716 A motations Am. Heart J. May, 19h.i

Notwithstanding the observation that, in general, older patients have derived less than optimal re- sults from operation, it is unjust to conclude that youth protects the myocardium.

The finding of significant pulmonary stenosis in patients who survive beyond the fourth decade is unusual. Results may be less than optimal when operation is carried out during middle or late life. In a series of 50 consecutive patients operated on for pulmonary stenosis at the Duke Medical Center,’ only 1 has died in the postsurgical period. This was a 42-year-old man who developed heart failure prior to operation and died several weeks after an apparently uncomplicated valvotomy. His course was inexorably downhill despite relief of the valvu- lar stenosis. This experience further emphasizes the deleterious effect of long-standing outflow obstruc- tion on cardiac performance.

There is a point in both the magnitude and the duration of obstruction after which surgical relief cannot be expected to result in restoration of normal cardiac function. This point cannot be predicted in a given patient. The operative technique for the relief of such obstruction has greatly improved, and surgical mortality and morbidity have greatI> decreased. It is our current belief that patients with isolated pulmonary valvular stenosis who have a normal or reduced flow and a transvalvular gradient of 40 mm. Hg or a right ventricular pres- sure above 6.5 mm. Hg should be considered for valvulotomy without undue delay. When such excellent surgical results may be expected, it appears

likely that the status of the myocardium is the final determinant of the clinical course and prog- nosis of pulmonic stenosis.

Henry D. McIntosh, M.D. Cardiovascular Laboratory

Department of Medicine Duke University Medical Centw

Durham, N. C.; and Allax I. Cohen, M.D.

2232 North Seventh 4~. Phoenix 7, Aria.

REFERENCES

1. Johnson, A. M.: Hypertrophic infundibular stenosis complicating simple pulmonary valve stenosis, Brit. Heart J. 21:429, 1959.

2. Campbell, M.: Valvulotomy as a curvative operation for simple pulmonary stenosis, Brit. Heart J. 21:41.5, 1959.

3. Brock, R.: The surgical therapy of pulmonary stenosis, Brit. Heart J. 23:337, 1961.

4. Allanby, K. D., and Campbell, M.: Congenital pulmonary stenosis with closed ventricular septum, Guy’s Hosp. Rep. 98:18, 1949.

5. Campbell, M.: Relationship of pressure and valve area in pulmonary stenosis, Brit. Heart J. 22:101, 1960.

6. Yahini, J. H., Dulfano, M. J., and Toot-, M.: Pulmonic stenosis: A clinical assessment of severity, Am. J. Cardiol. 5:744, 1960.

7. Scaly, W. C.: Personal comment.

Anticoagulant therapy

in acute myocardial infarction

The early studies of anticoagulant therapy produced good statistical evidence of its value in the preven- tion and treatment of venous thrombosis and pul- monary embolism. This evidence has been supported by later studies on surgical and gynecological opera- tion cased, parturient women, and patients suffering from fractured femur and from acute myocardial infarction.‘-7

In the case of venous thromboembolism the prob- lem examined is a limited one and does not make excessive demands upon the statistical method. The condition studied is the same in all the different types of clinical material, it is relatively easily recognized, and it is clearly related to the thrombotic process which the treatment is designed to combat. Finally, the results reported are remarkably uniform in the various studies, even though these differ ‘in their other conclusions.

The evidence relating to systemic arterial em- bolism, although less extensive, is similar in char- acter. It shows that anticoagulants have a prophy- lactic value against embolism, although their value in therapy is much less clear.*-‘0

The evidence in support of the use of anticoagu- lants in the prevention and treatment of venous thromboembolism and systemic arterial embolism can, therefore, be accepted and the measure of benefit to be expected can be fairly weighed against the possible risks of the treatment.

The evidence in regard to acute myocardial in- farction is much less satisfactory. It does support the effect of anticoagulants against the types of thromboembolic complication already mentioned. However, in most of the studies on myocardial in- farction the enquiries have been formulated on a much wider basis. The concept “thromboembolic complications” has been expanded to include “secon- dary myocardial infarction,” i.e., extensions of the original infarcted area or new areas of infarction in the myocardium. There are some theoretical diffi- culties here. It is now well recognized that myo- cardial infarction often occurs in the field of dis- tribution of a narrowed coronary artery, without any thrombotic occlusion of the vessel, probably by reason of functional depletion of the local supply of blood, conditioned by variation in arterial blood

Annotations 717

pressure. For example, Wright and associates5 recognized 24 secondary myocardial infarctions among their 91 autopsies, but new thrombus could be demonstrated in less than half of these secondary infarctions. Nevertheless, they included all such instances of secondary infarction, whether diagnosed clinically or at autopsy, under the heading of “thromboembolic complications” and presumed them all to be potentially preventable by anticoag- ulant therapy. A considerable number of these secondary infarctions appear to be unrelated to thrombosis.

In most of the studies of myocardial infarction the basis of assessment has been widened still further by using the over-all death rate as a measure of the value of the treatment. This approach has so complicated the problem as to raise some doubt whether the statistical method can justifiably be applied. The death rate in acute myocardial infarc- tion is influenced by many different factors, and a fair comparison between two series of cases is ex- tremely difficult. This is illustrated by the widely different death rates in different series treated without anticoagulants, ranging from 16 per cent to more than 50 per cent.“-”

In many studies the method used is to compare over-all death rate in two groups of patients, one group routinely treated with anticoagulants, the other group treated without them. This method lays on the investigator the responsibility of ensuring that the two groups of patients are similar in all respects, apart from the use of anticoagulants in treatment. The infinite variety of human patients in their reaction to disease and of human medical institutions in their attitude toward treatment makes this almost impossible. Selection factors beyond the control of the investigators will influence the char- acter of the two groups in ways which cannot be corrected by the most careful analysis. To take ex- amples from the many published studies, one pair each from the U.S.A., Great Britain, and Denmark, LVright and associates,5 Tulloch and Gilchrist,’ and Holten’g all reported a considerably lowered death rate with anticoagulant therapy, whereas Eastman and associates, 20 Honey and Truelove, and Hilden and associates’ could not show any significant effect.

i\ series of investigations of this type has shown a lower death rate in anticoagulant-treated cases than in “controls,” but in many of them the selection factors appear to have affected the constitution of the two groups in such ways as to raise doubts about the validity of the results. For example, Wright and associates,6 . 111 a study of 1,031 patients, con- cluded that the death rate could be reduced from 23 per cent to 16 per cent by routine anticoagulant therapy. This study has been widely regarded as authoritative, but critical examination of the data in the report raises many doubts. First, the attempt to secure random selection of patients by allocating them to “treatment” and “control” groups accord- ing to odd and even dates of admission to hospital was not successful. The disparity in numbers of the two groups (“treatment,” 589; “control,” 442) indi- cates that this rule must have been disregarded on many occasions. The authors suggested that in some cases the referring physician may have accelerated admission to hospital to ensure admission on an

odd date and so secure the expected benefit of anti- coagulant treatment. Secondly, the evidence in the report shows that in the first week of illness there was a higher incidence of signs of heart failure in the control group than in the treatment group. Thirdly, the cases studied were distributed in 16 different hospitals, situated in 9 different States, and were observed under the responsibility of 19 different investigators. This must have rendered coordination of the conditions of hospital care extremely difficult, and the report gives little indication of any stan- dardization in this respect.

The type of hospital care given was not uniform. The patients studied included both public ward cases and private cases, very unequally- distributed among the 16 hospitals. Death rates were consis- tently lower in private cases than in public ward cases, both in controls (19.8 and 25.2 per cent, respectively) and in treated cases (11.4 and 19.4 per cent, respectively). In fact, the difference in over-all death rates between private cases (14 per cent) and public ward cases (21 per cent) is slightly greater than that between anticoagulant-treated cases (16 per cent) and controls (23 per cent). The authors suggest that the lower death rate in private cases may have been due to the higher standard of nursing care which they received, but it seems likely that it was due largely to a higher proportion of mild cases of myocardial infarction. \Vealthier patients tend to seek medical care for mild symptoms more readily than do patients of lower economic status, and this tendency is increased by the private insurance for medical expenses commonly held in the United States. If we confine the comparison between treated cases and controls to the 8 hospitals which contributed only public ward cases, we find that the difference in death rates is negligible (172 treated cases, death rate of 18.6 per cent; 136 con- trols, death rate of 19.8 per cent). Similarly, if we confine the comparison to the two hospitals which contributed private cases almost exclusively, the difference in death rates is again small (149 treated cases, death rate of 14.1 per cent; 107 controls, death rate of 17.7 per cent). In the other 6 hospitals, which had substantial numbers both of private and of public ward patients, the difference in death rates was much more striking (268 treated cases, death rate of 15.3 per cent; 199 controls, death rate of 25.1 per cent). These results suggest that the death rates were unequally affected by factors other than anticoagulant therapy. There are grounds, therefore, for doubt as to the true comparability of the treatment and control groups in this study.

The study made in Copenhagen by Hilden and associates7 is comparable in the numbers of patients to that of Wright and associates. It was confined to 2 hospitals of similar type in the same city and was carried out by 4 investigators in close and con- tinuous collaboration. Some statistical criticisms have been made of this study,21-Z4 but its material was more uniform and there appears to have been much better standardization of the general condi- tions of hospital care than in the American study. The Danish workers found no significant difference in over-all death rates between the control group and the group treated with anticoagulants (25 and 23 per cent, respectively).

718 Annotations

There must be some scientific doubt, therefore, about the statistical evidence appearing to show a considerable lowering of over-all death rate in myocardial infarction by the routine use of anti- coagulant therapy. The evidence showing a re- duction in the incidence of venous thromboembolism is acceptable, but this complication is responsible for only a small part of the total death rate. More- over, it can be combated by other means, especial15 armchair treatment and earlier ambulation.25~2fi The use of anticoagulants may justifiably be con- sidered in selected patients who appear to have special liability to venous thromboemboiism, for example, obese patients, those with a previous his- tory of venous thrombosis, and those who for some reason have to be confined to bed for longer periods.

A factor which must be carefully weighed is the degree of risk involved in the treatment itself. The effect of any such risk rises to a maximum when the treatment is employed as a routine in all cases. It cannot be denied that there are risks in the thera- peutic use of anticoagulants, and these risks are not eliminated even by the most conscientious control of prothrombin levels. 27-30 Physicians who use anti- coagulant therapy must accept the fact that a certain number of their patients will suffer hemor- rhage, and that in a small proportion of these pa- tients the hemorrhage will be fatal. \Vright and associates discussed this problem, and their pro- nouncement must be quoted: ‘I. . . slightly less than two more deaths with haemorrhage or rupture as a major or contributing cause per hundred cases can probably be expected with anticoagulant therapy than without it. This regrettable loss fortunately is counterbalanced by a substantially lower expecta- tion of death due to thromboembolism with than without anticoagulant protection. As a result, the net saving in lives associated with anticoagulant therapy reported in Chapter SI was about 7 per hundred hospitalized cases of myocardial infarction.”

This is an extremely dubious ethical position for any physician. In plain terms it means that it is justifiable to sacrifice certain patients in the hope of saving a larger number of others. Anyone who has an absolute certainty of the validity of the sta- tistical evidence may perhaps be able to reconcile himself to this proposition, so long as he considers it purely in statistical terms. He must surely suffer misgivings if he tries to apply it in the case of an individual patient.

The ethical difficulty arises only when routine anticoagulant therapy is in question. In the case of any individual patient it is quite proper to balance the risk of thromboembolism against the risk of possible hemorrhage and to reach a derision based purely on that patient’s interests. Russek”’ has pointed out that there are many “good-risk” cases of myocardial infarction in which the risk of throm- boembolic complications is very small. It is surely questionable practice to employ anticoagulants as a routine treatment and to accept the risk of fatal hemorrhage in such patients for the sake of benefits which may be gained only by others.

This ethical difficulty, reinforced by doubts of the validity of the statistical evidence, should weigh heavily against the routine use of anticoagulants in patients who are suffering from acute myorardial

infarction. When each patient’s needs are considered individually, there will be a certain number in whom the use of the treatment is justified.

A. L. Jacobs, D.&f., F.R.C.P. Whittington Hospital, St. Mary’s Wing

Ha’ghgate Hill London N. 19, England

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Bauer, G.: Thrombosis. Early diagnosis and abortive treatment with heparin, Lancet 1:447, 1946. Zilliacus, H.: On the specific treatment of thrombosis and pulmonary embolism with anticoagulants, with particular reference to the post-thrombotic sequelae, Acta med. scandinav. SUDD~. 171. 1946. Chalmers, D.-e., Maiks, J., Bottomley, J. E., and Lloyd, 0.: Post-operative prophylactic anticoagulants. Five-year study in an obstetric and gynaecological unit, La&et 2:220, 1960. Sevitt. S.. and Gallacher. N. G.: Prevention of

” I

venous thrombosis and pulmonary embolism in injured patients, Lancet 2:981, 1959. Wright, I. S., Marple, C. D., and Beck, D. F.: Myocardial infarction, New York, 1954, Grune & Stratton, Inc. Honey, G. E., and Truelove, S. C.: Prognostic factors in myocardial infarction, Lancet 1:1155 and 1209, 1957. Hilden, T., Iversen, K., Raaschou, F., and Schwartz, M.: Anticoagulants in acute myo- cardial infarction, Lancet 2:327, 1961. Owren, P. A.: Antikoagulasjonsbehandling, Tskr. norske Laegeforen. 78:571, 1958. Soul& P., Chiche, P., DeGeorges, M., Acar, J., and Benaceraf, A.: fitude sur les embolies pCriphCriques du r&r&issement mitral et leur traitement par les anticoagulants, Semaine thCrap. 37:408, 1961. Jacobs, A. L.: Arterial embolism in the limbs, Edinburgh, 1959, E. & S. Livingstone, Ltd. Conner, L. .\., and Holt, E.: Subsequent course and prognosis in coronary thrombosis; analysis of 287 cases, AM. HEART J. 5:705, 1930. Harrington, A. W., and Wright, J. H.: Cardiac infarction: a study of 148 cases, Glasgow M. J. 119:1, 1933. Master, A. M., Dack, S., and Jaffe, H. L.: The treatment and the immediate prognosis of coronary thrombosis (267 attacks), AM. HEART

J. 12:549, 1936. Master, A. M., Dack, S., and Jaffe, H. L.: Coronary thrombosis: an investigation of heart failure and other factors in its course and prog- nosis, AM. HEART J. 13:330, 1937. Levine, S. A., and Rosenbaum, F. F.: Prog- nostic value of various clinical and electro- cardiographic features of acute myocardial infarction, Arch. Int. Med. 68:913, 1941. Katz, L. N., and Mintz, S. S.: Recent myo- cardial infarction: an analysis of 572 cases, Arch. Int. Med. 80:205. 1947. Evans, W.: Anticoagulant therapy in coronary occlusion, Proc. Roy. Sot. Med. 47:318, 1954. Tulloch, J. A., and Gilchrist, A. Ii.: Anticoagu-

Annotations 719

lants in treatment of coronary thrombosis, Brit. M. J., 2:965, 19.50.

19. Holten, C.: Anticoagulants in the treatment of coronary thrombosis, Acta med. scandinav. 140:340, 19.51.

20. Eastman, G. L., Cook, E. T., Shinn, E. T., 1)utton. R. E.. and Lvons. R. H.: A clinical study of anticoagulants in acute myocardial infarction, with particular reference to early heparin therapy, Am. J. M. SC. 233:647, 1957.

2 1. Holten, C. : Anticoagulants in acute myocardial infarction (Correspondence), Lancet 2:716, 1961.

22. Engelberg, H.: Anticoagulants in acute myo- cardial infarction (Correspondence), Lancet 1:103, 1962.

23. Friedberg, C. Ii. : Should we abandon anticoagu- lant therapy in acute myocardial infarction? J.A.M.A. 180:307, 1962.

24. Wright, I. S.: An evaluation of anticoagulant therapy for myocardial infarction, Lancet 2 :654, 1962.

25. Levine, S. A., and Lown, B.: “Armchair” treatment of acute coronary thrombosis, J.A.M.A. 148:1365, 1952.

26. Helander, S.: Armchair treatment with and without anticoagulants in cardiac infarction, Acta med. scandinav. 162:351. 1958.

27. Nichol, E. S.: Risk of hemorrhage in anticoagu- lant therapy, Ann. West. Med. & Surg. 4:71, 1950.

28. Anticoagulants as a cause of hemorrhage (Editorial), J.A.M.A. 144:1466, 1950.

29. Flaxman, N.: Drug fatalities, J.A.M.A. 147:377, 19.51.

30. Russek, H. I., and Zohman, B. L.: Anticoagu- lant therapy in acute myocardial infarction. A survey of specialists’ opinions concerning indi- cations, results and dangers, Am. J. M. SC. 225:8, 1953.

31. Russek, H. I.: Limited use of anticoagulants in acute myocardial infarction. Analysis of one thousand “good-risk” cases, J.A.M.A. 163:922, 1957.