years and may clarify the current situation. Sulphinpyrazone has been extensively evaluated in cerebrovascular and cardiovascular diseases and a number of clinical studies strengthen the evidence that platelet survival time is the most reliable test for evaluating the progress of arterial thromboembolic disease. In the field of transient cerebral ischaemia, indications that the drug might be useful are contradictory and weak, whilst there is firmer ground for belief that it is effective in arteriovenous-shunt thrombosis and in improving the general condition of elderly male patients suffering from complications of severe atherosclerosis. It is undoubtedly in coronary disease that sulphinpyrazone looks most promising; the evidence in this field is possibly the most impressive currently at hand for all antiplatelet agents. Before deciding upon a specific antithrombotic treatment, careful consideration should be given to patients who seem to be at a higher risk than others. The presence of risk factors seems to affect the efficacy of the drugs in a way which is not yet clearly understood. Patients with multiple transient ischaemic attacks are at a higher risk than those with single episodes; likewise, they apparently respond better to treatment than the latter. This 'high-risk-highresponse' factor is also found in hypertensives versus normotensives, appropriate carotid lesion versus non-appropriate lesion, men versus women. High-risk patients seem to be high responders to treatment, whilst the benefit appears to be fairly poor on low-risk subjects. Unfortunately the ideal clinical model to test antithrombotic drugs has not yet been found; most if not all clinical trials are carried out on patients whose diseases may be evaluated on a long-term basis only. This is a serious difficulty and it would be helpful if quick and reliable results were obtainable from short-term therapy. Investigations in this field are thus long, difficult and often tedious, but it is to be hoped that ever-increasing interest and research will in the end disclose an ideal and reliable clinical model. References Acheson J, Danta G & Hutchinson E C (1969) Briltish Medical Joulrnal i, 614-615 Acheson J & Hutchinson E C (1972) Atherosclerosis 15, 177-183 Anturane Reinfarction Trial Research Group (1978) Newz Eniglandl Jouirnal of Medicine 298 289-295 Arrants J E & Hairston P (1972) American Surgeon 38, 432-435 Blakely J A & Gent M (1975) In: Platelets, Drugs and Thrombosis. Ed. J F Cade et al. Karger, Basel; pp 284-291 Boston Collaborative Drug Surveillance Group (1974) British Medical Joulrnal i, 440--443 Canadian Co-operative Study Group (I1978) Newt Enqlland Journal of Medicine 299, 53-59 Committee of Principal Investigators (I1978) British Heart Journal 40, 1069-1118 Coronary Drug Project Research Group (I1975) Journwal of the American Medical Association 231, 360-381 Coronary Drug Project Research Group (I1976) Journal of Chronic Diseases 29 625-642 Dyken M L, Kolar 0 J & Jones F H (1973) Strok-e 4. 732-736
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Elwood P C, Cochrane A L, Burr M L, Sweetnam P M, Williams G, Welsby E, Hughes S J & Renton R (1974) British Medical Journal i, 436-440 Evans G (1972) Surgical Forum 23, 239-241 Fields W S, Lemak N A, Frankowski R F & Hardy R J (1977) Stroke 8, 301-314 Gent A E, Brook C G D, Foley T H & Miller T N (1968) British Medical Journal iv, 366-368 Harris W H, Salzman E W, Athanasoulis C A, Waltman A C & DeSanctis R W (1977) New England Journal ofMedicine 297, 1246-1249 Harrison M J G, Marshall J, Meadows J C & Russell R W R (1971) Lancet 2, 743-744 Kaegi A, Pineo G F, Shimizu A, Trivedi H, Hirsch J & Gent M (1975) Circulation 52, 497-499 Michie D D & Wombolt D G (1977) Current Therapeutic Research 22, 196-204 Newcastle upon Tyne Region Physicians (1971) British Medical Journal iv, 767-775 Scottish Society of Physicians (1971) British Medical Journal iv, 775-784 Steele P, Battock D & Genton E (1975) Circulation 52, 473-476 Steele P, Carroll J, Overfield D & Genton E (1977) Stroke 8, 396-398 Steele P, Ellis J H, Weily H S & Genton E (1977) Circulation 55, 660-662 Steele P P, Weily H S, Davies H & Genton E (1974) New England Journal of Medicine 290, 537-539 Steele P, Weily H, Davies H, Pappas G & Genton E (1975) Circulation 51, 358-362 Steele P P, Weily H S & Genton E (1973) New England Journal of Medicine 288, 1148-1152 Sullivan J M, Harken D E & Gorlin R (1971) New England Journal of Medicine 284, 1391-1394
513
Antiplatelet agents: a review' Michael L Gantmacher MD2 Geigy Pharmaceuticals, Macclesfield, Cheshire
The socioeconomic importance of cardiovascular and cerebrovascular arterial diseases is very well documented and need not be stressed here. Despite the progress accomplished in their understanding, treatment and prevention, they still hold the dubious honour of being the primary cause of death. Anticoagulants have for many years been the main or only therapy, one that has always been instituted too late (after the primary vascular event) and which has proven too often to be ineffective in preventing secondary episodes or death. The concept of antiplatelet agents (or platelet 'modulators') arose as a new approach to antithrombotic therapy and is gaining increasing support as the role of platelets in thrombus formation is recognized as a basic aetiopathological process of arterial thromboembolism. In the past decade, expansion of research in the field of thromboembolism has been considerable and a clinical review of the more important drugs which have been and are currently studied in man, is presented here. Clofibrate, dipyridamole, aspirin and sulphinpyrazone are still under extensive investigation, though not all four look as promising as a few years ago; continuing clinical research has failed to confirm earlier hypotheses, and new and more sophisticated experimental models and ex-vivo tests did not substantiate optimistic expectations. Only the outstanding clinical studies which have been carried out with these drugs and which cast some light on a rapidly developing field of research are mentioned here.
Clofibrate Cerebrovascular disease Only one study (Acheson & Hutchinson 1972) was published in this indication. Clofibrate was compared against placebo in patients grouped according to their clinical condition: single stroke, multiple stroke and transient cerebral ischaemia. All patients had a minimal serum cholesterol of 250 mg/ 100 ml. The end points (recurrence of stroke, death and further episodes of cerebral ischaemia) were not affected by the drug. A reduction of cholesterol levels was observed in all patients, but the mean proportional fall was significantly greater (as would be expected) on clofibrate in all clinical categories. The lack of clinical efficacy suggests that the lowering of serum cholesterol per se is of no benefit in respect of the natural history of cerebrovascular disease. Because of the low number ofpatients (95) this study is not conclusive. Ischaemic heart disease A total of 497 patients with symptoms of angina, myocardial infarction or both, were treated with clofibrate or placebo and observed over a period of five years (Newcastle upon Tyne Region Physicians 1971). Patients with a history of angina or both angina and myocardial infarction were protected by the drug against sudden death and nonfatal infarcts, but the drug was not effective in reducing the risk of fatal reinfarctions. The reduction in the number of deaths and infarcts is independent of the degree by which the cholesterol serum levels were reduced. In the study conducted by a research committee of the Scottish Society of Physicians (1971), 717 patients were grouped according to diagnosis of angina, myocardial infarct or both. Randomization flaws occurred: a significant difference in the initial serum cholesterol levels 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 11 April 1978. Accepted 28 April 1978 2 Present address: CIBA-GEIGY Limited, CH-4002 Basel, Switzerland
0 1 41-0768/79/070513-07/$Ol
-
00/0
'."
1979 The Royal Society of Medicine
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Journal of the Royal Society of Medicine Volume 72 July 1979
and systolic blood pressures, both higher in men in the placebo group. The end-points (sudden death, fatal and nonfatal myocardial infarction) were significantly reduced by the drug in patients with both angina and infarction; a similar trend was observed in the angina group. Patients with only myocardial infarction did not benefit, those on clofibrate being affected by a higher rate of fatal infarcts. These findings are contradictory and the trial is inconclusive. Likewise, no relationship between beneficial effects and lowering of serum cholesterol may be inferred from it. The Coronary Drug Project is a national collaborative study to assess long-term therapies which influence lipid metabolism. It is conducted on a sample population of men, aged 30-64 years who have recovered from one or more myocardial infarcts. In such a study, 3908 patients were treated with either clofibrate, nicotinic acid or placebo, and followed for approximately eight years. Total and cause-specific mortalities were not affected by clofibrate. There was a statistically significant excess of angina pectoris, cardiac arrhythmias, intermittent claudication and nonfatal cardiovascular events in the drug group as compared with the placebo one. The research group concluded that there is no evidence that justifies recommending the use of clofibrate in the treatment of coronary heart disease (Coronary Drug Project Research Group 1975). The results of an important international trial in the primary prevention of ischaemic heart disease are now available. The study is based on 15 745 men studied for an average period of 5.3 years (Committee of Principal Investigators 1978). All the statistical difference between the treated and the control high-cholesterol groups is accounted for by the difference in the incidence of nonfatal myocardial infarctions, which was significantly lower in the clofibratetreated group. No differences were found between both groups regarding fatal infarctions, sudden death or incidence of angina pectoris. An adverse important finding was that there were significantly more deaths from noncardiovascular diseases (liver, gallbladder, small and large intestines) in the clofibrate group than in the control group; there is no clear explanation for this finding which remains a reason for concern.
Dipyridamole Cerebrovascular disease A controlled study was conducted by Acheson et al. (1969) on 169 patients classified in the same diagnostic groups as for their clofibrate study: transient ischaemic attacks, single stroke and multiple strokes. A first treatment period with 400 mg a day lasted 14 months, after which the patients remaining in the study (14 died and 16 had been eliminated because of noncompliance) were followed for a further 11 months on 800 mg daily. The incidence of ischaemic attacks and recurrence of stroke was not affected by the drug nor was any difference detected between both dosage regimes. The natural history of the disease remained unchanged through the study. Ischaemic heart disease Similar deceptive results (Gent et al. 1968) were obtained in 103 patients with acute myocardial infarction. After a treatment period of 4 weeks (400 mg daily) the recorded mortality in the dipyridamole group was 15.7% (8 patients) and 5.8% (3 patients) in the control group. Though the higher mortality in the dipyridamole group could be influenced by the fact that more patients received the drug within the first 48 hours after infarction, as 74.8% of all patients (41 drug-treated, 36 placebo-treated) were admitted within the first three days after infarction it is unlikely that this would have influenced the final negative results. Prosthetic heart valves The value of the drug combined with anticoagulants in preventing thromboembolic events in 39 patients who had undergone successful insertions of mitral or aortic valve prostheses was evaluated against a retrospective assessment of 29 patients exclusively on anticoagulants (Arrants & Hairston 1972). Results suggest that the combination was more effective in preventing arterial emboli and death than anticoagulants alone. Unfortunately changes in the
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design of the valves which bias the results in favour of dipyridamole were introduced during the study. The control group studied retrospectively is also unsatisfactory and the results may not be accepted as conclusive. A similar study with a placebo group (Sullivan et al. 1971) included 163 patients (all on anticoagulants) controlled during 12 months following valve replacement. Emboli developed in 14% of the placebo-treated subjects but only in 1.3% of the dipyridamole group. Moreover, none of the patients on the drug died of embolic accidents, whilst two deaths were recorded in those on placebo. The results of this well-conducted trial are conclusive as far as the antithrombotic effect of the drug combined with anticoagulants is concerned, but no conclusion may be drawn regarding the antithrombotic effects of dipyridamole alone.
Aspirin Cerebrovascular disease The first report on the possible beneficial effects of aspirin on transient ischaemic attacks (Harrison et al. 1971) referred to two patients with amaurosis fugax in which 600 mg a day effectively reduced the number of attacks. A retrospective study on the differences in the number of carotid transient ischaemic attacks associated with antiplatelet therapy strongly suggested that aspirin could be of value in preventing these type of attacks (Dyken et al. 1973). The histories of 117 patients admitted during the previous 31 years with a diagnosis of transient ischaemic attacks were reviewed. After rigorous criteria were established for the selection of true transient ischaemic episodes, only 26 patients (22%) remained in the study, of which 15 had been treated with 600 mg a day of aspirin. Whilst 9 out of the 11 patients not receiving the drug had an additional attack, only 2 out of the 15 on the drug suffered from a further episode. There was no difference in the number of recorded deaths and infarctions. Two flaws reduce the reliability of this study: it is retrospective and the average follow-up period for the patients receiving aspirin was 14 months as against 29 months for those not on the drug. This large difference may have reduced the number of attacks recorded in the aspirin group compared with the non-treated group. The results of an excellent prospective controlled study (against placebo) were recently published (Fields et al. 1977). The objectives were to determine whether treatment with aspirin would reduce or prevent transient ischaemic attacks (including amaurosis fugax) and result in a reduction in the incidence of mortality and cerebral and retinal infarctions. The analysis of the sample as a whole (178 patients) at the end of the study did not reveal a significant difference between both treatments. The data were then stratified for two variables: (1) history of transient ischaemic attacks (single versus multiple episodes); (2) presence or absence of anatomic lesions appropriate to the presenting clinical picture (complete occlusion of the carotid artery was defined as a nonappropriate lesion). The data from patients with multiple episodes and from those with anatomic lesions appropriate to their symptomatology revealed statistical significance for the absolute end-points in favour of aspirin. An analysis of the cumulative probabilities of death or nonfatal cerebral or retinal infarction showed that patients with multiple ischaemic attacks are at a significantly higher risk than those with single attacks. These results stress the importance of making a clinical distinction between single and multiple attacks, let alone of a correct diagnosis of the causative lesion. A careful patient selection is essential before deciding upon antiplatelet therapy. The Canadian co-operative trial of platelet-suppressing drugs in transient cerebral ischaemia partly confirmed the above-mentioned results (Canadian Co-operative Study Group 1978). Patients who had experienced at least one episode of transient ischaemia in the three months prior to entry were admitted into one of four therapeutic groups: aspirin (1300 mg); sulphinpyrazone (800 mg); both drugs; placebo; and they were followed for at least one year. Follow-up data from 585 patients were examined for three events: number of transient ischaemic attacks, stroke, and death. The overall preliminary analysis showed that aspirin significantly reduced the risk of the three events, whilst sulphinpyrazone was of no benefit. The
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effect on stroke and death was positive for both drugs, though significant only for aspirin. Both were effective (not significantly) on single transient ischaemic attacks; aspirin benefited the patients with multiple attacks, reducing the risk of stroke or death by one third. These positive findings for aspirin apply only to normotensive men, as the drug was apparently ineffective among women and hypertensive patients. Both these findings need to be further clarified before any conclusion can be drawn in respect of high-risk patients and high responders to therapy. Deep venous thrombosis The effectiveness of aspirin in the prophylaxis of venous thromboembolism was studied in patients undergoing total hip replacement (Harris et al. 1977). Before operation, 95 patients were assigned to treatment with aspirin (1200 mg) or placebo. Thromboembolism developed in 45%O of the non-treated but only in 25% of those on the drug. This protection was limited to men-a difference between sexes similar to that observed by the Canadian Co-operative Study Group (1978). Most female patients in the study were postmenopausal and none were on contraceptive medications; hence, the interpretation of this different response is even more difficult. These results in venous thrombosis should be treated with caution and not extended to other types of venous diseases; as the authors rightly stress, hip surgery involves direct trauma to veins which may exaggerate the contribution of platelets to venous thrombosis. Cardiovascular disease Two large independent survey studies (Boston Collaborative Drug Surveillance Group 1974) in which information was obtained on regular drug intake before admission and on discharge diagnoses, involved 776 patients (treated in hospital and discharged as acute myocardial infarction) and almost 14 000 controls. A negative association between regular aspirin intake and nonfatal myocardial infarction was shown for patients with a first infarct as well as for those with a recurrent episode. In the field of secondary prevention of mortality from myocardial infarction, a study based on 1126 patients followed for 2 years (Elwood et al. 1974) showed that the mortality rate in the placebo group was always higher than in the aspirin group (though not reaching statistical significance). This study, however, suffers from a number of flaws: halfway through, the code was broken and the results disclosed; the age restriction of 65 years was removed; the interval between infarction and admission was changed from less than four weeks to six months or more; the group admitted earlier in the study consisted disproportionately of men from one specific area (a 'geographical' effect may hence not be discarded); the compliance is unknown, and it could be that the dose of aspirin (300 mg a day) was too low. In the Coronary Drug Project aspirin study, with results based on 1529 patients with a prior history of myocardial infarction, followed for an average of 22 months, the overall mortality was 5.8% in the aspirin group and 8.3% in the placebo group (Coronary Drug Project Research Group 1976). This difference of 30% is only suggestive and not large enough to be conclusive. Furthermore, only men with a prior history of oestrogen or dextrothyroxine therapy were included in this study, which precludes from extending these findings to other populations.
Sulphinpyrazone Cerebrovascular disease The study on patients with amaurosis fugax (Evans 1972), though well controlled is not conclusive. Twenty patients were randomly allocated to start treatment on either sulphinpyrazone (800 mg) or placebo, and then crossed over to the other therapeutic group, each treatment period lasting six weeks. Baseline numbers of attacks were similar for both groups. Subjects first treated with placebo showed no change from these, but when crossed over to sulphinpyrazone the incidence of attacks fell. The group first treated with the drug showed a reduction of the number of attacks, which rose when they received placebo. Thirteen subjects improved on the drug who did not improve whilst on placebo; all subjects who had improved on placebo also improved on sulphinpyrazone.
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Though these results are statistically highly significant, no short-term trial in a clinical condition which is itself so variable may be regarded as conclusive. Doubts were also raised regarding the correct diagnosis and selection of patients: this is not an easy condition to identify and the 20 patients were recruited in a short time by a single centre. General arterial disease The longevity study by Blakely & Gent (1975) showed that the survival of elderly male patients with a history of myocardial infarction, stroke and/or peripheral arterial disease could be prolonged by sulphinpyrazone. Out of 291 patients closely monitored for 4 years, 166 had a previous history of arterial disease. Sulphinpyrazone (600 mg) significantly reduced the total mortality in this group, remaining without effect in the patients without arterial disease. The benefit was even more striking when only deaths from vascular causes were taken into consideration. Unfortunately the cause of death was not accurately determined in all cases. These results may be applied only to a similar high risk group but should not be extended to the general population.
Platelet survival In clinical conditions such as transient cerebral ischaemic attacks (Steele et al. 1977), rheumatic heart disease (Steele et al. 1974), hypoxaemia and pulmonary hypertension (Steele et al. 1977), substitute heart valves (Steele et al. 1975), recurrent venous thrombosis (Steele et al. 1973) and coronary artery disease (Steele et al. 1975), platelet survival time was consistently shortened and significantly increased after treatment with 800 mg of sulphinpyrazone for periods ranging from 5 weeks to 38 months. Steele and his colleagues obtained dramatic clinical improvement in 7 patients with recurrent venous and arterial thrombosis, despite that platelet survival was normalized in only two. These authors also treated 19 patients with transient cerebral ischaemia for an average period of 30 months (six patients served as controls). The drug significantly increased platelet survival and a marked beneficial effect on the frequency of ischaemic attacks was observed in 10 patients, whilst a further 6 had a reduction of attacks by at least one half of pre-treatment levels (Steele et al. 1977).
Arteriovenous-shunt thrombosis In patients on renal dialysis (Kaegi et al. 1975) 600 mg a day of sulphinpyrazone significantly reduced the number of thrombi per patient-month. Significance was reached for male patients, whilst only a trend in favour of the drug was recorded in females. Similar results were confirmed by Michie & Wombolt (1977), who also found this therapeutic difference (which remains unexplained) between males and females. Cardiovascular disease It is perhaps in this field that the most exciting progress has been made. The initial results of a study in the prevention of cardiac mortality after a first myocardial infarct (Anturane Reinfarction Trial Research Group 1978) represent data accumulated on 1475 eligible patients entered at 25-35 days after myocardial infarction. There were 69 deaths of which 68 were of cardiac nature and 1 was cerebrovascular. For cardiac deaths the annual death rate was 9.5% in the placebo group and 4.9% in the sulphinpyrazone group; this represents a reduction of 48.5%. When the annual sudden cardiac death rate is analysed (sudden death being defined as that occurring within 60 minutes of the onset of symptoms) this rate was of 6.3% for the placebo group and 2.7% for the sulphinpyrazone one, representing a reduction of 57.2%. Discussion The only study in cerebrovascular disease with clofibrate did not produce evidence as to the effectiveness of the drug and it is difficult to assume that patients without hypercholesterolaemia would have benefited from treatment. Despite the claimed beneficial effect of the drug in coronary disease, this was not confirmed by the well conducted study by the Coronary
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Drug Project Research Group (1975). The results of the international trial in coronary ischaemic disease (Committee of Principal Investigators 1978) confirmed the basic hypothesis that reduction of high serum cholesterol can reduce the incidence of ischaemic heart disease, though the validity of this affirmation seems to be restricted to nonfatal infarctions. The results of this study are basically in agreement with the negative findings of the Coronary Drug Project, and clofibrate may not be recommended as a lipid-lowering drug for the primary prevention of coronary heart disease. Regarding dipyridamole, the total absence of effect on major end-points in cerebrovascular disease is disheartening, and inadequate designs of other trials preclude from drawing valid conclusions in this field. It has been proven effective when combined with anticoagulants in preventing thromboembolic accidents after cardiac valve replacements. The usefulness of the drug in improving the prognosis in ischaemic heart disease is unknown and the results of the Persantin-Aspirin Reinfarction Study should be awaited before trying to answer this question. The evidence that aspirin is helpful and beneficial in thromboembolic diseases is growing, but further results where major end points are unequivocally affected are required in ischaemic heart disease. Evidence is good regarding its effectiveness in transient ischaemia and deep venous thrombosis; in the field of coronary disease, results of ongoing studies such as the Aspirin Myocardial Infarction Study (USA) and a one-year study under the supervision of the Medical Research Council (UK) should be available in the course of the next two years and may clarify the current situation. Sulphinpyrazone has been extensively evaluated in cerebrovascular and cardiovascular diseases and a number of clinical studies strengthen the evidence that platelet survival time is the most reliable test for evaluating the progress of arterial thromboembolic disease. In the field of transient cerebral ischaemia, indications that the drug might be useful are contradictory and weak, whilst there is firmer ground for belief that it is effective in arteriovenous-shunt thrombosis and in improving the general condition of elderly male patients suffering from complications of severe atherosclerosis. It is undoubtedly in coronary disease that sulphinpyrazone looks most promising; the evidence in this field is possibly the most impressive currently at hand for all antiplatelet agents. Before deciding upon a specific antithrombotic treatment, careful consideration should be given to patients who seem to be at a higher risk than others. The presence of risk factors seems to affect the efficacy of the drugs in a way which is not yet clearly understood. Patients with multiple transient ischaemic attacks are at a higher risk than those with single episodes; likewise, they apparently respond better to treatment than the latter. This 'high-risk-highresponse' factor is also found in hypertensives versus normotensives, appropriate carotid lesion versus non-appropriate lesion, men versus women. High-risk patients seem to be high responders to treatment, whilst the benefit appears to be fairly poor on low-risk subjects. Unfortunately the ideal clinical model to test antithrombotic drugs has not yet been found; most if not all clinical trials are carried out on patients whose diseases may be evaluated on a long-term basis only. This is a serious difficulty and it would be helpful if quick and reliable results were obtainable from short-term therapy. Investigations in this field are thus long, difficult and often tedious, but it is to be hoped that ever-increasing interest and research will in the end disclose an ideal and reliable clinical model. References Acheson J, Danta G & Hutchinson E C (1969) Briltish Medical Joulrnal i, 614-615 Acheson J & Hutchinson E C (1972) Atherosclerosis 15, 177-183 Anturane Reinfarction Trial Research Group (1978) Newz Eniglandl Jouirnal of Medicine 298 289-295 Arrants J E & Hairston P (1972) American Surgeon 38, 432-435 Blakely J A & Gent M (1975) In: Platelets, Drugs and Thrombosis. Ed. J F Cade et al. Karger, Basel; pp 284-291 Boston Collaborative Drug Surveillance Group (1974) British Medical Joulrnal i, 440--443 Canadian Co-operative Study Group (I1978) Newt Enqlland Journal of Medicine 299, 53-59 Committee of Principal Investigators (I1978) British Heart Journal 40, 1069-1118 Coronary Drug Project Research Group (I1975) Journwal of the American Medical Association 231, 360-381 Coronary Drug Project Research Group (I1976) Journal of Chronic Diseases 29 625-642 Dyken M L, Kolar 0 J & Jones F H (1973) Strok-e 4. 732-736
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Elwood P C, Cochrane A L, Burr M L, Sweetnam P M, Williams G, Welsby E, Hughes S J & Renton R (1974) British Medical Journal i, 436-440 Evans G (1972) Surgical Forum 23, 239-241 Fields W S, Lemak N A, Frankowski R F & Hardy R J (1977) Stroke 8, 301-314 Gent A E, Brook C G D, Foley T H & Miller T N (1968) British Medical Journal iv, 366-368 Harris W H, Salzman E W, Athanasoulis C A, Waltman A C & DeSanctis R W (1977) New England Journal ofMedicine 297, 1246-1249 Harrison M J G, Marshall J, Meadows J C & Russell R W R (1971) Lancet 2, 743-744 Kaegi A, Pineo G F, Shimizu A, Trivedi H, Hirsch J & Gent M (1975) Circulation 52, 497-499 Michie D D & Wombolt D G (1977) Current Therapeutic Research 22, 196-204 Newcastle upon Tyne Region Physicians (1971) British Medical Journal iv, 767-775 Scottish Society of Physicians (1971) British Medical Journal iv, 775-784 Steele P, Battock D & Genton E (1975) Circulation 52, 473-476 Steele P, Carroll J, Overfield D & Genton E (1977) Stroke 8, 396-398 Steele P, Ellis J H, Weily H S & Genton E (1977) Circulation 55, 660-662 Steele P P, Weily H S, Davies H & Genton E (1974) New England Journal of Medicine 290, 537-539 Steele P, Weily H, Davies H, Pappas G & Genton E (1975) Circulation 51, 358-362 Steele P P, Weily H S & Genton E (1973) New England Journal of Medicine 288, 1148-1152 Sullivan J M, Harken D E & Gorlin R (1971) New England Journal of Medicine 284, 1391-1394
