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Low dose heparin in the prevention of deepvein thromboses in patients with acute myocardial infarction
Low dose heparin in the prevention of deepvein thromboses in patients with acute myocardial infarction
Aubrey Pitt, M.D., F.R.A.C.P. Stanley T. Anderson, F.R.A.C.P. Peter G. Habersberger, .F.R.A.C.P. David S. Rosengarten, F.R.A.C.S. Melbourne, Australia
The radioactive fibringen test has been shown to accurately detect lower limb deep vein thrombosis.‘-’ Studies in patients with acute myocardial infarction using this technique have indicated an incidence of venous thrombosis of 29% to 38%.+13 Anticoagulants have been shown to significantly reduce the frequency of leg vein thrombosis and pulmonary embolism after acute myocardial infarction.‘“~ 13.I4 In postoperative patients where the incidence of deep vein thrombosis is of the same order as after myocardial infarction, low doses of heparin have been shown to be as efficacious as full anticoagulation in decreasing the incidence of deep vein thrombosislj-lB and fatal thromboembolism.‘” In a previous report from this department,“” the incidence of venous thrombosis in a fully anticoagulated group of patients with acute myocardial infarction was 9.4% and not significantly different from the 12.7% incidence in patients given 1,000 units of heparin by intravenous infusion daily for 48 hours. This report is of a second trial and presents the incidence of leg vein thrombosis in patients with myocardial infarction and compares a control group with two anticoagulant regimes, one using a low dose of intravenous heparin and the other full anticoagulation using heparin and warfarin sodium. The influence of cardiac failure in promoting venous thrombosis is also presented. From the Cardiovascular bourne, Australia.
Diagnostic
Service,
Received
for publication
Sept.
26, 1979.
Accepted
for publication
Nov.
16, 1979.
Reprint requests: Melbourne 3181,
574
May,
Dr. Aubrey Australia.
Pitt,
Alfred
1980, Vol. 99, No. 5
Hospital,
Alfred
Hospital,
Commercial
Mel-
Road,
Patients
and
methods
All patients with a myocardial infarction of less than 48 hours duration were considered for inclusion in the trial unless there was contraindication to anticoagulants, where the patient was already on anticoagulants, or if cardiogenic shock was present, since these patients were unlikely to survive the duration of the trial period. One hundred and fifteen patients entered the trial and of these, seven were withdrawn, three because of death before completion of the trial period, three due to technical problems with the counting equipment, and one because the attending physician requested a change in the anticoagulation regime. There were no instances of deep vein thrombosis or pulmonary embolism in the patients withdrawn from the trial. Patients were randomized into one of three groups by the drawing of a sealed envelope. A “fully anticoagulated”group typically received 5,000 units of heparin intravenously as a loading dose and then 20,000 units by intravenous infusion every 12 hours for 48 hours, the dose being adjusted to maintain a whole blood clotting time between 30 and 90 minutes. These patients were also given warfarin sodium on admission and this was continued after the cessation of heparin in sufficient dosage to maintain the prothrombin index between 10% and 35%. A “low dose heparin” group were given 500 units of heparin in 5% dextrose by intravenous infusion every 12 hours for 48 hours. The “control group” received only 5% dextrose by intravenous infusion for 2 to 3 days. No anticoagulants were given to the latter two groups after cessation of intravenous theraPY. 0002-8703/80/050574
+ 05$0050/O
0 1980
The
C. V. Mosby
Co.
Low dose heparin and deep-vein thromboses
On admission to the coronary care unit patients were given sodium iodide intravenously followed by oral potassium iodide so as to block thyroid gland uptake of radioiodine. One hour after the adminstration of sodium iodide, 200 microcuries of ‘251-labelled fibrinogen was given intravenously. Using a Pitman portable scintillation counter, counts were made daily over the precordium and on eight sites on each leg for 7 to 10 days. The legs were elevated to 15 degrees for at least 5 minutes prior to counting. The leg counts were expressed as a percentage of the precordial count, a difference of more than 15% between adjacent sites on the calf or between identical positions on each leg was accepted as evidence of a venous thrombosis. Patients were permitted to use a bedside commode but were otherwise confined to bed during the study period. All patients undertook active leg and breathing exercises daily under the supervision of nursing staff. Daily examination was made of the legs to ascertain if clinical signs of venous thrombosis were present. Patients were also assessed as to the presence or absence of cardiac failure, which was diagnosed if there was a third heart sound, basal moist sounds not clearing on coughing, or evidence of pulmonary venous congestion on a chest x-ray which was taken daily for 3 days. Statistical analyses were made with the Fisher exact probability test. Results
Thirty-seven patients were in the control group, 36 in the low dose heparin group, and 35 in the “fully anticoagulated” group. The average age of patients in each group was similar. The control and fully anticoagulated groups showed a similar preponderance of males while there were only three females in the low dose heparin group. Mean admission time after infarction was slightly longer in the fully anticoagulated group. The mean SGOT was slightly lower in the control group compared with either treatment group (T&e I). The groups were not significantly Lurterent when height, weight, body surface area, or site of infarction as determined by ECG were compared The frequency of venous thrombosis (Table II), was 29.7% in the control group, 13.9% in the low dose heparin group, and 11.4% in the fully anticoagulated group. The difference between either’ of the treatment groups when compared with the control group was significant (p < 0.05), but American Heart Journal
Table I
Control
Low dose heparin
coagulated
56.9 30 7 7.8
54.4 33 3 7.1
56.2 27 8 9.5
Mean age (years) Sex M F Mean admission time (hours) after infarction Mean S.G.O.T.* *R&man-Frankel
193
232
Fully anti-
225
units.
Table II No. of patients Control Low dose heparin Fully anticoagulatd
37 36 35
Venous thrombosis 11 5 4
56 incidence 29.7 13.9 11.4
there was no significant difference between treatment groups. When divided according to the presence or absence of cardiac failure, there was a slight preponderance of patients with failure in the fully anticoagulated group compared with the control and low dose heparin patients (Table III). No significant differences were present in age or admission time after infarction. Patients with failure had higher mean peak SGOT levels compared with patients with no failure. In the control group the patients with cardiac failure had a significantly higher incidence of venous thrombosis when compared to patients with no failure (p < 0.02) (Table IV). In the low dose heparin group and in the fully anticoagulated group there was no significant difference between patients with and without cardiac failure. In patients without cardiac failure, there was no significant difference between the control and either treatment groups. Conversely, in patients with cardiac failure, control patients had a significantly higher incidence of venous thrombosis when compared with the low dose heparin group (p < 0.05) or the fully anticoagulated group (p < 0.02), but the two treatment groups were not significantly different. Of the 20 patients with venous thrombosis, seven were persistent lasting 48 hours or more and 13 were transient. The right leg was involved in nine patients, the left in five, and six were bilat575
Pitt et al.
Table
III Control
Loul
No CCF
No. of patients Mean (years) Mean S.G.O.T.* Mean admission time (hours) after infarction
CCF
30
7
56.6
57.4 225 5.1
196 8.3
No CCF
27 53.3 205 7.5
dose heparin
Fully CCF
anticoagulated
No CCF
9 57.8 311 6.0
CCF
21
14
55.7 187 9.3
57.1 284 10.1
CCF = cardiac failure. *Reitman-Frankel units.
Table
IV No. of patients
Control
No CCF
Low dose heparin Fully anticoagulated
No CCF CCF NoCCF CCF
CCF
30 7
27 9 21 14
Venous thrombosis 6 5 4
% incidence 20.0 71.4 14.8
1
11.1
3
14.3
1
7.1
CCF = cardiac failure.
eral. No trend was apparent in the persistence or otherwise of venous thrombosis in the different treatment groups. The time of diagnosis of the venous thrombosis varied between 1 and 8 days after admission, the average being 4.5 days. Again no difference was apparent in the different groups. Venous thromboses were confined to below the knee and in no patient was the thrombus observed to extend above midthigh. In only one patient was there clinical evidence of a venous thrombosis, and no patient suffered a clinical pulmonary embolus. Discussion
The incidence of venous thrombosis of the legs in the control patients was 29.7% and is similar to the previously reported incidence of venous thrombosis in acute myocardial infarction+‘” and also in postoperative patients.“, .i. “. Ii. “’ Several reports have confirmed that anticoagulation reduces the frequency of venous thrombosis in patients with infarction; from 38% to 5.5% using 40,000 units of heparin by intravenous infusion daily with oral anticoagulants’“; from 29% to 0% using 40,000 units of heparin adjusted to maintain whole blood clotting time between 2% and 3% times normal.‘” The Medical Research Council reported a diminished frequency of thromboembolism in patients receiving full anticoagulation using heparin and phenindione when compared 576
with a control group of low dosage phenindione,” but the diagnosis of events was made on clinical grounds only. Low dosage heparin has been reported to reduce the incidence of venous thrombosis in postoperative patients when the labelled fibrinogen technique has been used to detect this complication. Using aqueous calcium heparin in a dose of 5,000 units subcutaneously every 12 hours, Kakkar and colleaguesli demonstated a reduction in incidence from 26% in controls to 4% in treated patients. Similarly Gordon-Smith and colleagues” used 5,000 units of subcutaneous sodium heparin every 12 hours for three doses or 5 days and both groups had a lower incidence (l3.5%1and 8.3%) or venous thrombosis compared with controls (42%). Nicolaides and associates’” used 5,000 units subcutaneously every 12 hours for 7 days and had an incidence of 0.8% compared with 24% in the control group. Gallus and co-workers,‘” using 5,000 units of heparin subcutaneously three times daily, reduced the incidence from 16.1% to 1.9% after elective surgery and from 48% to 13% after hip fracture. We have previously reported a trial comparing two regimes of anticoagulants in effecting the incidence of venous thrombosis in patients with acute myocardial infarction.“’ Low dose heparin (1,000 units daily) was not significantly different, from a therapeutic regime of full heparin dosage (controlled by whole blood clotting time) and warfarin sodium (controlled by prothrombin index), the incidence being 12.7% and 9.4%, respectively. The present trial extends these results and confirms that a low dose heparin and a fully anticoagulated group have significantly lessvenous thrombosis than do controls receiving no anticoagulants. In both trials the fully anticoagulated group showed a slightly lesser incidence than the low dose heparin group, but the differences were not statistically significant. May,
1980,
Vol.
99, No.
5
Low dose heparin and deep-vein thromboses
When the results of the current trial are further examined to determine the difference in incidence of venous thrombosis in patients with and without cardiac failure, there was inequality of numbers of patients in each group, but those with cardiac failure on no therapy had a significantly higher incidence than did patients without failure. That patients with cardiac failure have a higher incidence of venous thrombosis is not surprising, as it is well established that venous stasis is a predisposing cause of venous thrombosis.?? In the two treatment groups statistical significance was not obtained when patients with and without failure were compared, nor was there a difference in the three groups in patients without failure. Hence, if these figures are confirmed by further trials, anticoagulants have their major prophylactic role in patients with cardiac failure and very low dose heparin may confer the same benefit as full dosage of anticoagulants. Previous reports in the literature have also shown that patients with cardiac failure have an increased frequency of venous thrombosis. Maurer and colleagues” found a higher incidence of venous thrombosis in patients with a myocardial infarction complicated by left ventricular failure or cardiogenic shock, compared with uncomplicated patients, but the differences did not reach statistical significance. Miller and co-workers,‘” in studying the effect of early ambulation on the incidence of venous thrombosis, showed a significant increase in incidence in those patients with failure who were confined to bed. Kotilainen and associates” found an increased incidence in patients with cardiac failure; however, this did not reach statistical significance if patients with cardiogenic shock were excluded. Cristal et al.,‘” using a modified coronary prognostic index, showed a significant difference in venous thrombosis when comparing patients in good clinical condition with those who were severely ill. Handley’” showed no difference in the incidence of deep-vein thrombosis after myocardial infarction when 26 patients given low dose subcutaneous heparin were compared with 24 control patients. However, the frequency of cardiac failure and the admission time after infarction were not indicated. The former, as shown in this report, is associated with a high incidence of venous thrombosis and if one group were weighted with a larger number of patients with failure, and two groups may not be comparable. Further, as Handley suggests, low dose heparin prophylaxis may American Heart Journal
not be effective if given some time after the event initiating the venous thrombosis, but he does not state the admission time of his patients. In the present trial only patients with a myocardial infarct of less than 48 hours duration were accepted, and the average admission time was less than 10 hours in each of our three groups. Kotilainen and colleaguesZ” used only oral anticoagulant therapy with warfarin sodium, and as these may not be effective in preventing development of thrombi during the first 3 to 5 days, these authors showed a relatively high incidence overa-all of 21%. In the currently reported series, patients were confined to bed (apart from use of a bedside commode) for the duration of the study. Miller and colleagues”” have demonstrated a significant reduction associated with early mobilization. The utilization of very low dosage heparin intravenously for the initial 48 hours, together with early mobilization, would seem to offer the greatest benefit with the least risk. The labelled fibrinogen technique is only useful in the detection of calf vein and low thigh thrombosis and has little diagnostic capability for femoral vein thrombosis above midthigh. There is evidence that thromboses limited to the calf have a lower risk of leading to pulmonary embolism. 16.“. ” Conversely, there have been reports of pulmonary emboli in patients with thrombosis apparently confined to the calf.“. ‘I. I3 In any case, in a clinical study, Sharnoff and de Blasiolg reported a lower incidence of fatal thromboembolism in a group of operative patients receiving prophylactic heparin compared with controls. The possible mode of action of low dose heparin remains speculative. There is evidence that heparin may potentiate the activity of a naturally occurring inhibitor to activated factor X.“. Z9.3o Small doses of heparin may be adequate before tissue trauma activates factor X, but if given later, larger doses of heparin are required to reduce enhanced platelet stickiness that is observed following surgery”’ and myocardial infarction.“’ O’Brien33 has recently reviewed the possible modes of action of heparin in preventing venous thrombosis. Summary
Patients with acute myocardial infarction of less than 48 hours duration were randomized into three groups. The “fully anticoagulated” group received heparin by intravenous infusion and warfarin sodi-
577
Pitt
et al.
urn to maintain a whole blood clotting time of 30 to 90 minutes and a prothrombin index of 10% to 35%. The “low dose” heparin group received 000 units by intravenous infusion every 12 hours. The control group received no anticoagulants. The radioactive fibrinogen test was used to diagnose the presence of leg vein thromboses. The control group had an incidence of venous thrombosis of 29.7% compared with 13.9% in the low dose group and 11.3% in the fully anticoagulated group. Patients in the control group who had cardiac failure had a significantly higher incidence of venous thromboses (71.4%) when compared with patients not in failure (20.0%). In the two treatment groups no significant difference was observed in patients with and without cardiac failure. Patients with cardiac failure complicating an acute myocardial infarction have a high incidence of venous thromboses. Anticoagulants significantly reduce this incidence and low dose intravenous heparin is as efficacious as full anticoagulation.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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Negus, S., Pinto, D., Le Quesne, L. P., Brown, N., and Chapman, M.: lzSI-labelled fibrinogen in the diagnosis of deep-vein thrombosis and its correlation with phlebography, Br. J. Surg. 55:835, 1968. Flanc, C., Kakkar, V. V., and Clarke, M. B.: The detection of venous thrombosis of the legs using ‘?“Ilabelled fibrinogen, Br. J. Surg. 55:742, 1968. Kakkar, V. V., Flanc, C., and Tsapogas, M. J.: Role of phlebography in deep-vein thrombosis, Br. J. Surg. 55: 384, 1968. Palko, P. D., Nanson, E. M., and Fedoruk, S. D.: The early detection of deep venous thrombosis using I’,“taeeed human fibrinoeen. Can. J. Sum. 17:215. 1964. Lambie, J. M., Mahaffy, R. G., Barber, D. C., Karmody, A. M., Scott, M. M., and Matheson, N. A.: Diagnostic accuracy in venous thrombosis, Br. Med. J. 2:142, 1970. Atkins, P. and Hawkins, L. A.: Detection of venous thrombosis in the legs, Lancet 2:1217, 1965. Mason, E. M., Palko, P. D., Dick, A. A., and Feddruk, S. 0.: Early detection of deep venous thrombosis of the legs using I’?’ tagged human fibrinogen, Ann. Surg. 162:438, 1965. Atkins, P., and Hawkins, L. A.: The diagnosis of deepvein thrombosis in the leg using ‘*“I-fibrinogen, Br. J. Surg. 55:825, 1968. Murray, T. S., Lorimer, A. R., Cox, F. C., and Lawrie, T. D. V.: Leg-vein thrombosis following myocardial infarction, Lancet 2:792, 1970. Nicolaides, A. N., Kakkar, V. V., Renney, J. T. G., Kinder, P. H., Hutchison, D. C. S., and Clark, M. B.: Myocardial infarction and deep-vein thrombosis, Br. Med. J. 1:432, 1971. Maurer, B. J., Wray, R., and Shillingford, J. P.: Frequency of venous thrombosis following myocardial infarction, Lancet 2:1385, 1971. Maurer, B. J.: The incidence of venous thrombosis after myocardial infarction, Q. J. Med. 39:630, 1970.
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Handley, A. J., Emerson, P. A., and Fleming, P. R.: Heparin in the prevention of deep vein thrombosis after myocardial infarction, Br. Med. J. 2:436, 1972. Medical Research Council: Assessment of short-term anticoagulant administration after cardiac infarction, Br. Med. d. 1:335, 1969. Nicolaides, A. N., DuPont, P. A., Desai, S., Lewis, J. D., Douglas, J. N., Dodsworth, H., Fourides, G., Luck, R. J., and Jamieson, C. W.: Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery, Lancet 2:890, 1972. Gordon-Smith, I. C., Grundy, D. J., Le Quesne, L. P., Newcombe, J. F., and Bramble, F. J.: Controlled trial of two regimens of subcutaneous heparin in prevention of postoperative deep-vein thrombosis, Lancet 1: 1133, 1972. Kakkar, V. V., Field, E. S., Nocolaides, A. N., Flute, P. T., Wessler, S., and Yin, E. T.: Low doses of heparin in prevention of deep-vein thrombosis, Lancet 2:669, 1971. Gallus, A. S., Hirsh, J., Tuttle, R. J., Trebilcock, R., O’Brien, S. E., Carroll, J. J., Minden, J. H., and Hudecki, S. M.: Small subcutaneous doses of heparin in prevention of venous thrombosis, N. Engl. J. Med. 288545, 1973. Sharnoff, J. G., and de Blasio, G.: Prevention of fatal postoperative thromboembolism by heparin prophylaxis, Lancet 2:1006, 1970. Habersberger, P. G., Pitt, A., and Anderson, S. T.: Venous thrombosis in myocardial infarction. Comparison in heparin dosage, Br. Heart J. 35:538, 1973. Rosengarten, D. S., Land, J., Jeyasingh, K., and Martin, P.: The failure of compression stockings to prevent deep venous thrombosis after operation, Br. J. Surg. 57:296, 1970. Beeson, P. B., and McDermott, W.: Pulmonary embolism and infarction, in Cecil, R. L. F., and Loeb, R. F., eds.: Cecil-Loeb Textbook of Medicine, Philadelphia, 1967, W. B. Saunders Company, p. 534. Miller. R. R.. Lies. J. E.. Carretta. R. F.. Wamnold. D. B.. De N&do, d. L.,’ Kraus, J. F., Amsterdam, E. A., and Mason, D. T.: Prevention of lower extremity venous thrombosis by early mobilization Ann. Intern. Med. 84:700, 1976. Kotilainen, M., Ristola, P., Ikkala, E., and Pyorala, K.: Leg vein thrombosis diagnosed by ‘z51-fibrinogen test after acute myocardial infarction, Ann. Clin. Res. 5:365,1973. C&al, N., Stern, J., Ronen, M., Silverman, C., Ho., W., and Bartov, E.: Identifying patients at risk for thromboembolism. J.A.M.A. 236:2755. 1976. Handley, A. J.: Low-dose heparin after myocardial infarction, Lancet 2:623, 1972. Kakkar, V. V., Howe, C. T., Flanc, C., and Clarke, M. B.: Natural history of postoperative deep-vein thrombosis, Lancet 2:230, 1969. Browse, N. L.: The problems of deep vein thrombosis, AM. HEART J. 84:149, 1972. Yin, E. T., Wessler, S., and Stoll, P. J.: Biological properties of the naturally occurring plasma inhibitor to activated Factor X, J. Biol. Chem. 246:3703, 1971. Biggs, R., Denson, K. W. E., Akmon, M., Barrett, R., and Hodden, M.: Antithrombin III, antifactor Xa and heparin, Br. J. Haematol. 19:283, 1970. Negus, D., Pinto, D. J., and Slack, W. W.: Effect of small doses of heparin on platelet adhesiveness and lipoproteinlipase activity before and after surgery, Lancet 1:1202, 1971. McDonald, L., and Edgill, M.: Coagulability of the blood in ischaemic heart disease, Lancet 2:457, 1957. O’Brien, J. R.: Heparin. platelets, and venous thrombosis, AM. HEART J. 85:435, 1973.
May, 1980, Vol. 99, NO. 5
Aubrey Pitt, M.D., F.R.A.C.P. Stanley T. Anderson, F.R.A.C.P. Peter G. Habersberger, .F.R.A.C.P. David S. Rosengarten, F.R.A.C.S. Melbourne, Australia
The radioactive fibringen test has been shown to accurately detect lower limb deep vein thrombosis.‘-’ Studies in patients with acute myocardial infarction using this technique have indicated an incidence of venous thrombosis of 29% to 38%.+13 Anticoagulants have been shown to significantly reduce the frequency of leg vein thrombosis and pulmonary embolism after acute myocardial infarction.‘“~ 13.I4 In postoperative patients where the incidence of deep vein thrombosis is of the same order as after myocardial infarction, low doses of heparin have been shown to be as efficacious as full anticoagulation in decreasing the incidence of deep vein thrombosislj-lB and fatal thromboembolism.‘” In a previous report from this department,“” the incidence of venous thrombosis in a fully anticoagulated group of patients with acute myocardial infarction was 9.4% and not significantly different from the 12.7% incidence in patients given 1,000 units of heparin by intravenous infusion daily for 48 hours. This report is of a second trial and presents the incidence of leg vein thrombosis in patients with myocardial infarction and compares a control group with two anticoagulant regimes, one using a low dose of intravenous heparin and the other full anticoagulation using heparin and warfarin sodium. The influence of cardiac failure in promoting venous thrombosis is also presented. From the Cardiovascular bourne, Australia.
Diagnostic
Service,
Received
for publication
Sept.
26, 1979.
Accepted
for publication
Nov.
16, 1979.
Reprint requests: Melbourne 3181,
574
May,
Dr. Aubrey Australia.
Pitt,
Alfred
1980, Vol. 99, No. 5
Hospital,
Alfred
Hospital,
Commercial
Mel-
Road,
Patients
and
methods
All patients with a myocardial infarction of less than 48 hours duration were considered for inclusion in the trial unless there was contraindication to anticoagulants, where the patient was already on anticoagulants, or if cardiogenic shock was present, since these patients were unlikely to survive the duration of the trial period. One hundred and fifteen patients entered the trial and of these, seven were withdrawn, three because of death before completion of the trial period, three due to technical problems with the counting equipment, and one because the attending physician requested a change in the anticoagulation regime. There were no instances of deep vein thrombosis or pulmonary embolism in the patients withdrawn from the trial. Patients were randomized into one of three groups by the drawing of a sealed envelope. A “fully anticoagulated”group typically received 5,000 units of heparin intravenously as a loading dose and then 20,000 units by intravenous infusion every 12 hours for 48 hours, the dose being adjusted to maintain a whole blood clotting time between 30 and 90 minutes. These patients were also given warfarin sodium on admission and this was continued after the cessation of heparin in sufficient dosage to maintain the prothrombin index between 10% and 35%. A “low dose heparin” group were given 500 units of heparin in 5% dextrose by intravenous infusion every 12 hours for 48 hours. The “control group” received only 5% dextrose by intravenous infusion for 2 to 3 days. No anticoagulants were given to the latter two groups after cessation of intravenous theraPY. 0002-8703/80/050574
+ 05$0050/O
0 1980
The
C. V. Mosby
Co.
Low dose heparin and deep-vein thromboses
On admission to the coronary care unit patients were given sodium iodide intravenously followed by oral potassium iodide so as to block thyroid gland uptake of radioiodine. One hour after the adminstration of sodium iodide, 200 microcuries of ‘251-labelled fibrinogen was given intravenously. Using a Pitman portable scintillation counter, counts were made daily over the precordium and on eight sites on each leg for 7 to 10 days. The legs were elevated to 15 degrees for at least 5 minutes prior to counting. The leg counts were expressed as a percentage of the precordial count, a difference of more than 15% between adjacent sites on the calf or between identical positions on each leg was accepted as evidence of a venous thrombosis. Patients were permitted to use a bedside commode but were otherwise confined to bed during the study period. All patients undertook active leg and breathing exercises daily under the supervision of nursing staff. Daily examination was made of the legs to ascertain if clinical signs of venous thrombosis were present. Patients were also assessed as to the presence or absence of cardiac failure, which was diagnosed if there was a third heart sound, basal moist sounds not clearing on coughing, or evidence of pulmonary venous congestion on a chest x-ray which was taken daily for 3 days. Statistical analyses were made with the Fisher exact probability test. Results
Thirty-seven patients were in the control group, 36 in the low dose heparin group, and 35 in the “fully anticoagulated” group. The average age of patients in each group was similar. The control and fully anticoagulated groups showed a similar preponderance of males while there were only three females in the low dose heparin group. Mean admission time after infarction was slightly longer in the fully anticoagulated group. The mean SGOT was slightly lower in the control group compared with either treatment group (T&e I). The groups were not significantly Lurterent when height, weight, body surface area, or site of infarction as determined by ECG were compared The frequency of venous thrombosis (Table II), was 29.7% in the control group, 13.9% in the low dose heparin group, and 11.4% in the fully anticoagulated group. The difference between either’ of the treatment groups when compared with the control group was significant (p < 0.05), but American Heart Journal
Table I
Control
Low dose heparin
coagulated
56.9 30 7 7.8
54.4 33 3 7.1
56.2 27 8 9.5
Mean age (years) Sex M F Mean admission time (hours) after infarction Mean S.G.O.T.* *R&man-Frankel
193
232
Fully anti-
225
units.
Table II No. of patients Control Low dose heparin Fully anticoagulatd
37 36 35
Venous thrombosis 11 5 4
56 incidence 29.7 13.9 11.4
there was no significant difference between treatment groups. When divided according to the presence or absence of cardiac failure, there was a slight preponderance of patients with failure in the fully anticoagulated group compared with the control and low dose heparin patients (Table III). No significant differences were present in age or admission time after infarction. Patients with failure had higher mean peak SGOT levels compared with patients with no failure. In the control group the patients with cardiac failure had a significantly higher incidence of venous thrombosis when compared to patients with no failure (p < 0.02) (Table IV). In the low dose heparin group and in the fully anticoagulated group there was no significant difference between patients with and without cardiac failure. In patients without cardiac failure, there was no significant difference between the control and either treatment groups. Conversely, in patients with cardiac failure, control patients had a significantly higher incidence of venous thrombosis when compared with the low dose heparin group (p < 0.05) or the fully anticoagulated group (p < 0.02), but the two treatment groups were not significantly different. Of the 20 patients with venous thrombosis, seven were persistent lasting 48 hours or more and 13 were transient. The right leg was involved in nine patients, the left in five, and six were bilat575
Pitt et al.
Table
III Control
Loul
No CCF
No. of patients Mean (years) Mean S.G.O.T.* Mean admission time (hours) after infarction
CCF
30
7
56.6
57.4 225 5.1
196 8.3
No CCF
27 53.3 205 7.5
dose heparin
Fully CCF
anticoagulated
No CCF
9 57.8 311 6.0
CCF
21
14
55.7 187 9.3
57.1 284 10.1
CCF = cardiac failure. *Reitman-Frankel units.
Table
IV No. of patients
Control
No CCF
Low dose heparin Fully anticoagulated
No CCF CCF NoCCF CCF
CCF
30 7
27 9 21 14
Venous thrombosis 6 5 4
% incidence 20.0 71.4 14.8
1
11.1
3
14.3
1
7.1
CCF = cardiac failure.
eral. No trend was apparent in the persistence or otherwise of venous thrombosis in the different treatment groups. The time of diagnosis of the venous thrombosis varied between 1 and 8 days after admission, the average being 4.5 days. Again no difference was apparent in the different groups. Venous thromboses were confined to below the knee and in no patient was the thrombus observed to extend above midthigh. In only one patient was there clinical evidence of a venous thrombosis, and no patient suffered a clinical pulmonary embolus. Discussion
The incidence of venous thrombosis of the legs in the control patients was 29.7% and is similar to the previously reported incidence of venous thrombosis in acute myocardial infarction+‘” and also in postoperative patients.“, .i. “. Ii. “’ Several reports have confirmed that anticoagulation reduces the frequency of venous thrombosis in patients with infarction; from 38% to 5.5% using 40,000 units of heparin by intravenous infusion daily with oral anticoagulants’“; from 29% to 0% using 40,000 units of heparin adjusted to maintain whole blood clotting time between 2% and 3% times normal.‘” The Medical Research Council reported a diminished frequency of thromboembolism in patients receiving full anticoagulation using heparin and phenindione when compared 576
with a control group of low dosage phenindione,” but the diagnosis of events was made on clinical grounds only. Low dosage heparin has been reported to reduce the incidence of venous thrombosis in postoperative patients when the labelled fibrinogen technique has been used to detect this complication. Using aqueous calcium heparin in a dose of 5,000 units subcutaneously every 12 hours, Kakkar and colleaguesli demonstated a reduction in incidence from 26% in controls to 4% in treated patients. Similarly Gordon-Smith and colleagues” used 5,000 units of subcutaneous sodium heparin every 12 hours for three doses or 5 days and both groups had a lower incidence (l3.5%1and 8.3%) or venous thrombosis compared with controls (42%). Nicolaides and associates’” used 5,000 units subcutaneously every 12 hours for 7 days and had an incidence of 0.8% compared with 24% in the control group. Gallus and co-workers,‘” using 5,000 units of heparin subcutaneously three times daily, reduced the incidence from 16.1% to 1.9% after elective surgery and from 48% to 13% after hip fracture. We have previously reported a trial comparing two regimes of anticoagulants in effecting the incidence of venous thrombosis in patients with acute myocardial infarction.“’ Low dose heparin (1,000 units daily) was not significantly different, from a therapeutic regime of full heparin dosage (controlled by whole blood clotting time) and warfarin sodium (controlled by prothrombin index), the incidence being 12.7% and 9.4%, respectively. The present trial extends these results and confirms that a low dose heparin and a fully anticoagulated group have significantly lessvenous thrombosis than do controls receiving no anticoagulants. In both trials the fully anticoagulated group showed a slightly lesser incidence than the low dose heparin group, but the differences were not statistically significant. May,
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Low dose heparin and deep-vein thromboses
When the results of the current trial are further examined to determine the difference in incidence of venous thrombosis in patients with and without cardiac failure, there was inequality of numbers of patients in each group, but those with cardiac failure on no therapy had a significantly higher incidence than did patients without failure. That patients with cardiac failure have a higher incidence of venous thrombosis is not surprising, as it is well established that venous stasis is a predisposing cause of venous thrombosis.?? In the two treatment groups statistical significance was not obtained when patients with and without failure were compared, nor was there a difference in the three groups in patients without failure. Hence, if these figures are confirmed by further trials, anticoagulants have their major prophylactic role in patients with cardiac failure and very low dose heparin may confer the same benefit as full dosage of anticoagulants. Previous reports in the literature have also shown that patients with cardiac failure have an increased frequency of venous thrombosis. Maurer and colleagues” found a higher incidence of venous thrombosis in patients with a myocardial infarction complicated by left ventricular failure or cardiogenic shock, compared with uncomplicated patients, but the differences did not reach statistical significance. Miller and co-workers,‘” in studying the effect of early ambulation on the incidence of venous thrombosis, showed a significant increase in incidence in those patients with failure who were confined to bed. Kotilainen and associates” found an increased incidence in patients with cardiac failure; however, this did not reach statistical significance if patients with cardiogenic shock were excluded. Cristal et al.,‘” using a modified coronary prognostic index, showed a significant difference in venous thrombosis when comparing patients in good clinical condition with those who were severely ill. Handley’” showed no difference in the incidence of deep-vein thrombosis after myocardial infarction when 26 patients given low dose subcutaneous heparin were compared with 24 control patients. However, the frequency of cardiac failure and the admission time after infarction were not indicated. The former, as shown in this report, is associated with a high incidence of venous thrombosis and if one group were weighted with a larger number of patients with failure, and two groups may not be comparable. Further, as Handley suggests, low dose heparin prophylaxis may American Heart Journal
not be effective if given some time after the event initiating the venous thrombosis, but he does not state the admission time of his patients. In the present trial only patients with a myocardial infarct of less than 48 hours duration were accepted, and the average admission time was less than 10 hours in each of our three groups. Kotilainen and colleaguesZ” used only oral anticoagulant therapy with warfarin sodium, and as these may not be effective in preventing development of thrombi during the first 3 to 5 days, these authors showed a relatively high incidence overa-all of 21%. In the currently reported series, patients were confined to bed (apart from use of a bedside commode) for the duration of the study. Miller and colleagues”” have demonstrated a significant reduction associated with early mobilization. The utilization of very low dosage heparin intravenously for the initial 48 hours, together with early mobilization, would seem to offer the greatest benefit with the least risk. The labelled fibrinogen technique is only useful in the detection of calf vein and low thigh thrombosis and has little diagnostic capability for femoral vein thrombosis above midthigh. There is evidence that thromboses limited to the calf have a lower risk of leading to pulmonary embolism. 16.“. ” Conversely, there have been reports of pulmonary emboli in patients with thrombosis apparently confined to the calf.“. ‘I. I3 In any case, in a clinical study, Sharnoff and de Blasiolg reported a lower incidence of fatal thromboembolism in a group of operative patients receiving prophylactic heparin compared with controls. The possible mode of action of low dose heparin remains speculative. There is evidence that heparin may potentiate the activity of a naturally occurring inhibitor to activated factor X.“. Z9.3o Small doses of heparin may be adequate before tissue trauma activates factor X, but if given later, larger doses of heparin are required to reduce enhanced platelet stickiness that is observed following surgery”’ and myocardial infarction.“’ O’Brien33 has recently reviewed the possible modes of action of heparin in preventing venous thrombosis. Summary
Patients with acute myocardial infarction of less than 48 hours duration were randomized into three groups. The “fully anticoagulated” group received heparin by intravenous infusion and warfarin sodi-
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urn to maintain a whole blood clotting time of 30 to 90 minutes and a prothrombin index of 10% to 35%. The “low dose” heparin group received 000 units by intravenous infusion every 12 hours. The control group received no anticoagulants. The radioactive fibrinogen test was used to diagnose the presence of leg vein thromboses. The control group had an incidence of venous thrombosis of 29.7% compared with 13.9% in the low dose group and 11.3% in the fully anticoagulated group. Patients in the control group who had cardiac failure had a significantly higher incidence of venous thromboses (71.4%) when compared with patients not in failure (20.0%). In the two treatment groups no significant difference was observed in patients with and without cardiac failure. Patients with cardiac failure complicating an acute myocardial infarction have a high incidence of venous thromboses. Anticoagulants significantly reduce this incidence and low dose intravenous heparin is as efficacious as full anticoagulation.
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