Anticoagulants

742 In an article on p. 726 of this issue Dr. VAKIL rauwolfia : "clinical results are often disof says

urgently.

appointing

in

malignant, nephrosclerotic, nephritic,

and arteriosclerotic forms of hypertension " ; and the results described by JOINER and KAUNTZE9 confirm this. Certainly in some cases of severe hypertension rauwolfia has given real benefit 5 6 ; but some of these results must be interpreted with care, and even with reserve. Sphygmomanometer readingsparticularly of the diastolic level-are subjective measurements. Yet in many instances the clinical observer was aware of the treatment that the patient was receiving. Furthermore, although mean values of readings of diastolic and systolic pressures (and in some cases the mean blood-pressure) have been recorded before and after treatment, the figures have not been analysed statistically ; and by recording only derived data most workers make such analysis impossible. Finally, so far no objective evidence of improvement in prognosis has been reported. The conviction of Dr. VAKIL and other responsible workers that rauwolfia deserves a place in treatment cannot be ignored ; but their observations do not excuse us from seeking

objective proof. In Rauwolfia serpentina we apparently have a safe drug with a mild hypotensive effect; but its value in treatment has still to be defined.

Anticoagulants AT the International Conference on Thrombosis held at Basle in July and in recent published reports, two topics have been much discussed. One is the and the value of treatment of practicability long-term other is the with the outpatients anticoagulants ; constantly increasing number of anticoagulant drugs. At Basle OWREN,10 of Oslo, discussed his results with long-term anticoagulant treatment of coronaryartery disease. The short-term treatment of acute myocardial infarction with anticoagulants has now been very extensively applied and the results voluminously reported ; it is generally agreed that this treatment reduces the death-rate, principally by minimising the secondary tbrombo-embolic complications. OWREN pointed out, however, that myocardial damage from coronary thrombosis is irreversible, and in this sense anticoagulant treatment is too late. He suggested that it is more reasonable to treat patients known to have coronary-artery disease prophylactically by continuous administration of dicoumarol or other anticoagulant drug. Since 1948 OWREN himself has treated in this way about 700 patients. From this group he selected for particular study 236 with coronary-artery disease, half of whom had had one infarction before treatment was begun. These patients all received dicoumarol ; but recently OwREN and his colleagues have preferred phenylindanedione, which they find gives smoother control. They control dosage, not by the popular Quick onestage prothrombin-time, but by a method of their own which they consider takes account of changes in prothrombin and in proconvertin (factor VII). Intermittent dosage and daily maintenance dosage and for this long-term therapy were both tried ; control was more complete with the latter method.

It is not easy to decide the correct dose, since individual responses to dicoumarol vary greatly both in duration and in intensity. In order to establish the right scale of dose, the prothrombin-proconvertin level of the blood was checked on alternate days for the first eight to fourteen days ; when a proper and stable level of hypocoagulability had been reached, the interval between blood tests was lengthened to one week, then to two weeks, and finally to three weeks. A chart is kept for each patient to show the trend of the test results, and the dose is adjusted a few milligrammes up or down according to the rise The average initial dose of or fall of the test results. dicoumarol is 240 mg. on the first day, 120 mg. on the second day, then 100-50 mg. daily according to the result of the blood test. Patients’ needs vary from time to time, and stability can never be taken for

granted.

OwREN described the results in 128 patients who had angina pectoris without infarction ; 56 had been treated for up to one year, 41 for one to two years, 22 for two to three years, and 9 for three to five years. Myocardial infarction occurred during treatment in 10 patients (in 6 cases during the first year), and 8 of the 10 died. A second group consisted of 108 patients who had survived their first myocardial infarction for up to five years ; 7 of these patients had a further infarction, and 6 of these died. The mortality in OWREN’S cases of angina pectoris was less than 5% in the first year, and this compares

favourably with known statistics on the prognosis of angina not treated with anticoagulants. Most of the patients, both with and without myocardial infarction, stated that they were much better on OWREN records, rather anticoagulant treatment. ominously, that patients who stop anticoagulant treatment for any

reason are very liable to have a, fatal infarction quite soon. NICHOL et al.11 have noted the same effect ; of 110 patients who stopped anticoagulant treatment for coronary disease after one to eighty-two months, 34 died from infarction, most of them within six months. TULLOCH and IRVING WRIGHT 12 have recorded experience with 227 outpatients who had prolonged The biggest outpatient anticoagulant treatment. were from group (117) suffering thrombophlebitis; 38 had rheumatic heart-disease with embolic complications ; and 32 had myocardial infarction or ischsemia. Most of the patients had been treated for up to one year. Some patients were treated with dicoumarol and some with ethyl biscoumacetate, and their experience suggests that dicoumarol is the better drug for long-term use. The doses were controlled by the Quick prothrombin-time method ; at first tests were needed up to three times weekly, then after stabilisation the patients attended weekly and a few fortnightly for tests. Of the 32 patients with myocardial disease 2 had fresh infarcts during treatment; of the 117 with thrombophlebitis only 7 developed fresh lesions while under treatment. No fewer than 70 patients had haemorrhagic complications at some time, hsematuria being one of the commonest; lowering of the dose or temporary discontinuation of the anticoagulant checked these complications

11.

9. Joiner, C. L., Kauntze, R. Lancet, 1954, i, 1097. Owren, P. Schweiz. med. Wschr. 1954, 84, 822.

10.

Nichol, E. S., Phillips, W. C., Jenkins,

V. E.

Med. Clin. N.

Amer. 1954, 38, 399.

12. Tulloch, J., Wright, I. S. Circulation, 1954, 9,

823.

743

in all except 11 cases ; these were treated with vitamin K or vitamin Kv and 2 needed blood-transfusion. TULLOCH and WRIGHT conclude that, provided proper laboratory facilities arc available, treatment of outpatients with anticoagulants is fairly safe and lessens the incidence of thrombo-embolic episodes. SHAPIRO,13 of New York, still regards the intermittent dosage as better for prolonged anticoagulant treatment, because haemorrhagic complications seem to be less than with the daily maintenance doses. This may be because prolonged hypoprothrombinsemia damages factors that maintain the integrity of the vessel walls. A drug with a reasonably long action must be used, such as dicoumarol, cyclocoumarol, or ’Warfarin Sodium ’ which is especially useful since repeated doses can be relied on to produce much the same effect. By this method the initial dose is that which will prolong the prothrombin-time by two to two and a half times, and a further dose is not given until the prothrombin-time begins to rise again. For outpatients the disadvantage of the method seems to be that frequent prothrombin estimations are needed.

Warfarin is one of the coumarin derivatives synthesised by LINK and his associates. The sodium salt can be given intravenously in a dose of 1 mg. per kg. bodyweight ; but it does not act particularly quickly by this route,’so CLATANOFF et al.15administer it by mouth. Given this way warfarin acts about as quickly as ethyl biscoumacetate and therapeutic prothrombin levels are reached within twentv-four hours. But the action of warfarin is as long as that of dicoumarol ; it also has a high potency for a drug of this type, so the dose at Maintenance any one time should not exceed 75 mg. doses of 12’5-25 mg. produce a steady level of prothrombin, but frequent prothrombin estimations to control the dosage are no less necessary than with other anticoagulants. Its action is easily stopped by

vitamin Kl’

’Dipaxin,’ a variant of phenylindanedione (it is 2-diphenylacetyl-l, 3 indanedione) is a relatively longacting anticoagulant. PASCALE and OLWIN 16 treated 80 patients with this drug. They found that the prothrombin level is lowered to therapeutic levels in about forty hours, but the prothrombin remains depressed for as long as fifteen to twenty days. Dipaxin is a potent drug; the initial dose is only 20-25 mg., and the maintenance dosage-dictated by the prothrombin level-is up to 7 mg. daily. With this drug the prothrombin level can be kept very even. If, for any reason, the prothrombin level must be raised quickly, the drug’s action can be rapidly neutralised by vitamin Ki. Bleeding episodes occurred in 2 % of the cases reported by PASCALE and OLwiN ; but in only 1 could the bleeding be definitely attributed to the low prothrombin level. Dipaxin may prove suitable for outpatients. Long-term treatment of thrombo-embolic diseases with anticoagulants is so far practised only by a few enthusiasts. Better. and more stable anticoagulant drugs are now available ; but, because of the uncontrollable factors of individual variations in response to a given dose, and of varying response at different times in any one patient, regular control by estimation of the blood-prothrombin level is still essential. Thus outpatient clinics must be organised in conjunction with a service for taking blood and for estimating prothrombin levels in a reasonably short time; most patients will have to attend weekly and 13. Shapiro, S. Schweiz. med. Wschr. 1954, 84, 830. 14. Wolff, J. M., Barker, N. W., Gifford, R. W., Mann, F. D. Proc. Mayo Clin. 1953, 28, 489. 15. Clatanoff, D. V., Triggs, P. O., Meyer, O. O. Arch. intern. Med.

1954, 94, 213.

16. Pascale, L. R., Olwin, J. H. Circulation, 1954, 9, 230.

few less often than fortnightly. Clinics involving close laboratory control are, of course, already common—for example, those dealing with the treatment of diabetes or of leukaemia. Yet another laboratory service for outpatients would strain resources ; and before this is supplied those concerned will have to be convinced that the effort is worth while. Here lies the difficulty ; far we are still not certain that every patient with angina pectoris needs to be kept on anticoagulant therapy for the rest of his life ; nor is there agreement on how long anticoagulant treatment should be continued in a patient who has had a myocardial infarct. Long-term anticoagulant therapy is not free of risks, one of which seems to be undue liability to further thrombo-embolic episodes if treatment is stopped. Are these risks slighter than the risk of recurrence in the natural course of the disease ? OWREN and IRVING WRIGHT think that such treatment is worth while ; and we should be grateful to them for the years of effort that they have already put into their studies. But we should not be surprised if most physicians still feel doubtful about long-term anticoagulant treatment, except for patients who have a condition, such as thrombophlebitis migrans, in which its use is clearly indicated.

Annotations NUMBERS OF MAN AND ANIMALS IT needs no great insight to see that some of the most serious political, social, and medical problems of the next fifty years will be due to the present explosive growth in the numbers of mankind. Last month this subject was discussed in Rome at an international conference organised by the United Nations ; and on Sept. 24 and 25 the Institute of Biology held in London a conference at which animal demographers, economists, and doctors exchanged views on the same topic. At this conference Mr. D. Lack, SC.D., F.R.S., of the Institute of Ornithology at Oxford, held that in animal populations the limiting -factor was usually food-supply. Predators, disease, and any effect of density on fertility only a secondary part. He asked what was the main cause of mortality in man in under-developed countries -was it food deficiency or disease ?-but received no clear answer. The essential figures for the growth of world population were graphically described by Mr. A. S. Parkes, D.sc., F.R.S. : in 1800, the population was 906 million; in 1850, 1171 million ; in 1900, 1608 million ; in 1950, close on 2500 million. Extrapolation of these figures gives a total in A.D. 2100 of no less than 10,000 million-an average of 200 to the square mile, including Antarctica, the Sahara, and the like. The cause of this astonishing rise is clear enough. It is due to a fall in the death-rate without a corresponding fall in the birth-rate. Prof. A. L. Banks described how in Western Europe the fall in the death-rate In England it fell from 22.9 per 1000 in 1870 to was slow. 11.3 in 1952. The fall in deaths has now been balanced by a fall in births, and the English population may soon reach something like equilibrium. But the fall in mortality that took a century in England may now occupy less than i tenth of that time in other countries. Professor Banks cited the figures for Ceylon, where mortality in 1945 was 22.0 but in 1948 only 132. Where a sharp rise in population follows a steep fall in mortality, the answer to Dr. Lack’s question is clearly that disease has been the limiting factor. But for how long

ecologists,

played