Original Article
Acenocoumarol and Heparin Compared with Acenocoumarol Alone in the Initial Treatment of Proximal-Vein Thrombosis
N Engl J Med 1992; 327:1485-1489November 19, 1992
- Abstract
- Abstract
Background.
In most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries.
Methods.
In a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up.
Results.
The study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P<0.001). Major bleeding complications were infrequent and comparable in the two groups.
Conclusions.
Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy. (N Engl J Med 1992;327:1485–9.)
Media in This Article
Figure 1
Mean (±SD) Daily Dose of Acenocoumarol (Open Symbols) and Mean Daily INR (Solid Symbols) in the Combined-Therapy Group (Triangles, N = 56) and the Acenocoumarol Group (Circles, N = 58).Table 1
Base-Line Clinical Characteristics of 120 Patients with Proximal-Vein Thrombosis Treated with Heparin plus Acenocoumarol or Acenocoumarol Alone.Article Activity
- Article
TRADITIONALLY, patients with deep-vein thrombosis have been treated first with intravenous heparin and then with a course of oral anticoagulants for three months.1 Acenocoumarol or another vitamin K antagonist is usually begun after a few days of heparin treatment. The rationale for beginning treatment with heparin is based on its potential to block the activated coagulation system immediately. However, the evidence that heparin is needed to prevent the extension or recurrence of venous thrombosis in these circumstances is derived from studies in animals2 , 3 and comparisons with historical controls.4 , 5 Controlled clinical studies that support initial heparin treatment, as compared with other initial regimens, in patients with deep-vein thrombosis are lacking.6 Furthermore, two large, randomized clinical studies have recently shown that the duration of heparin therapy can safely be shortened from the standard 10 days to 5 days, by starting acenocoumarol at the same time as heparin.7 , 8
In several European countries, including the Netherlands,9 the common practice has been to treat a substantial proportion of outpatients with deep-vein thrombosis with acenocoumarol alone, on the hypothesis that an initial high dose of a fast-acting oral anticoagulant obviates the need for heparin therapy. The effectiveness of this treatment strategy has never been demonstrated in a properly designed clinical investigation, however. The advantage of treating patients with acenocoumarol alone, if it was found to be effective, is that it would make hospitalization unnecessary.
In our opinion, treatment of such patients is an example of so-called "clinical equipoise,"10 which can be defined as a state of genuine uncertainty within the medical community about which treatment is preferable. To compare the efficacy and safety of intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone, we performed a randomized, double-blind clinical trial in outpatients with a first episode of proximal deep-vein thrombosis.
The trial was stopped early by the Data Safety and Monitoring Committee because of a clinically important excess of symptomatic events in the patients receiving acenocoumarol alone.
Methods
Patients
Consecutive symptomatic outpatients referred by their general practitioners to the Academic Medical Center or the Slotervaart Ziekenhuis with proximal deep-vein thrombosis documented by venography were potentially eligible for the study. Patients were excluded if they had previously diagnosed deep-vein thrombosis; if they had clinically suspected pulmonary embolism, bilateral venous thrombosis, or phlegmasia at the time of referral; if they were already receiving anticoagulant therapy; if they were pregnant; if they were younger than 18 years or older than 85; if they had a life expectancy of less than 6 months; if they were known to have a coagulation-inhibitor deficiency; or if they were unwilling to give written informed consent.
Study Design
The study was a randomized clinical trial comparing heparin plus acenocoumarol with acenocoumarol alone in the treatment of proximal deep-vein thrombosis. We used a double-blind design to ensure an unbiased assessment of the outcome events. Each patient was followed for six months. Patients were randomly assigned to one of the following treatments: heparin by continuous intravenous infusion for a minimum of seven days, plus acenocoumarol; or an identical infusion of placebo, plus acenocoumarol. In both groups, acenocoumarol therapy began at the same time as the infusion. Within 24 hours of randomization, a base-line perfusion—ventilation lung scan and chest roentgenogram were obtained. Perfusion—ventilation lung scanning and venography were repeated after one week. The method of Rabinov and Paulin was used for venography.11 We analyzed both venograms to assess the extent of the venous thrombus, using a quantitative scoring system.12 Six-view perfusion scanning was performed with macroaggregated albumin labeled with technetium-99m. Ventilation scanning, in the same six views, was performed with krypton-81m gas. The scintigrams were classified according to previously described criteria.13
All the patients were examined daily during their hospital stay for signs or symptoms of extending venous thrombosis, pulmonary embolism, or bleeding. On discharge, the patients were instructed to contact the thrombosis unit immediately if symptoms of recurrent venous thrombosis or pulmonary embolism developed or if they had hemorrhage. In addition, the patients were seen routinely at the thrombosis unit 6, 12, and 24 weeks after randomization. Patients with symptomatic extension, recurrent deep-vein thrombosis, or symptomatic pulmonary embolism underwent objective testing with impedance plethysmography, leg scanning with iodine-125—labeled fibrinogen, and venography if recurrent deep-vein thrombosis was suspected,11 , 14 and with perfusion—ventilation lung scanning and pulmonary angiography (if needed) if pulmonary embolism was suspected.13 All diagnostic tests were interpreted independently by a panel of experienced observers unaware of the group to which the patient had been assigned and unaware of whether the test was performed at base line or as a repeated test. The study protocol was approved by the ethics committees of the two hospitals.
Treatment Strategies
The patients assigned to the combined-therapy group received heparin in the form of an intravenous loading dose of 5000 units followed by an infusion of 1250 units per hour. Patients in the acenocoumarol group received an intravenous loading dose of placebo and an infusion solution identical in appearance to the heparin. The rate of infusion was adjusted daily to maintain the activated partial-thromboplastin time between 60 and 90 seconds according to a dosage schedule established before the study began (corresponding to a ratio of two to three times the mean of the normal control value with the Actin-FS reagent [Dade, Miami]).
An unblinded investigator who was not involved in the care of the study patients was the only person with access to the daily results of the activated partial-thromboplastin times; he reported these results to the attending physician. For the patients receiving placebo, computer-generated fictitious thromboplastin times were reported; these times included both therapeutic and subtherapeutic values. All the patients received 6 mg of acenocoumarol (Sintromitis, Ciba—Geigy, Arnhem, the Netherlands) on the first day, followed by 4 mg the next day. Subsequent dose adjustments were made by the attending physicians on the basis of the daily prothrombin-time results (Thrombotest, Nyegaard, Oslo, Norway), aiming at an International Normalized Ratio (INR) of 2.0 to 3.0.15 The intravenous study medication was continued for at least seven days and was then stopped if on two consecutive measurements the prothrombin time was in the therapeutic range. Treatment with acenocoumarol was continued for 12 weeks.
Outcome Events
The principal outcome event was a symptomatic extension of venous thrombosis, symptomatic pulmonary embolism, or symptomatic recurrence of venous thrombosis as documented by objective testing during the six-month follow-up period. A diagnosis of symptomatic extension of venous thrombosis (during the first week of treatment) was made if a new, constant intraluminal filling defect not present on the base-line venogram was seen on the subsequent venogram. In patients with clinically suspected pulmonary embolism, the diagnosis was made if the second perfusion—ventilation lung scan showed a new defect indicating a high probability of embolism, if pulmonary angiography revealed embolism in patients whose lung scans did not show high-probability defects, or if embolism was documented at autopsy. Recurrent deep-vein thrombosis (after the first week of treatment) was diagnosed when a new intraluminal filling defect was seen by repeated venography. If the venogram was nondiagnostic, recurrent venous thrombosis was diagnosed if an impedance plethysmogram was abnormal (and the previous one had been normal) or a leg scan was positive.14
In addition to the assessment of symptomatic events, which were considered the most clinically relevant outcomes, all the patients had venography and perfusion—ventilation lung scanning repeated on day 7 to assess the frequency of asymptomatic extension of venous thromboembolism. This assessment was chosen to evaluate the dynamics of the thrombotic process during treatment. A substantial extension of thrombosis was considered to be present if the second venogram increased the quantitative score by 20 percent or more from the base-line venogram.12 A new high-probability defect on the second lung scan was considered to be evidence of asymptomatic pulmonary embolism.
Bleeding during the first three months was considered an outcome event. Bleeding was classified as major if it was overt and was associated with a decrease of 20 g per liter or more in the hemoglobin level, led to the transfusion of two or more units of blood, or was intracranial or retroperitoneal. All other episodes of bleeding were defined as minor.
Safety Monitoring and Statistical Analysis
Confirmed symptomatic extension or the recurrence of venous thromboembolism during follow-up was the primary outcome measure. The calculation of sample size was based on the following considerations. From previous studies of the efficacy of heparin combined with oral anticoagulants in patients with deep-vein thrombosis, the expected incidence of the primary outcome over a six-month period was approximately 8 percent.16 , 17 The true incidence of this outcome in patients treated with acenocoumarol alone is unknown. The trial was designed to have a minimum of 250 patients, to ensure that a twofold increase in the rate of symptomatic extension or recurrence of venous thromboembolism in the group receiving acenocoumarol alone would be detected with a power of 0.80 (two-sided test, with a level of significance of 0.05). Fisher's exact test was to be used to compare the frequencies of symptomatic thromboembolic events.18 The decision to terminate the study early was to be made by the independent Data Safety and Monitoring Committee. A formal interim analysis of efficacy was prompted by an unexpectedly high overall incidence of the primary outcome. As a result of this interim analysis, and given the high rate of asymptomatic extension of venous thromboembolism in the group receiving acenocoumarol alone, it was decided to stop the further recruitment of patients and to complete follow-up among the patients being followed.
Results
Patients
At the termination of the study, 120 consecutive patients with proximal-vein thrombosis had been enrolled. Before randomization, 99 other patients were excluded because of previously diagnosed deep-vein thrombosis (23 patients), symptoms suggestive of pulmonary embolism at presentation (21), life expectancy of less than 6 months (11), ongoing anticoagulant therapy (10), an age of less than 18 or more than 85 years (8), bilateral thrombosis or phlegmasia (5), or a known deficiency of antithrombin III (1); 20 other patients refused to give informed consent.
Sixty patients were randomly assigned to receive heparin plus acenocoumarol, and 60 to receive acenocoumarol alone. In seven patients (five in the combined-therapy group and two in the acenocoumarol group) study medication was interrupted. The reasons for interruption in the five receiving heparin plus acenocoumarol were the withdrawal of consent (two patients, on day 2 of the study), the diagnosis of acute myeloid leukemia (one, on day 2), acute priapism (one, on day 5), and a refusal to continue with secondary prophylaxis (one, on day 43). In the acenocoumarol group, septic shock complicated by disseminated intravascular coagulation developed in one patient, and an acute psychosis developed in the other, both on day 3. In all but one patient (who refused to continue secondary prophylaxis), heparin therapy was instituted. None of these seven patients had signs or symptoms of recurrent venous thromboembolism or died during the six-month follow-up period. The patients in the two treatment groups had similar clinical characteristics at base line (Table 1Table 1
Base-Line Clinical Characteristics of 120 Patients with Proximal-Vein Thrombosis Treated with Heparin plus Acenocoumarol or Acenocoumarol Alone.). None of the 120 patients were lost to follow-up.Symptomatic Extension or Recurrence of Venous Thromboembolism
During the six-month study period, 4 of the 60 patients in the combined-therapy group (6.7 percent) had a symptomatic extension or recurrence of venous thromboembolism that was confirmed by objective testing, as compared with 12 of the 60 patients in the acenocoumarol group (20 percent; P = 0.058 by two-tailed test). Among the patients receiving acenocoumarol alone, 3 of the 12 symptomatic events occurred in the first week, and 6 others occurred during the three-month period of secondary prophylaxis (Table 2Table 2
Cases of Confirmed Symptomatic Extension or Recurrence of Venous Thromboembolism, According to Treatment Group.). In addition to the confirmed symptomatic events, there were symptoms suggestive of a recurrence of venous thromboembolism in 11 other patients, but these could not be confirmed by objective investigation (5 of the patients were receiving heparin plus acenocoumarol [8.3 percent of the group], and 6 acenocoumarol alone [10 percent of the group]).Asymptomatic Extension of Venous Thromboembolism
At the end of the first week, the rates of asymptomatic extension of venous thrombosis and occurrence of silent pulmonary embolism were calculated for patients who did not have a symptomatic thromboembolic event in the first week and who had test results that could be interpreted. In the combined-therapy group, 4 of the 49 patients who could be evaluated (8.2 percent) had evidence of asymptomatic worsening of thromboembolic disease (1 with an extension of deep-vein thrombosis and 3 with new high-probability defects on lung scanning), as compared with 21 of the 53 patients receiving acenocoumarol alone who could be evaluated (39.6 percent) (15 patients with venographic evidence of an extension of thrombosis and 7 with new high-probability defects on lung scanning; 1 of the patients had both an extension of deep-vein thrombosis and a new high-probability defect on perfusion—ventilation lung scanning). This difference was statistically significant (P<0.001).
Hemorrhagic Complications
Major bleeding occurred in two patients who received heparin plus acenocoumarol (3 percent) and in three who received acenocoumarol alone (5 percent). All bleeding episodes occurred between weeks 6 and 12. Major bleeding in the two patients in the combined-therapy group (hematemesis from an unsuspected duodenal ulcer in one and gross hematuria after cystoscopy in the other) occurred while the INR was in the therapeutic range. In one patient in the acenocoumarol group with excessive vaginal bleeding and spontaneous subcutaneous hematoma, the INR (3.9) was above the therapeutic range, whereas in the remaining two patients in this group (one with repeated severe epistaxis and the other with postmenopausal vaginal bleeding) the INR was within the prescribed range. Bleeding stopped after the temporary discontinuation of acenocoumarol. There were no episodes of symptomatic recurrence of venous thromboembolism in any patients during follow-up. Three patients in the combined-therapy group and six in the acenocoumarol group had minor bleeding, all during the second half of the period of secondary prophylaxis.
Mortality
One patient in the combined-therapy group committed suicide in month 6. There were two cancer-related deaths (documented by autopsy) in the acenocoumarol group, one in week 11 and the other in week 12.
Dose and Effect of Anticoagulant Therapy
Figure 1Figure 1
Mean (±SD) Daily Dose of Acenocoumarol (Open Symbols) and Mean Daily INR (Solid Symbols) in the Combined-Therapy Group (Triangles, N = 56) and the Acenocoumarol Group (Circles, N = 58). shows the mean daily doses of acenocoumarol and the corresponding effects on the prothrombin time (expressed as the mean daily INR) during the first seven days of the study. The dose of acenocoumarol was almost identical in the two treatment groups. The lower limit of the therapeutic range (INR, 2.0) was reached in both groups after three to four days. The study groups did not differ significantly in either the dose of acenocoumarol or the anticoagulant effect measured as the INR during week 1. The mean doses of heparin (excluding the loading dose of 5000 units) on days 1 through 4 in the combined-therapy group were 29,890, 29,045, 26,835, and 24,728 units, respectively.Discussion
This randomized study was terminated early because the regimen of acenocoumarol alone resulted in an unacceptably high incidence of symptomatic extension or recurrence of venous thromboembolism (20 percent) during follow-up. In the patients treated with the combination of intravenous heparin and acenocoumarol the incidence was 6.7 percent (by intention-to-treat analysis; P = 0.058 by two-tailed test), which is consistent with the rate observed in previous trials.7 , 8 , 17 , 19 The failure of acenocoumarol alone to inhibit the thrombotic process was further substantiated by the five-times-higher frequency of worsening of asymptomatic thromboembolic disease, as demonstrated by repeated venography and lung scanning.
It should be noted that in our analysis of the primary outcome event the difference between groups came close to statistical significance (P = 0.058). The existence of a true difference between the two groups in the progression of thrombus was convincingly supported by the observation of asymptomatic extension. Finally, it is biologically inconceivable that the use of heparin would increase the risk of recurrent venous thromboembolism, as compared with acenocoumarol alone. Thus, it appears that heparin added to oral anticoagulants is required in the initial treatment of patients with proximal-vein thrombosis.
Major hemorrhagic complications were infrequent during anticoagulant treatment in both groups. The observed frequency of hemorrhage in the combined-therapy group is in agreement with earlier studies7 , 8 and confirms the safety of combining the drugs. The initiation of acenocoumarol therapy at the same time as heparin did not affect the intensity of initial heparinization, since the mean doses of heparin in the first days were comparable with those in previous reports in which oral anticoagulants were begun after six days.17 , 20
Interestingly, the majority of symptomatic recurrences of venous thromboembolism in the patients given acenocoumarol alone occurred after the first month of treatment. A similar delay in symptomatic recurrent thrombotic events and a similar frequency were observed by Hull and associates in patients with venous thrombosis who received subtherapeutic dosages of heparin by intermittent subcutaneous injection.17 These observations suggest that the failure to achieve an adequate anticoagulant effect early in the course of treatment can lead to later recurrences. Recent in vitro investigations have revealed the importance of completely inhibiting clot-bound thrombin in blocking further thrombus growth.21 This is apparently not achieved by lowering the concentrations of prothrombin, factor IX, factor VII, and factor X through acenocoumarol therapy, or by giving suboptimal doses of heparin.
We conclude that full-dose heparin is required in the initial treatment of patients with proximal deep-vein thrombosis. This can safely be combined with acenocoumarol therapy begun at the same time as heparin.
Supported in part by a grant from the Amstol Foundation. Dr. Büller is the recipient of a fellowship from the Royal Netherlands Academy of Arts and Sciences.
We are indebted to M. Gent, D.Sc., and J. Hirsh, M.D. (Hamilton Civic Hospitals Research Center, Hamilton, Ont.), for their participation on the independent Data Safety and Monitoring Committee; to L.W. Statius van Eps, M.D., and J. Vreeken, M.D., for their support and cooperation; to the residents of the departments of internal medicine of the Slotervaart Ziekenhuis and the Academic Medical Center for their expert help in the care of the patients; to A. van de Ende, M.D., and F. Berends, M.D., for assistance in laboratory monitoring; and to D. Batchelor, M.D., D. Westra, M.D., K. Hoefnagel, M.D., and E.A. van Royen, M.D., for their support in the performance of venography and lung scanning.
Source Information
From the Center for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center (D.P.M.B., H.H., H.R.B., H.J., J.W.t.C.), and the Department of Medicine, Slotervaart Ziekenhuis (D.P.M.B., M.R.), both in Amsterdam. Address reprint requests to Dr. Brandjes at the Department of Medicine, Slotervaart Ziekenhuis, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
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