Original Article
Subcutaneous Low-Molecular-Weight Heparin Compared with Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis
N Engl J Med 1992; 326:975-982April 9, 1992
- Abstract
- Abstract
Background.
Low-molecular-weight heparin has a high bioavailability and a prolonged half-life in comparison with conventional unfractionated heparin. Limited data are available for low-molecular-weight heparin as compared with unfractionated heparin for the treatment of deep-vein thrombosis.
Methods.
In a multicenter, double-blind clinical trial, we compared fixed-dose subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion for the initial treatment of patients with proximal-vein thrombosis, using objective documentation of clinical outcomes.
Results.
Six of 213 patients who received low-molecular-weight heparin (2.8 percent) and 15 of 219 patients who received intravenous heparin (6.9 percent) had new episodes of venous thromboembolism (P = 0.07; 95 percent confidence interval for the difference, 0.02 percent to 8.1 percent). Major bleeding associated with initial therapy occurred in 1 patient receiving low-molecular-weight heparin (0.5 percent) and in 11 patients receiving intravenous heparin (5.0 percent), a reduction in risk of 91 percent (P = 0.006). This apparent protection against major bleeding was lost during long-term therapy. Minor hemorrhagic complications were infrequent. Ten patients receiving low-molecular-weight heparin (4.7 percent) died, as compared with 21 patients receiving intravenous heparin (9.6 percent), a risk reduction of 51 percent (P = 0.049).
Conclusions.
Low-molecular-weight heparin is at least as effective and as safe as classic intravenous heparin therapy under the conditions of this study and more convenient to administer. The simplified therapy provided by low-molecular-weight heparin may allow patients with uncomplicated proximal deep-vein thrombosis to be cared for in an outpatient setting. (N Engl J Med 1992;326: 975–82.)
Media in This Article
Figure 1
Frequency of Objectively Documented Recurrent Venous Thromboembolism in the Treatment Groups.Figure 2
Time-to-Event Analysis for Patients Who Had Recurrent Venous Thromboembolism or Died.Article Activity
- Article
THE classic treatment for acute deep-vein thrombosis is initial therapy with continuous intravenous heparin,1 2 3 4 5 followed by long-term oral anticoagulant therapy.6 7 8 9 The use of accurate objective tests to detect venous thromboembolism10 11 12 13 14 has led to randomized trials of various treatments for venous thrombosis,1 2 3 4 5 , 7 8 9 , 15 , 16 which have shown that the intensity of the initial heparin treatment must be sufficient to prevent recurrent venous thromboembolism.5 Patients with proximal deep-vein thrombosis who receive inadequate anticoagulant therapy have a risk of recurrent venous thromboembolism that approaches 50 percent.7 Recent trials have also demonstrated that the duration of initial heparin therapy can be shortened from 10 to 14 days to approximately 5 days,15 , 16 which offers a substantial financial benefit.17
In recent years, low-molecular-weight fractions of heparin have been prepared with a mean molecular weight of 4000 to 5000 daltons as compared with conventional heparin, which has a mean molecular weight of 12,000 to 16,000 daltons.18 , 19 Pharmacokinetic studies indicate that the bioavailability of low-molecular-weight heparin after subcutaneous injection is very high20 21 22 23 24 and that the half-life of low-molecular-weight fractions of heparin is longer than that of unfractionated heparin.20 21 22 , 24 25 26
Studies of models of venous thrombosis in laboratory animals have shown that some low-molecular-weight fractions of heparin have antithrombotic efficacy equal to or greater than that of heparin, with fewer hemorrhagic effects.18 , 19 , 27 , 28 These properties have not been consistently demonstrated in humans.18 , 29 30 31 32 A meta-analysis33 of randomized clinical trials evaluating low-molecular-weight heparin as prophylaxis against deep-vein thrombosis29 , 30 , 32 suggested that it is more effective than low-dose heparin, but with an increased risk of bleeding. In contrast, a large randomized trial34 comparing the prophylactic use of low-molecular-weight heparin with moderate doses of subcutaneous heparin showed that low-molecular-weight heparin produced significantly fewer hemorrhagic complications for an apparently equivalent antithrombotic effect. Whether this reflects an intrinsic property of low-molecular-weight heparin or an effect related to the dose is uncertain.35
Limited data based on venographic observations rather than clinical outcome are available for low-molecular-weight heparin as compared with unfractionated heparin for the treatment of deep-vein thrombosis.36 37 38 39 40 41 42 43 44 45 46 47 They suggest that low-molecular-weight heparin administered subcutaneously twice a day is as effective and safe as continuous intravenous heparin. Recent pharmacodynamic data suggest that a low-molecular-weight fraction of heparin (Logiparin, Novo Nordisk, Denmark) can be administered only once daily to achieve sustained effects throughout the 24-hour period, without the need for monitoring.40 It is uncertain whether findings associated with one preparation of low-molecular-weight heparin can be extended to a different one.
For these reasons, we evaluated the effectiveness and safety of a single subcutaneous injection of low-molecular-weight heparin per day as compared with continuous intravenous heparin for the initial treatment of patients with proximal-vein thrombosis. If unmonitored low-molecular-weight heparin were as effective and safe as intravenous heparin, its use might allow patients with uncomplicated venous thrombosis to be treated at home, reducing the risk of nosocomial infection and other hospital hazards48 49 50 and providing substantial cost savings by eliminating the need for a hospital stay.
Methods
Study Design
The American—Canadian Thrombosis Study was a multicenter, randomized, double-blind clinical trial comparing unfractionated continuous intravenous heparin with once-daily subcutaneous low-molecular-weight heparin (Logiparin) in patients with acute proximal deep-vein thrombosis. Fifteen centers in the United States and Canada participated in the trial. The protocol was approved by the institutional review board at each center.
Patients
Consecutive eligible patients 18 years of age or older with proximal deep-vein thrombosis (thrombosis of the popliteal or more proximal deep veins of the legs) documented by venography were enrolled in the study. Patients were eligible if they had none of the following: currently active bleeding or disorders contraindicating anticoagulant therapy; allergy to heparin, bisulfites, or fish; pregnancy; two or more previously documented episodes of deep-vein thrombosis or pulmonary embolism; a history of protein C deficiency; a history of heparin-associated thrombocytopenia; severe malignant hypertension (blood pressure, ≥250 mm Hg systolic and ≥130 mm Hg diastolic); severe hepatic failure (hepatic encephalopathy); severe renal failure necessitating dialysis; or geographic inaccessibility preventing them from attending follow-up visits. Eligible patients were excluded if they had received treatment with warfarin, low-molecular-weight heparin, or heparinoids within the seven days before study entry; if they had received treatment with therapeutic subcutaneous heparin within the preceding 12 hours; if they were receiving intravenous heparin (265 patients); or if they declined to give written informed consent (148 patients).
Before randomization, the patients were stratified into groups according to the study center where they were treated, the presence or absence of a history of venous thrombosis, the presence or absence of one or more risk factors for bleeding (surgery within the previous 14 days, a history of peptic ulcer disease, thrombotic stroke within the previous 14 days, and a platelet count less than 150×109 per liter). A randomized, computer-derived treatment schedule was used to assign the patients to receive intravenous heparin or subcutaneous low-molecular-weight heparin. Within each stratum, the randomization schedule was balanced in blocks of four.
In each patient, anticoagulant therapy was started as soon as possible after proximal-vein thrombosis had been documented objectively, either by ascending contrast venography or by impedance plethysmography or B-mode imaging using venous compression. 51 , 52 The rates at which impedance plethysmography or B-mode imaging was initially used were comparable in each group. In the case of patients studied by these methods, the diagnosis was also confirmed as soon as possible by venography.
Regimens
The patients in the intravenous-heparin group received an initial intravenous bolus dose of 5000 USP units of heparin, followed by a continuous intravenous infusion of heparin. The initial dose was 40,320 units every 24 hours for patients without the designated risk factors for bleeding, and 29,760 units every 24 hours for patients who had one or more designated risk factors. Fifty-three patients randomly assigned to receive intravenous heparin had one or more designated risk factors for bleeding, as compared with 56 patients randomly assigned to receive low-molecular-weight heparin. These doses were chosen to minimize the risk of insufficient heparin treatment during the first 24 hours of therap5 , 16 , 53 and to avoid high initial doses of heparin in the patients with designated risk factors for bleeding.16
The dose of continuous intravenous heparin was adjusted according to the results of laboratory monitoring by means of the activated partial-thromboplastin time. This was obtained 4 hours after the start of the initial treatment, and the test was repeated every 4 to 6 hours until the result was within the prescribed therapeutic range (approximately 1.5 to 2.5 times the mean normal control value of 30 seconds obtained with Actin FS thromboplastin reagent [Dade]). Thereafter, the activated partial-thromboplastin time was measured once daily unless the result was subtherapeutic, in which case the test was repeated every four hours until the therapeutic range was reached again.
The patients in the group receiving low-molecular-weight heparin were given a fixed dose of 175 International Factor Xa Inhibitory Units per kilogram of body weight subcutaneously once every 24 hours. This regimen was chosen because pharmacokinetic studies in normal subjects demonstrated that it produced a sustained anticoagulant response (anti—factor Xa activity) throughout the 24-hour dosing period; when given for five to six days, this dose was not associated with a substantial accumulation of the anticoagulant effect.
All the patients received long-term therapy with warfarin sodium for at least three months, in a dose of 10 mg per day beginning on the second day of the initial therapy, then adjusted daily according to the results of laboratory monitoring of the prothrombin time; the therapeutic range was standardized among the participating hospitals with use of the international normalized ratio. This ratio is the prothrombin-time ratio obtained by testing a given sample with the World Health Organization reference thromboplastin, which has an international sensitivity index of 1.0. The warfarin dose was adjusted to maintain the international normalized ratio between 2.0 and 3.O.54 After the first six days, the dose was adjusted weekly by the patient's primary physician. Treatment with either intravenous heparin or subcutaneous low-molecular-weight heparin was discontinued on the sixth day, provided the international normalized ratio was 2.0 or more.
The patients randomly assigned to receive intravenous heparin also received a subcutaneous injection of placebo once every 24 hours. The patients assigned to receive subcutaneous low-molecular-weight heparin also received an intravenous bolus of placebo and a continuous intravenous infusion of placebo throughout the initial therapy.
To maintain blinding with regard to each patient's treatment assignment, the activated partial-thromboplastin time was reported only to a member of the health care team who was not involved in assessing the patient's outcome; nor was this information recorded on the patient's chart during the study or reported to any other member of the health care team. Adjustments in the rate of infusion of intravenous heparin or placebo were made by an unblinded physician according to dosing schedules established before the trial began.
At entry into the study, all the patients underwent clinical and laboratory investigations, which were repeated on day 6. The results of the laboratory investigations, including details of assays and their standardization, the use of central laboratory facilities, and the findings of the assays, will be reported separately.
The use of drugs containing acetylsalicylic acid was prohibited during the study, and the use of sulfinpyrazone, dipyridamole, and indomethacin was strongly discouraged.
Surveillance and Follow-up
All the patients were examined daily during the initial therapy; symptoms or signs of recurrent deep-vein thrombosis, pulmonary embolism, or bleeding were sought. Perfusion lung scanning was performed routinely in all patients within 48 hours of study entry. Approximately 50 to 60 percent of patients with acute proximal-vein thrombosis have asymptomatic pulmonary embolism at the time of presentation55 , 56; the base-line lung scan was used as a basis for comparison with lung-scan abnormalities found at the time of any subsequent presentation with symptoms or signs of pulmonary embolism. All the patients were followed for three months to assess the possibility that inadequate initial therapy could lead to a thrombotic recurrence or pulmonary embolization during long-term therapy with warfarin sodium.5 Patients were asked to come to the hospital immediately if symptoms or signs of recurrent deep-vein thrombosis or pulmonary embolism developed. Those with suspected recurrent venous thrombosis underwent impedance plethysmography and venography; the diagnostic criteria are described elsewhere.5 , 7 8 9 10 , 13 , 57 , 58 Recurrent venous thrombosis was diagnosed when venography revealed a constant intraluminal filling defect that was not present in the deep veins on the base-line venogram.13 If the second venogram was difficult to interpret (because of the presence of collateral veins, persistent intraluminal filling defects, or unfilled venous segments), recurrent venous thrombosis was diagnosed if the results of impedance plethysmography had changed from negative to positive (and clinical disorders known to produce false positive findings were absent). Such results are associated with a high frequency of new episodes of acute venous thrombosis.13 When pulmonary embolism was suspected in a patient on the basis of clinical signs or symptoms, the diagnosis was confirmed either by lung scanning (showing a new perfusion defect, segmental or larger, with a ventilation mismatch) that indicated a high probability of pulmonary embolism59 60 61 or by positive pulmonary angiography (revealing a constant intraluminal filling defect on multiple films),14 , 62 which was performed in patients in whom lung scanning did not indicate a high probability of pulmonary embolism.60 , 61
Bleeding was classified as major or minor, according to criteria described elsewhere.5 , 7 8 9 , 16
Data on the outcome measures of effectiveness (recurrent venous thromboembolism) and safety (bleeding complications) and on patients' deaths were interpreted by a central adjudicating committee. Adjudication was made by two committee members not involved in the patient's care, and disputes were resolved independently by a third. The results of objective tests were interpreted independently and without the interpreter's knowledge of the other results, the patient's clinical findings, or the patient's treatment group.
Statistical Analysis
We estimated that a sample containing 200 patients per group would be large enough that a 95 percent confidence interval for the difference in frequencies (based on the normal approximation to the binomial distribution) would exclude differences of 5 percent or more, assuming observed frequencies of the order of 5 percent in the two treatment groups.
Fisher's exact test and the uncorrected chi-square test were used to compare the frequencies of death, recurrent venous thromboembolism, and bleeding in the two treatment groups. Ninety-five percent confidence limits for the true incidences of recurrent venous thromboembolism and bleeding complications were calculated from the binomial distribution. Confidence intervals for the difference between the two treatment groups in the incidence of recurrent venous thromboembolism and bleeding complications were calculated with the normal approximation to the binomial distribution. The log-rank test was used to assess differences in the cumulative incidence of death and recurrent thromboembolism.
In the characterization of anticoagulant therapy, the values for the activated partial-thromboplastin time obtained in a given test were plotted as a box whose top and bottom correspond to the upper and lower quartiles of the sample, with the sample median and two bars indicated. The bars extend to the minimal and maximal values in the sample or to limits based on the interquartile range, defined as the distance between the lower quartile and the upper quartile. Outliers beyond this range were plotted separately.63
Results
Patients
Four hundred thirty-two consecutive patients were enrolled in the study; 219 patients were assigned to receive unfractionated continuous intravenous heparin and subcutaneous placebo, and 213 patients to receive subcutaneous low-molecular-weight heparin and continuous intravenous placebo (Table 1Table 1
Clinical Characteristics of Patients with Proximal Venous Thrombosis Treated with Unfractionated Continuous Intravenous Heparin or Low-Molecular-Weight Heparin.). The treatment groups were comparable at entry except for sex; there were more women in the intravenous-heparin group. To assess the possible effect of this potential sex imbalance, multiple logistic regression was used. No significant effect of sex was found. All the patients were followed during the initial therapy and during three months of long-term therapy; none were lost to follow-up.Recurrent Venous Thromboembolism
Six of the patients who received low-molecular-weight heparin (2.8 percent) and 15 of those who received intravenous heparin (6.9 percent) had new episodes of symptomatic venous thromboembolism documented by objective testing(P = 0.07 by Fisher's exact test; 95 percent confidence interval for the difference, 0.02 percent to 8.1 percent). These patients presented with overt symptoms and signs of thromboembolism. Analysis by the log-rank test, which takes into account the length of time to an event, demonstrated a significant difference (P = 0.049) in the frequency of thromboembolic events (Fig. 1Figure 1
Frequency of Objectively Documented Recurrent Venous Thromboembolism in the Treatment Groups.).Of the six patients receiving low-molecular-weight heparin who had new episodes of venous thromboembolism, three had new episodes of pulmonary embolism (i.e., a high-probability lung scan showed segmental or greater perfusion defects with ventilation mismatch), and three had recurrent deep-vein thrombosis. Recurrent venous thrombosis was documented by venography in one patient, who was found to have new constant proximal intraluminal filling defects. In the remaining two patients, recurrent venous thrombosis was documented by impedance plethysmography that changed from negative to positive.
Of the 15 patients in the intravenous-heparin group who had new episodes of venous thromboembolism, 6 had new episodes of pulmonary embolism (4 documented by high-probability lung scans and 2 confirmed by autopsy). Venography documented new constant intraluminal filling defects in the proximal veins in three patients, and recurrent venous thrombosis was documented in the remaining six patients by impedance plethysmography. The activated partial-thromboplastin time during the initial heparin treatment was therapeutic in 13 patients and subtherapeutic in 2. During long-term follow-up, therapeutic prothrombin times were noted before or at the time of the recurrent venous thromboembolic event in 12 of the 15 patients receiving intravenous heparin and in 3 of the 6 patients receiving low-molecular-weight heparin.
Bleeding Complications
Major bleeding occurred during or immediately after the initial therapy in 1 patient receiving low-molecular-weight heparin (0.5 percent) and in 11 patients receiving intravenous heparin (5.0 percent) (P = 0.006; reduction in risk, 91 percent) (Table 2Table 2
Bleeding Complications during or Immediately after the Initial Treatment in the Two Groups.*). The activated partial-thromboplastin time was supratherapeutic in 3 of the 11 patients receiving intravenous heparin. Among the 12 patients with major bleeding, the prothrombin time was supratherapeutic in the patient receiving low-molecular-weight heparin and in 2 of the 11 patients receiving intravenous heparin.Minor hemorrhagic complications occurred during or immediately after the initial therapy in five patients receiving low-molecular-weight heparin (2.4 percent) and in four patients receiving intravenous heparin (1.8 percent) (Table 2). In addition, two patients receiving low-molecular-weight heparin and three patients receiving intravenous heparin had brief, self-limiting episodes of epistaxis. Overall, therefore, minor bleeding occurred in seven patients receiving low-molecular-weight heparin (3.3 percent) and seven patients receiving intravenous heparin (3.2 percent) (Table 2). The activated partial-thromboplastin time was supratherapeutic in five of the seven patients receiving intravenous heparin who had minor bleeding. The prothrombin time was supratherapeutic at or before the time of bleeding in one of the seven patients receiving low-molecular-weight heparin who had minor bleeding and in none of those receiving intravenous heparin.
Major bleeding remote from the time of initial therapy occurred during long-term warfarin therapy in five patients who had received low-molecular-weight heparin (2.3 percent) and involved hematuria, hematemesis, hematemesis and melena, melena, and hematoma on days 18, 24, 47, 51, and 56, respectively; such bleeding occurred in none of those who had received intravenous heparin (P = 0.028). The prothrombin time was supratherapeutic at or before the time of bleeding in four of the five patients who had received low-molecular-weight heparin (two of those who bled had recurrent episodes of major bleeding 10 and 13 days after warfarin was stopped).
Minor bleeding remote from the time of initial therapy occurred during long-term warfarin therapy in six patients who had received low-molecular-weight heparin (2.8 percent) (hematemesis, hematochezia, hemoptysis, vaginal bleeding, hematuria, and hematoma on days 10, 10, 23, 38, 44, and 82, respectively) and in eight patients who had received intravenous heparin (3.7 percent) (epistaxis, hemoptysis, bleeding from the site of insertion of a central line, hematuria, hematochezia, epistaxis, hematochezia, and epistaxis on days 12, 18, 19, 25, 41, 49, 67, and 70, respectively). The prothrombin time was supratherapeutic at or before the time of bleeding in two of the six patients who had received low-molecular-weight heparin and in four of the eight patients who had received intravenous heparin.
Deaths
Ten patients assigned to receive low-molecular-weight heparin (4.7 percent) and 21 patients assigned to receive intravenous heparin (9.6 percent) died during the three months of follow-up (P = 0.062 by Fisher's exact test; P = 0.049 by the uncorrected chi-square test; reduction in risk, 51 percent) (Table 3Table 3
Causes of Death in the Two Treatment Groups.). Since the observed difference in the incidence of death between the groups was 4.9 percent, with a lower incidence for low-molecular-weight heparin, it is unlikely (P<0.05) that this difference would be less than 0.1 percent, and it could be as great as 9.7 percent in favor of low-molecular-weight heparin.Three patients receiving low-molecular-weight heparin died abruptly (1.4 percent), as compared with 13 patients receiving intravenous heparin (5.9 percent) (P = 0.019) (Table 3).
Other Findings
Six patients receiving low-molecular-weight heparin (2.8 percent) and three patients receiving intravenous heparin (1.4 percent) had thrombocytopenia (platelet count, <150×109) during initial therapy. The majority of the events according to which effectiveness was determined occurred during the first six weeks of follow-up (Fig. 2Figure 2
Time-to-Event Analysis for Patients Who Had Recurrent Venous Thromboembolism or Died.).Analysis of Activated Partial-Thromboplastin Times
The activated partial-thromboplastin times for all patients during initial therapy are shown in Figure 3Figure 3
Activated Partial-Thromboplastin Times for the Study Patients during Initial Treatment, According to Treatment Group and Test Sequence. according to treatment group and test sequence.Discussion
This study indicates that low-molecular-weight heparin is as effective and as safe as intravenous unfractionated heparin therapy in patients with acute proximal-vein thrombosis. Time-to-event analysis suggests that low-molecular-weight heparin may be more effective than unfractionated heparin (P = 0.049) (Fig. 1).
The regimen of low-molecular-weight heparin in this trial resulted in significantly fewer major bleeding complications during or immediately after initial therapy (P = 0.006) (Table 2). This protective effect was lost during long-term therapy with warfarin. It is possible that the long-term use of low-molecular-weight heparin instead of warfarin sodium would have provided continued protection against bleeding; this possibility should be studied in future clinical trials. The frequency of minor hemorrhagic complications was similar during both initial and long-term therapy. The majority of the major hemorrhagic complications occurred in patients with predisposing disorders, supporting previous observations that the underlying risk factors in a patient are the chief determinants of bleeding during therapy with intravenous heparin.16 , 64 The incidence of major bleeding was evenly distributed between men and women.
The intravenous-heparin group had a higher overall mortality (Table 3). The increased mortality among patients receiving unfractionated heparin may in part reflect the excess of patients with recurrent venous thromboembolism or hemorrhagic complications, but the actual reasons for the difference in mortality are unclear. It is evident from the timing of deaths and thromboembolic events (Fig. 2) that the majority of these events occurred early. It was recently reported that as compared with prophylaxis using oral anticoagulants, the prophylactic use of heparinoids in patients with fractured hips was associated with fewer deaths.65 The reasons for the lower death rate among the patients receiving heparinoids are also uncertain.65 Whether these differences in mortality indicate a true effect of these agents, antithrombotic or otherwise,66 remains to be determined.
The results of this study appear to show, at the least, that treatment with low-molecular-weight heparin is equivalent to classic intravenous heparin therapy. Evidence in the literature, largely based on venographic findings, also suggests that low-molecular-weight heparin is as effective as intravenous heparin.36 37 38 39 40 41 42 43 44 45 46 47 The reduced frequency of major bleeding complications early in our study was also consistent with findings in animal models of venous thrombosis27 , 28; in addition, it supports recent clinical observations.34
Care was taken throughout the study to ensure that adequate doses of intravenous heparin were administered. The standardized protocol used achieves therapeutic levels in 90 percent or more of patients during the first 24 hours and maintains them thereafter.53 This strategy was important, because the subtherapeutic administration of heparin is associated with a high frequency of recurrent venous thromboembolism.5 It could be argued that in the effort to avoid subtherapeutic heparin administration, excess doses of intravenous heparin were given that caused excess bleeding, but this is unlikely, since the relatively low frequency (5.0 percent) of major bleeding during initial therapy in the intravenous-heparin group was similar to previously reported rates of bleeding.5 , 16 , 67 68 69
To avoid a selection bias, care was taken to ensure that the participating physicians adhered to the protocol. Before the study, the criteria for eligibility were specified; 51 percent of the eligible patients were randomized. The clinical characteristics of the randomized and nonrandomized patients were similar. The nonfatal and fatal outcomes observed in the study were dispersed across the centers rather than being confined to a few centers. For these reasons, it is likely that our results are generalizable to the population at large.
Subcutaneous low-molecular-weight heparin may be an intrinsically safer antithrombotic agent than unfractionated heparin given by continuous intravenous infusion. Because the need for intravenous infusion and for monitoring is eliminated and a single subcutaneous injection of a fixed dose is given daily, the potential exists to provide antithrombotic treatment in an outpatient setting for patients with uncomplicated proximal-vein thrombosis.
Supported in part by a grant from the Heart and Stroke Foundation of Alberta and also by Novo Nordisk.
*See the Appendix for a list of additional participants in the study.
We are indebted to the medical, surgical, emergency, nursing, pharmacy, and support staff of all the sites participating in the study.
Source Information
From the Clinical Trials Unit, Division of General Internal Medicine, University of Calgary, Calgary, Alta. (R.D.H., G.E.R., G.F.P., D.R., R.B.); the University of British Columbia (T.S., C.J.C., J.W.) and the Lions Gate Hospital (W.M.), both in Vancouver; Northwestern University, Rehabilitation Institute of Chicago, Chicago (D.G.); Texas A & M University, Scott and White Clinic, Temple (A.A.T.); the University of Utah, LDS Hospital, Salt Lake City (C.G.E.); New York Medical College, Westchester County Medical Center, Valhalla (R.G.L.); Methodist Hospital of Indiana, Indianapolis (J.H.); the University of Colorado, University Hospital, Denver (H.R.B.); Penrose Hospital, Colorado Springs, Colo. (J.N.); Mercy Hospital and Medical Center, San Diego, Calif. (R.G.); and Jefferson Medical Center, Philadelphia (G.M.). Address reprint requests to Dr. Hull at the University of Calgary, Department of Medicine, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Appendix
The following persons also participated in the American-Canadian Thrombosis Study: University of Calgary, Calgary, Aha. — Calgary General Hospital site: W. Blahey, J.F.T. Thaell, R. Dear, T. Godinez, P. Hardin, D. Linden, D. McKeage, and A. Wilson; Foothills Hospital site: B. Baylis, N. Campbell, A. Ferland, C.B. Hatfield, R.E. Hatfield, CD. Thompson, L. Styner, and R. Mulcair; Northwestern University, Rehabilitation Institute of Chicago, Chicago: H. Kohl, N. Reynolds, and J. Deutsche; Texas A & M University, Scott and White Clinic, Temple: E.J. Schoolar and B. Woodruff; University of Utah, LDS Hospital, Salt Lake City: M. Suchyta, S. Yeates, M. Boyer, and N. Kitterman; New York Medical College, Westchester County Medical Center, Valhalla: J. Nelson, E. Scorcia, and P. Pugni; Methodist Hospital of Indiana, Indianapolis: S. Gamache, R. Hahn, S. Rolfe, K. Berron, K. Colvin, and S. Kerner-Slemons; University of British Columbia, Vancouver: S. Krikler and S. Fowler; University of Colorado, University Hospital, Denver: B. Whitcomb, L.A. Barbour, D. Tanaka, R.G. Badgett, and M. LoVerde; Penrose Hospital, Colorado Springs, Colo.: J. Hillman and M. Dieterich; Mercy Hospital and Medical Center, San Diego, Calif: M. Sullivan and K. Engstrand; Jefferson Medical College, Philadelphia: L. Doyle and C. Pilgrim; Lions Gate Hospital, Vancouver, B.C.: R. Cohen, M. Dart, and S. Regehr; Clinical Trials Group, University of Calgary: B. Doucette and L. Styner; Safely monitor: D. Bergqvist; Liaison with Novo Nordisk: A. Brusby, N. Griffin, K. Birch, S. Glazer, and U. Hedner.
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