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Aspirin in the prevention of thrombosis
l’olume
Number
86
Annotations
5
high frequency response with a flat response from DC to perhaps 2,000 Hz. Paper speed should be faster and accurately timed. Amplitudes should probably be increased, at least in those leads with very low voltage. There should be a built-in testing system which can check the continuity of all leads, the fun&on of networks used in unipolar leads, current leakage, frequency response, and decay times.
New
J. Scott Butterworth, M.D.* Ephraim Glassman, M.D. Department of Medicine York University School of Medicine New York, N. Y. *Present address: 104 E. 40th St. New I’ork, IV. Y. 10016
Aspirin
in the prevention
It has been demonstrated that aspirin inhibits the platelet release reaction, which suggests that the prolongation of the bleeding time by aspirin is probably, but not necessarily, secondary to this action. This finding raised the possibility that aspirin might prove valuable in some pathological conditions involving thrombosis. The idea needed exploring in view of the enormous medical, social, and economic importance of thrombotic conditions in the \I’estern world, and it was decided that the following trials should be carried out. Before their selected operation, and daily for five days thereafter, 303 patients were gi\-en 600 mg. of aspirin or a placebo in a carefully controlled double-blind study carried out in four separate hospitals. The patients’ legs were scanned daily after the injection of 1Z51-labelled fibrinogen for “hot spots,” which indicate local fibrin deposition, i.e., a thrombus. The result was clear cut. A dose of 600 mg. of aspirin has no effect at all on the incidence of “hot spots” during the first five postoperative days and the incidence of clinically detectable thrombosis was too low for a meaningful comparison, but the few cases observed occurred equally in the treated and placebo groups.’ Although platelets are believed to play a vital part in blood coagulation, the extent to which they are in\-olved in the deposition of isotopically labelled fibrinogen in the legs is, of course, not known. However, it can now be deduced with certainty that the release reaction and any other changes brought about by aspirin play no part in the formation of these thrombi after operations. This is a strong assertion, particularly in the present climate of opinion about the role of platelets in clinically detectable thrombotic disease and the widespread use of aspirin clinically to protect patients from thrombosis. So the following points must be made. Aspirin has no effect on the primary wave of platelet aggregation-stickinessinduced by adeno-
711
REFERENCES 1. Willems, J. L., Poblete, P. F., and Pipberger, H. V.: Day-to-day variation of the normal orthogonal electrocardiogram and vectorcardiogram, Circulation 45:1057, 1972. 2. Kossmann, C. E., Brady, D. A., Burch, G. E., et al.: Recommendations for standardization of leads and specifications for instruments in electrocardiography and vectorcardiography, Circulation 35:583, 1967.
of thrombosis
sine diphosphate, so this mechanism could still be involved in venous thrombosis detected by the *Ilabelled fibrinogen method used in the study. This can be resolved only by finding compounds which interfere with this process and subjecting them to a similar clinical trial. Are the “hot spots” detected by the r*sI fibrinogen method a true reflection of clinical thrombosis? There is no doubt that the accumulation of fibrinogen in the leg veins does indicate a thrombus locally and this can usually be demonstrated by venography. But there are certain important differences between thrombi detected by this method and the clinical disease we have known so long. For example, “hot spots” occur frequently (in up to 71 per cent of some prolonged operations;).” Furthermore they are usually small, arise in the calf, and are often found on the first postoperative day. The vast majority are clinically silent and are associated with no know-n sequelae. By contrast, clinically detectable postoperative venous thrombi are usually recognized later, are found in the thigh, and of course occur much less frequently. XII the differences can be attributed to the fact that only a small proportion of rz51 fibrinogen type thrombi extend along the veins up into the thighs where they are found later and much less frequently. So that, although the very great value of the tz51 fibrinogen test in research and sometimes in clinical conditions is accepted, it is pertinent to ask if it is too sensiti\-e on the one hand or whether the condition we need to investigate is a succe&on of e\-ents which occur subsequent to the deposition of the original thrombus. Ii-hen one considers the most serious complication of postoperative thrombosis, pulmonary embolism; it is probably true that the ‘%I fibrinogen test would be positive in all cases even in patients with silent pulmonary thrombi; but this does not explain why it is positive in such very large numbers of patients who remain free from all symptoms. It might be suggested, therefore, bearing in mind
the marked difference between icsl lit,rinogen -dctected thromhi and the clinically detectable diho.tse, that some additional hypothetical factor is necehsary for the former to devrelop into the latter. If this were so then it is highly prohahle that any treatment which prevented the formation of iZsl fibrinogen detectable thromhi would also prev-ent the superimposed clinical disease. But one could also argue, at least theoretically, that it might be possible to block the hypothetical factor necessary for the development of the full clinical picture without necessarily altering the incidence of ‘26lldetectable thrombosis. It is highly unlikely that aspirin would affect such a hypothetical additional factor and indeed the evidence is against it’; nevertheless, there are some who would argue that it would he desirable, despite the discouraging findings in the present trial, to carry out a further investigation, involving very much larger numbers of patients, to decide whether aspirin has an effect on clinical postoperative venous thrombosis or not, particularly since one study has been reported claiming to demonstrate some clinical benefit from the administration of aspirin3 Clearly, many factors, both known and unknown, contribute to the development of venous and arterial thrombosis. Local precipitating abnormalities must be important in thromhus formation because venous and arterial systems as a whole never clot solid. Platelets almost certainly play a far larger part in arterial thrombosis and it would seem rational, indeed mandatory, in view of the great importance of arterial thrombosis, to evaluate the effect of aspirin in as many thrombotic situations as possible, with a view to identifying those conditions where its specific effects have therapeutic benefit. There is already convincing evidence that aspirin is of real value in patients with amaurosis fugax.4,5
Left hemiblocks histopathological
One recognizes daunting logistic problem\ in organizing suitnhle trials, especially in myoc,udial infarction, which is a rare disease in term> of llatientyears. Furthermore, it will prov’e difficult to keep the “control” subjects from taking aspirin as it is now consumed on such ;i vast scale throiighout the LYestern world. Nevertheless, we hope si1t.h trials will he pushed through to their logical conclu-ion despite the evidence that aspirin is vvithoiit effect in postoperative v’enous thrombosis and vve awAit the results of those trials already cinder wriy with keenest interest. J. R. O’Brien St. Mary’s Hospital Portsmouth PO 3 6dG W. J. H. Autterjield University of 1Vottingham Nottinghum, NG7, 2RD, England KEFERENCES 1. Report of the Steering Committee of a trial sponsored by the Medical Research Council: Effect of aspirin on postoperative venous thrombosis, Lancet 2:441, 1972. 2. O’Brien, J. R., Tulevski, V., and Etherington, M. : Two in-vivo studies comparing high and low aspirin dosage, Lancet 1:399, 1971. 3. Salzman, E. W., Harris, W. H., and De Sanctis, R. W.: Reduction in venous thromboembolism by agents affecting platelet function, N. Engl. J. Med. m:1287, 1971. 4. Harrison, M. J. G., Marshall, J., Meadows, J. C., and Ross Russell, R. W.: Effect of aspirin in amaurosis fugax, Lancet 2:743, 1971. 5. Evans, G.: Use of platelet suppressive drugs on the incidence of recurrent venous thrombosis and transient cerebral ischaemia, Ahstr. Int. Sot. Thromh. Haemostasis, Washington, 40, 1972.
revisited from viewpoint
The introduction of the concept of left hemihlockr1~2 undoubtedly represented a fundamental step forward in the understanding of intraventricular conduction disturbances. The assumptions which formed the basis of this concept were extremely useful, especially for didactic purposes. Nevertheless, in course of time, it seems that these assumptions deserve further attention, in particular from the anatomical and histopathological viewpoints. It is, for example, generally agreed that the left branch is “anatomically a bifascicular system which acts physiologically as such.“2 We3 recently had the opportunity to test this assumption in a histological study of the left bundle branch system carried out on 20 hearts from patients devoid of conduction defects. This investigation confirmed the consistent
the
presence of a thin and elongated anterior radiation and of a wider posterior one. However, in addition to these two well-known fasciculi, the left branch was observed to frequently give off a third radiation designated to cover the midseptal surface (11 out of 20 cases). This easily identified structure emerged either from the common left bundle (five cases) or from the anterior (three cases) or posterior radiation (three cases). In the remaining nine instances, the septal coverage was supplied either by the posterior radiation (three cases) or by a complicated plexus of ramifications given off by both the anterior and posterior fasciculi (six cases). The anatomical features were such that, in most cases, it seemed reasonable to describe the left ventricular Purkinje network as composed of three main, widely inter-
Number
86
Annotations
5
high frequency response with a flat response from DC to perhaps 2,000 Hz. Paper speed should be faster and accurately timed. Amplitudes should probably be increased, at least in those leads with very low voltage. There should be a built-in testing system which can check the continuity of all leads, the fun&on of networks used in unipolar leads, current leakage, frequency response, and decay times.
New
J. Scott Butterworth, M.D.* Ephraim Glassman, M.D. Department of Medicine York University School of Medicine New York, N. Y. *Present address: 104 E. 40th St. New I’ork, IV. Y. 10016
Aspirin
in the prevention
It has been demonstrated that aspirin inhibits the platelet release reaction, which suggests that the prolongation of the bleeding time by aspirin is probably, but not necessarily, secondary to this action. This finding raised the possibility that aspirin might prove valuable in some pathological conditions involving thrombosis. The idea needed exploring in view of the enormous medical, social, and economic importance of thrombotic conditions in the \I’estern world, and it was decided that the following trials should be carried out. Before their selected operation, and daily for five days thereafter, 303 patients were gi\-en 600 mg. of aspirin or a placebo in a carefully controlled double-blind study carried out in four separate hospitals. The patients’ legs were scanned daily after the injection of 1Z51-labelled fibrinogen for “hot spots,” which indicate local fibrin deposition, i.e., a thrombus. The result was clear cut. A dose of 600 mg. of aspirin has no effect at all on the incidence of “hot spots” during the first five postoperative days and the incidence of clinically detectable thrombosis was too low for a meaningful comparison, but the few cases observed occurred equally in the treated and placebo groups.’ Although platelets are believed to play a vital part in blood coagulation, the extent to which they are in\-olved in the deposition of isotopically labelled fibrinogen in the legs is, of course, not known. However, it can now be deduced with certainty that the release reaction and any other changes brought about by aspirin play no part in the formation of these thrombi after operations. This is a strong assertion, particularly in the present climate of opinion about the role of platelets in clinically detectable thrombotic disease and the widespread use of aspirin clinically to protect patients from thrombosis. So the following points must be made. Aspirin has no effect on the primary wave of platelet aggregation-stickinessinduced by adeno-
711
REFERENCES 1. Willems, J. L., Poblete, P. F., and Pipberger, H. V.: Day-to-day variation of the normal orthogonal electrocardiogram and vectorcardiogram, Circulation 45:1057, 1972. 2. Kossmann, C. E., Brady, D. A., Burch, G. E., et al.: Recommendations for standardization of leads and specifications for instruments in electrocardiography and vectorcardiography, Circulation 35:583, 1967.
of thrombosis
sine diphosphate, so this mechanism could still be involved in venous thrombosis detected by the *Ilabelled fibrinogen method used in the study. This can be resolved only by finding compounds which interfere with this process and subjecting them to a similar clinical trial. Are the “hot spots” detected by the r*sI fibrinogen method a true reflection of clinical thrombosis? There is no doubt that the accumulation of fibrinogen in the leg veins does indicate a thrombus locally and this can usually be demonstrated by venography. But there are certain important differences between thrombi detected by this method and the clinical disease we have known so long. For example, “hot spots” occur frequently (in up to 71 per cent of some prolonged operations;).” Furthermore they are usually small, arise in the calf, and are often found on the first postoperative day. The vast majority are clinically silent and are associated with no know-n sequelae. By contrast, clinically detectable postoperative venous thrombi are usually recognized later, are found in the thigh, and of course occur much less frequently. XII the differences can be attributed to the fact that only a small proportion of rz51 fibrinogen type thrombi extend along the veins up into the thighs where they are found later and much less frequently. So that, although the very great value of the tz51 fibrinogen test in research and sometimes in clinical conditions is accepted, it is pertinent to ask if it is too sensiti\-e on the one hand or whether the condition we need to investigate is a succe&on of e\-ents which occur subsequent to the deposition of the original thrombus. Ii-hen one considers the most serious complication of postoperative thrombosis, pulmonary embolism; it is probably true that the ‘%I fibrinogen test would be positive in all cases even in patients with silent pulmonary thrombi; but this does not explain why it is positive in such very large numbers of patients who remain free from all symptoms. It might be suggested, therefore, bearing in mind
the marked difference between icsl lit,rinogen -dctected thromhi and the clinically detectable diho.tse, that some additional hypothetical factor is necehsary for the former to devrelop into the latter. If this were so then it is highly prohahle that any treatment which prevented the formation of iZsl fibrinogen detectable thromhi would also prev-ent the superimposed clinical disease. But one could also argue, at least theoretically, that it might be possible to block the hypothetical factor necessary for the development of the full clinical picture without necessarily altering the incidence of ‘26lldetectable thrombosis. It is highly unlikely that aspirin would affect such a hypothetical additional factor and indeed the evidence is against it’; nevertheless, there are some who would argue that it would he desirable, despite the discouraging findings in the present trial, to carry out a further investigation, involving very much larger numbers of patients, to decide whether aspirin has an effect on clinical postoperative venous thrombosis or not, particularly since one study has been reported claiming to demonstrate some clinical benefit from the administration of aspirin3 Clearly, many factors, both known and unknown, contribute to the development of venous and arterial thrombosis. Local precipitating abnormalities must be important in thromhus formation because venous and arterial systems as a whole never clot solid. Platelets almost certainly play a far larger part in arterial thrombosis and it would seem rational, indeed mandatory, in view of the great importance of arterial thrombosis, to evaluate the effect of aspirin in as many thrombotic situations as possible, with a view to identifying those conditions where its specific effects have therapeutic benefit. There is already convincing evidence that aspirin is of real value in patients with amaurosis fugax.4,5
Left hemiblocks histopathological
One recognizes daunting logistic problem\ in organizing suitnhle trials, especially in myoc,udial infarction, which is a rare disease in term> of llatientyears. Furthermore, it will prov’e difficult to keep the “control” subjects from taking aspirin as it is now consumed on such ;i vast scale throiighout the LYestern world. Nevertheless, we hope si1t.h trials will he pushed through to their logical conclu-ion despite the evidence that aspirin is vvithoiit effect in postoperative v’enous thrombosis and vve awAit the results of those trials already cinder wriy with keenest interest. J. R. O’Brien St. Mary’s Hospital Portsmouth PO 3 6dG W. J. H. Autterjield University of 1Vottingham Nottinghum, NG7, 2RD, England KEFERENCES 1. Report of the Steering Committee of a trial sponsored by the Medical Research Council: Effect of aspirin on postoperative venous thrombosis, Lancet 2:441, 1972. 2. O’Brien, J. R., Tulevski, V., and Etherington, M. : Two in-vivo studies comparing high and low aspirin dosage, Lancet 1:399, 1971. 3. Salzman, E. W., Harris, W. H., and De Sanctis, R. W.: Reduction in venous thromboembolism by agents affecting platelet function, N. Engl. J. Med. m:1287, 1971. 4. Harrison, M. J. G., Marshall, J., Meadows, J. C., and Ross Russell, R. W.: Effect of aspirin in amaurosis fugax, Lancet 2:743, 1971. 5. Evans, G.: Use of platelet suppressive drugs on the incidence of recurrent venous thrombosis and transient cerebral ischaemia, Ahstr. Int. Sot. Thromh. Haemostasis, Washington, 40, 1972.
revisited from viewpoint
The introduction of the concept of left hemihlockr1~2 undoubtedly represented a fundamental step forward in the understanding of intraventricular conduction disturbances. The assumptions which formed the basis of this concept were extremely useful, especially for didactic purposes. Nevertheless, in course of time, it seems that these assumptions deserve further attention, in particular from the anatomical and histopathological viewpoints. It is, for example, generally agreed that the left branch is “anatomically a bifascicular system which acts physiologically as such.“2 We3 recently had the opportunity to test this assumption in a histological study of the left bundle branch system carried out on 20 hearts from patients devoid of conduction defects. This investigation confirmed the consistent
the
presence of a thin and elongated anterior radiation and of a wider posterior one. However, in addition to these two well-known fasciculi, the left branch was observed to frequently give off a third radiation designated to cover the midseptal surface (11 out of 20 cases). This easily identified structure emerged either from the common left bundle (five cases) or from the anterior (three cases) or posterior radiation (three cases). In the remaining nine instances, the septal coverage was supplied either by the posterior radiation (three cases) or by a complicated plexus of ramifications given off by both the anterior and posterior fasciculi (six cases). The anatomical features were such that, in most cases, it seemed reasonable to describe the left ventricular Purkinje network as composed of three main, widely inter-