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Long-term Low-Molecular-Weight Heparin versus Usual Care in Proximal-Vein Thrombosis Patients with Cancer

      Abstract

      Purpose

      A substantial clinical need exists for an alternative to vitamin K antagonists for treating deep-vein thrombosis in cancer patients who are at high risk of both recurrent venous thromboembolism and bleeding. Low-molecular-weight heparin, body-weight adjusted, avoids anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy.

      Subjects and Methods

      Subjects were patients with cancer and acute symptomatic proximal-vein thrombosis. We performed a multi-centre randomized, open-label clinical trial using objective outcome measures comparing long-term therapeutic tinzaparin subcutaneously once daily with usual-care long-term vitamin-K-antagonist therapy for 3 months. Outcomes were assessed at 3 and 12 months.

      Results

      Of 200 patients, 100 received tinzaparin and 100 received usual care. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=.44; absolute difference −9.0; 95% confidence interval [CI], −21.7 to −0.7). Bleeding, largely minor, occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference −3.0; 95% CI, −9.1 to 15.1). In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 0 of 51 patients (0%) receiving tinzaparin and 1 of 48 patients (2.1%) receiving usual care. Mortality at 1 year was high, reflecting the severity of the cancers; 47% in each group died.

      Conclusion

      Our findings confirm the limited but benchmark data in the literature that long-term low-molecular-weight heparin is more effective than vitamin-K-antagonist therapy for preventing recurrent venous thromboembolism in patients with cancer and proximal venous thrombosis.

      Keywords

      The classic long-term treatment for deep-vein thrombosis is vitamin-K-antagonist therapy overlapped with initial heparin or low-molecular-weight heparin therapy.
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      There is a need for effective and safe alternate therapy to vitamin-K-antagonists in cancer patients with venous thrombosis. The aggregate data
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      for patients receiving vitamin-K-antagonist therapy show that recurrent venous thromboembolism occurs more frequently in cancer patients than in noncancer patients.
      • Long-term low-molecular-weight heparin offers an alternative strategy to vitamin-K-antagonist therapy without requiring anticoagulant monitoring.
      • Cancer is a risk factor for bleeding.
      • Long-term low-molecular-weight heparin offers the hope of improved quality of life, particularly in patients without additional risk factors for bleeding.
      • The improved efficacy against recurrent thromboembolism for long-term low-molecular-weight heparin may reflect the fact that cancer patients are less responsive to vitamin-K-antagonist therapy than noncancer patients.
      The use of accurate objective tests to detect venous thromboembolism has led to randomized trials evaluating initial short-term therapy or long-term anticoagulants for venous thrombosis, which have advanced our therapeutic understanding. Initial short-term low-molecular-weight heparin therapy is effective and is preferred over intravenous heparin because anticoagulant monitoring is not required, facilitating outpatient therapy.
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      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
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      • et al.
      Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home.
      For vitamin-K-antagonist therapy,
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      • Hull R.D.
      • et al.
      Antithrombotic therapy for venous thromboembolic disease.
      • Hull R.D.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Hirsh J.
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      Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
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      Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.
      the importance of maintaining a therapeutic international normalized ratio (INR) (2.0-3.0) is well documented; this necessitates frequent INR monitoring.
      Renewed interest in the interaction of antithrombotic regimens on the survival of cancer patients resulted from the findings of randomized trials evaluating low-molecular-weight heparin treatment of deep-vein thrombosis, which revealed a reduction in cancer mortality.
      • Green D.
      • Hull R.D.
      • Brant R.F.
      • Pineo G.F.
      Lower mortality in cancer patients treated with low-molecular-weight heparin versus standard heparin.
      Subsequently, this revived interest in antithrombotic therapy in cancer patients has been reinforced by the outcomes of several trials evaluating long-term low-molecular-weight heparin therapy. Vitamin-K-antagonist therapy was associated with an excess of major bleeding compared with long-term low-molecular-weight heparin in the secondary prevention of venous thromboembolism in patients with cancer and venous thromboembolism; bleeding was in part associated with supratherapeutic INR values.
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      Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
      Subsequently, a benchmark study showed that long-term low-molecular-weight heparin was more effective than vitamin-K-antagonist treatment for preventing recurrent venous thromboembolism in cancer patients with venous thromboembolism.
      • Lee A.Y.Y.
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      • et al.
      CLOT Investigators
      Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
      Most recently, a brief course of subcutaneous low-molecular-weight heparin was shown to favorably influence survival in patients with advanced malignancy.
      • Klerk C.P.
      • Smorenburg S.M.
      • Otten H.M.
      • et al.
      The effect of low molecular weight heparin on survival in patients with advanced malignancy.
      There is a clear need for ongoing study to further our understanding of the role of low-molecular-weight heparin therapy in cancer patients with venous thromboembolism. The difficulty of successfully completing clinical trials evaluating antithrombotic therapy in patients with cancer and deep-vein thrombosis is illustrated by the fact that, of the 3 trials (enrolling 146 patients, 672 patients and 88 patients, respectively)
      • Meyer G.
      • Marjanovic Z.
      • Valcke J.
      • et al.
      Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
      • Lee A.Y.Y.
      • Levine M.N.
      • Baker R.I.
      • et al.
      CLOT Investigators
      Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
      • Deitcher S.R.
      • Kessler C.M.
      • Merli G.
      • et al.
      Secondary prevention of venous thromboembolic events (VTE) in patients with active malignancy: a randomized study of enoxaparin sodium alone vs. initial enoxaparin sodium followed by warfarin for a 180-day period.
      reported to date, 2 trials had to close early due to poor enrollment.
      • Meyer G.
      • Marjanovic Z.
      • Valcke J.
      • et al.
      Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
      • Deitcher S.R.
      • Kessler C.M.
      • Merli G.
      • et al.
      Secondary prevention of venous thromboembolic events (VTE) in patients with active malignancy: a randomized study of enoxaparin sodium alone vs. initial enoxaparin sodium followed by warfarin for a 180-day period.
      We had the opportunity to address the effectiveness and safety of differing long-term antithrombotic therapies in patients with cancer suffering proximal-vein thrombosis under the auspices of our “long-term innovations in treatment program.” We performed a multicenter, randomized open-label clinical trial to evaluate the effectiveness and safety of the low-molecular-weight heparin, tinzaparin, versus usual heparin care and vitamin-K-antagonist therapy in preventing recurrent venous thromboembolism in a broad spectrum of patients; these findings are reported elsewhere.
      • Hull R.D.
      • Pineo G.F.
      • Brant R.F.
      LITE Trial Investigators
      Self-managed long-term low-molecular-weight compared with usual-care anticoaguation for patients with proximal venous thrombosis: harm associated with bleeding.
      A priori, cancer patients were randomized as a separate category with the intent to evaluate and report the findings for cancer patients with proximal venous thrombosis as a distinct entity. Accordingly, we report our unpublished data concerning our cancer trial, which assessed the benefits and potential harms of long-term low-molecular-weight heparin therapy compared with usual-care vitamin-K-antagonist therapy in cancer patients with proximal venous thrombosis.

      Methods

      Study Design

      We used a multicenter, open-label randomized design and compared long-term subcutaneous low-molecular-weight heparin against usual-care initial intravenous heparin and long-term oral warfarin sodium for a therapy duration of 3 months in cancer patients with proximal-vein thrombosis. An evaluation of patients with cancer and proximal deep-vein thrombosis was planned prospectively as cancer patients were randomized separately within the Main-LITE population of patients. Patients with cancer and deep-vein thrombosis were identified a priori and randomized as a separate population within the overall Main-LITE population; the findings for cancer patients only have not been reported previously.
      Our cancer study is one of a set of studies using a randomized design with objective assessment of outcome. The set of studies was performed under the auspices of the Long-term Innovations in TreatmEnt program (LITE) funded by the Canadian Institutes of Health Research, formerly Medical Research Council, and industry. The individual studies included Main-LITE cancer, Main-LITE broad spectrum of patients (which is reported separately), and Home-LITE, a home treatment study evaluating quality of life and the postphlebitic syndrome, which is reported separately. The Main-LITE studies differed in their design from the Home-LITE study with regards to the treatment groups, and are entirely separate studies. For the Main-LITE studies, a consecutive population of hospitalized patients was entered and the comparison group was given intravenous heparin and vitamin-K-antagonist therapy, whereas patients randomized to Home-LITE received initial low-molecular-weight heparin therapy and either continued low-molecular-weight heparin therapy or crossed over to vitamin-K-antagonist therapy for 3 months. The requirement for intravenous heparin in the comparison group mandated that patients participating in Main-LITE be hospitalized should they be randomized to receive intravenous heparin. Cancer patients with proximal venous thrombosis who were eligible for home treatment could not be randomized to Main-LITE because they were ineligible for admission to hospital.
      Thirty centers in Canada participated. The protocol was approved by the institutional review board at each center. Written informed consent was obtained from all patients.
      Our study and the reporting of the findings comply with the CONSORT (Consolidated Standards of Reporting Trials) statement
      • Altman D.G.
      • Schulz K.F.
      • Moher D.
      • et al.
      The revised CONSORT statement for reporting randomized trials: explanation and elaborations.
      • Moher D.
      • Schulz K.F.
      • Altman D.
      CONSORT Group
      The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.
      and the more recent updating of the agreement “Better reporting of harms in randomized trials: an extension of the CONSORT statement.”
      • Ioannidis J.P.A.
      • Evans S.J.W.
      • Gotzsche P.C.
      • et al.
      CONSORT Group
      Better reporting of harms in randomized trials: an extension of the CONSORT Statement.

      Patients

      Patient eligibility and allocation are shown in Table 1.
      Table 1Patient Eligibility and Allocation
      Consecutive eligible cancer patients 18 years of age or older with acute proximal-vein thrombosis (popliteal, femoral or iliac-vein thrombosis) documented by venography or compression ultrasonography were enrolled in the study. Patients presenting with pulmonary embolism were eligible, providing they had proximal-vein thrombosis.
      Patients were eligible if they had none of the following:A bleeding diathesis or bleeding contraindicating anticoagulation; pregnancy; breast-feeding; allergy to heparin or bisulfates; a history of heparin-associated thrombocytopenia; malignant hypertension or blood pressure ≥250 mm Hg systolic or 130 mm Hg diastolic; hepatic encephalopathy; renal failure necessitating dialysis; neurological or ophthalmic surgery within 14 days; pulmonary embolism requiring thrombolysis, thrombectomy or vena cava interruption; life expectancy <3 months; lumbar puncture within 24 hours; receiving oral anticoagulation for other conditions; unable to discontinue acetylsalicylic acid; were eligible for home therapy with low-molecular-weight heparin but could not be allocated to intravenous heparin, which requires hospitalization; participating in another trial; unable to inject (eg, arthritis or lack of family support); or geographic inaccessibility for follow-up.
      Eligible patients were excluded if they:Received heparin, low-molecular-weight heparin or oral anticoagulant therapy for more than 2 days (575 patients); or were unable or declined to give written informed consent (900 patients).
      Before randomization, cancer patients were stratified according to:Study center; whether primary or recurrent venous thrombosis and high or low risk for bleeding.
      • Hull R.D.
      • Raskob G.E.
      • Rosenbloom D.
      • et al.
      Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Rosenbloom D.
      • et al.
      Optimal therapeutic level of heparin therapy in patients with venous thrombosis.
      With regard to the risk of bleeding, patients were stratified into groups according to:The absence (low risk) or presence (high risk) of one or more risk factors for bleeding including surgery or trauma within the previous 14 days, a history of peptic-ulcer disease, bleeding into the gastrointestinal or genitourinary tract, thrombotic stroke within the previous 14 days, a platelet count <150×109 per liter or miscellaneous reasons (predisposing disorders) for a high risk of bleeding.
      RandomizationA computer-derived randomized treatment schedule was used; within each stratum, the randomized schedule was balanced in blocks of 2 and 4.

      Treatment Regimens

      Patients assigned to low-molecular-weight heparin received tinzaparin (Innohep; Leo Pharmaceutical Products Ltd. A/S, Ballerup, Denmark) subcutaneously in a fixed dose of 175 International Factor Xa Inhibitory Units per kilogram of body weight once daily. Patients were taught to self-administer injections; for some, family members administered the injection. Patients receiving low-molecular-weight heparin underwent platelet counts at 14 and 21 days.
      Patients receiving unfractionated heparin and warfarin sodium were given an intravenous heparin bolus of either 5000 units or 80 units per kilogram, followed by a continuous intravenous infusion. The heparin infusion was administered according to 1 of 2 validated protocols for ensuring adequate heparin therapy.
      • Hull R.D.
      • Raskob G.E.
      • Rosenbloom D.
      • et al.
      Optimal therapeutic level of heparin therapy in patients with venous thrombosis.
      • Raschke R.A.
      • Reilly B.M.
      • Guidry J.R.
      • et al.
      The weight-based heparin nomogram compared with a ‘standard care’ nomogram: a randomized controlled trial.
      The heparin infusion was adjusted according to the results of laboratory monitoring using the activated partial thromboplastin time (APTT) described elsewhere.
      • Hirsh J.
      • Warkentin T.E.
      • Shaughnessy S.G.
      • et al.
      Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.
      Warfarin sodium was commenced on day 1 at 5-10 mg then adjusted daily to maintain the INR between 2.0 and 3.0,
      • Hyers T.M.
      • Agnelli G.
      • Hull R.D.
      • et al.
      Antithrombotic therapy for venous thromboembolic disease.
      • Hirsh J.
      • Dalen J.E.
      • Anderson D.R.
      • et al.
      Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
      overlapping with heparin to day 6 when heparin was discontinued if the INR was therapeutic. Thereafter, INR monitoring was performed every 1-2 weeks until cessation of therapy.
      Acetylsalicylic acid use was prohibited, and ticlopidine, sulfinpyrazone, dipyridamole, and nonsteroidal anti-inflammatory drug use were strongly discouraged.
      On completing the study drug at 12 weeks, therapy was discontinued unless oral anticoagulation was indicated; this was determined for each patient by the primary care physician according to the standard of care.

      Surveillance and Follow-up

      Patients were instructed to seek care immediately if they had symptoms or signs of venous thromboembolism, or bleeding. Patients presenting with clinically suspected recurrent venous thromboembolism underwent objective testing. Patients routinely attended the clinic at 12 weeks. At 1 year, all patients or their primary care physicians were contacted to determine whether the patient had suffered documented recurrent venous thromboembolism and was alive.
      Primary outcome measures were assessed at 3 months and included objectively documented recurrent venous thromboembolism or death. Patients were then followed by telephone at 1 year and assessed for objectively documented venous thromboembolism or death. Recurrent venous thrombosis was diagnosed when a previously compressible proximal vein segment was not compressible on ultrasonography,
      • Levine M.
      • Gent M.
      • Hirsh J.
      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
      • Koopman M.M.W.
      • Prandoni P.
      • Piovella F.
      • et al.
      Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home.
      • Lensing A.W.A.
      • Prandoni P.
      • Brandjes D.
      • et al.
      Detection of deep-vein thrombosis by real-time B-mode ultrasonography.
      The Columbus Investigators
      Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.
      or by the presence of a constant intraluminal filling defect in the deep veins that was not present on the baseline venogram.
      • Rabinov K.
      • Paulin S.
      Roentgen diagnosis of venous thrombosis in the leg.
      • Hull R.D.
      • Carter C.J.
      • Jay R.M.
      • et al.
      The diagnosis of acute, recurrent, deep-vein thrombosis: a diagnostic challenge.
      For patients with clinically suspected pulmonary embolism, the diagnosis was confirmed by: high probability lung scan findings;
      • Hull R.D.
      • Hirsh J.
      • Carter C.J.
      • et al.
      Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan.
      The PIOPED investigators
      Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED).
      a nondiagnostic lung scan with documented new deep-vein thrombosis;
      • Hull R.D.
      • Hirsh J.
      • Carter C.J.
      • et al.
      Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan.
      spiral computed tomography
      • Rathbun S.W.
      • Raskob G.E.
      • Whitsett T.L.
      Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review.
      showing thrombus in the central pulmonary arteries; pulmonary angiography
      • Hull R.D.
      • Hirsh J.
      • Carter C.J.
      • et al.
      Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan.
      • Dalen J.E.
      • Brooks H.L.
      • Johnson L.W.
      • et al.
      Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients.
      revealing a constant intraluminal filling defect or cutoff of a vessel greater than 2.5 mm in diameter; or pulmonary embolism found at autopsy.
      The primary safety endpoint for assessing harm was the occurrence of bleeding (all, major, or minor) during the 12-week treatment interval. Bleeding was classified as major if it was overt and associated with a fall in the hemoglobin level of 2 g per deciliter or more; if it led to the transfusion of 2 or more units of blood; and if it was retroperitoneal, occurred into a major joint, or was intracranial.
      • Hull R.D.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Genton E.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Pineo G.F.
      • et al.
      Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Carter C.
      • et al.
      Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Hirsh J.
      • et al.
      Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.
      Bleeding was defined as minor if it was clinically overt, but did not meet other criteria for major bleeding.
      • Hull R.D.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Genton E.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Pineo G.F.
      • et al.
      Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Carter C.
      • et al.
      Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Hirsh J.
      • et al.
      Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.
      These criteria were used successfully in previous studies.
      • Hull R.D.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Genton E.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Pineo G.F.
      • et al.
      Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.
      • Hull R.
      • Delmore T.
      • Carter C.
      • et al.
      Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.
      • Hull R.D.
      • Raskob G.E.
      • Hirsh J.
      • et al.
      Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.
      All suspected events including recurrent deep-vein thrombosis, pulmonary embolism, bleeding or death were interpreted independently without knowledge of the other findings by a central, independent adjudication committee. Adjudication was made by 2 committee members not involved in the patient’s care, and disputes were resolved independently by a third. Members of the committee were unaware of the patients’ treatment assignments.

      Statistical Analysis

      There were 200 patients with cancer and proximal venous thrombosis enrolled. The sample size for the cancer patients was not powered to evaluate mortality. The trial evaluated a sufficient number of patients to detect a difference in recurrent venous thromboembolism at 12 months and provides an assessment of harm due to bleeding.
      The comparison of the frequency of events (recurrent venous thromboembolism, bleeding, death) between the 2 groups in the first 12 weeks was based on the chi-squared test and associated confidence intervals. Cumulative incidence estimates to 1 year were derived from Kaplan-Meier survival curves and compared using the log-rank test after assessing the proportional hazard assumption.
      • Kalbfleish J.D.
      • Prentice R.L.
      Proportional hazards test diagnostics were based on weighted residuals.
      • Kalbfleish J.D.
      • Prentice R.L.
      Confidence intervals were derived from standard errors calculated from Greenwood’s formula. The meta-analysis was conducted following a fixed-effects approach based on the Mantel-Haenszel method as implemented in the metan procedure
      • Bradburn M.J.
      • Deeks J.J.
      • Altman D.G.
      Metan—an alternative meta-analysis command.
      of Stata software, release 6.0 (StataCorp, College Station, Tex).
      The protocol was designed by 3 investigators. The steering committee, central adjudication committee, and statistical analysis were performed independently of the sponsor. The Thrombosis Research Unit, University of Calgary coordinated the study and carried out the data management and administrative duties. Statistical analysis was carried out by the Department of Community Health Sciences, University of Calgary.

      Results

      Study Population

      Two hundred patients were recruited and randomized to tinzaparin (100 patients) or usual-care anticoagulants (100 patients). Figure 1 shows the patient flow for the eligible patients and for those randomized to the treatment groups. The tinzaparin and usual-care groups were comparable at entry (Table 2). The study began in 1994 at 23 centers across Canada (Table 3). Due to difficulties with occasional patient follow-up, which were overcome, successful patient follow-up was completed in July 2003.
      Figure thumbnail gr1
      Figure 1Participant flow chart.
      Table 2Clinical Characteristics of Cancer Patients with Proximal-Vein Thrombosis Treated with Long-Term Low-Molecular-Weight Heparin or Oral Anticoagulant Therapy
      CharacteristicNo. of Patients (%)
      Low-molecular-weight heparin n=100Intravenous heparin/warfarin n=100
      Age (years) <60, ≥6038, 6224, 76
      Sex (M, F)52, 4850, 50
      Status at entry
       Symptomatic deep-vein thrombosis92 (92)94 (94)
       Symptoms of pulmonary embolism21 (21)21 (21)
       Previous venous thromboembolism18 (18)20 (20)
       Factor V Leiden gene mutation10 (10)8 (8)
      Clinical measures at entry
       Surgery or trauma in past 6 months53 (53)49 (49)
       Coronary heart disease16 (16)29 (29)
       Diabetes15 (15)14 (14)
       Chronic obstructive pulmonary disease8 (8)10 (10)
       Peripheral vascular disease9 (9)3 (3)
       Congestive heart disease8 (8)8 (8)
       Leg paralysis7 (7)3 (3)
       Liver disease5 (5)6 (6)
       High risk of bleeding49 (49)52 (52)
      Cancer
       Solid tumor
        Nonmetastatic4351
        Metastatic4736
        Hematologic1013
      Table 3Participating Sites
      Site Name, LocationPrincipal Investigator(s), Coordinator(s)No. of Patients Enrolled
      Foothills Hospital, Calgary, ABR. Hull, D. Kimmett, K. Morrison, H. Hair, B. Sham;54
      St. Boniface General Hospital, Winnipeg, MBT. Wong, S. Erickson-Nesmith;24
      Peter Lougheed Centre, Calgary, ABR. Dear, T. Mooers, C. Dielissen, J. Gardner, D. Mckeage;23
      Montreal General Hospital, Montreal, QCS. Solymoss, S. Finkenbine, B. St. Jacques20
      Rockyview General Hospital, Calgary, ABR. Cook, D. Burnand, J. Dear, J. Davis, M. McDonald13
      Hotel Dieu de Hospital, Montreal, QCP. Nguyen, B. LeCours, S. Roy;9
      Ottawa General Hospital, Ottawa, ONM. Rodger, A.M. Clement, B. Kearns8
      Jewish General Hospital, Montreal, QCS. Kahn, C. Strulovitch7
      Royal Alexandra Hospital, Edmonton, ABC. Harley, E. Konopad, P. Nicholls, N. Whalen, V. Troncoso6
      Kelowna General Hospital, Kelowna, BCJ. Sutherland, M. Mantle, S. Shori6
      University Hospital, London, ONM. Cruickshank (deceased), M. von Lewinski5
      St. Paul’s Hospital, Vancouver, BCL. Vickars, L. Bachop, L. Wadup, D. Heinrich, M. Rusak, D. Michaels, J. Poirier, S. Taylor5
      Group Health Centre, Sault Ste. Marie, ONH. Lee (deceased), S. McLean, K. Barban, J. Sloss3
      St. Mary’s Hospital Centre, Montreal, QCS. Solymoss, S. Finkenbine, B. St. Jacques, L. Porco, M. Iskander3
      Red Deer Regional Hospital, Red Deer, ABJ. Singh, J. Glen2
      Grey Bruce Regional Health Centre, Owen Sound, ONJ. Ostrander, S. St. Croix2
      University Hospital, Edmonton, ABM. Mant, P. Donahue, M. MacDonald2
      St. Joseph’s General Hospital, Comox, BCR. Engman, B. Paulson2
      Centre Universitaire de Sante, Fleurimont, QCM. Lepine-Martin, L. Claprood, M. Grondin2
      St. Joseph’s Health Centre, London, ONW. Brien, B. Palmer, M. von Lewinski1
      Memorial University, St. John’s, NFL. Whitman, J. Watson1
      St. Michael’s Hospital, Toronto, ONJ. Teitel, R. Tanzini1
      Burnaby Hospital, Burnaby, BCT. Sparling, W. Leong, E Asirvatham, M. Bernard, L. Scoffield, L. Brown, D. Jay1
      Adjudicators:G. Elliott, J. George, G. Raskob
      Data Safety Monitoring:C. Carter, Chair.
      Acknowledgments:The authors thank Jeanne Sheldon, BA for her assistance in the preparation of the manuscript.
      Sponsorship:The study was supported by a Medical Research Council (now Canadian Institutes for Health Research) and industry grant (Leo Pharmaceutical Products Ltd. A/S of Denmark). Additional funding was provided by Pharmion and Dupont Pharmaceuticals. Leo provided study drug and drug safety monitoring. The funding organization(s) and sponsor(s) did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or approval of the manuscript.
      In the low-molecular-weight heparin group, no patients withdrew or were lost to follow-up at 3 months; 1 patient withdrew consent at 1 year. In the usual-care group, 1 withdrew at 3 months; no additional patients withdrew consent or were lost to follow-up at 1 year. Thus, 198 of the 200 patients (99%) randomized completed the 12-month protocol.

      Recurrent Venous Thromboembolism

      The outcomes for recurrent venous thromboembolism at 3 and 12 months are shown in Table 4 and Figure 2. Of the 200 patients, 100 received tinzaparin and 100 usual care. At 12 months, cancer patients receiving usual care had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P=.044; risk ratio=0.44; absolute difference −9.0%, 95% confidence interval [CI], −21.7% to −0.7%).
      Table 4Outcomes at 3 and 12 Months
      Tinzaparin n=100 n (%)Usual Care
      Unfractionated heparin and vitamin-K-antagonist therapy.
      n=100 n (%)
      Difference, (95% CI)P-Value
      New episodes of venous thromboembolism
       At 3 months
      At 3 months, 6 patients in the low-molecular-weight heparin group=1 pulmonary embolism (documented by: spiral CT); 5 recurrent deep-vein thrombosis (documented by: duplex ultrasonography). 10 patients in the heparin-warfarin group=3 pulmonary embolism (documented by: high-probability lung scan); 7 recurrent deep-vein thrombosis (documented by: venography, n=1; duplex ultrasonography, n=6).
      6 (6)10 (10)−4.0 (−12.0 to 4.1)
       At 12 months
      At 12 months, 7 patients in the low-molecular-weight heparin group=1 pulmonary embolism (documented by: lung scan); 6 deep-vein thrombosis (documented by: duplex ultrasonography). 16 patients in the heparin-warfarin group=8 pulmonary embolism (documented by: autopsy, n=3; high-probability lung scan, n=3; spiral CT scan, n=2); 8 deep-vein thrombosis (documented by: venography, n=1; duplex ultrasonography, n=7).
      Long-term vitamin-K-antagonist therapy was administered by the primary-care physician, if indicated; in patients such as those with recurrent deep-vein thrombosis at entry, or who, in the physician’s judgment, remained at risk. The physician either instituted or continued vitamin-K-antagonist therapy long term in 37 patients assigned to low-molecular-weight heparin (mean duration 215 days, median duration 272) and in 57 patients assigned to intravenous heparin-warfarin (mean duration 165 days, median duration 152).
      7 (7)16 (16)−9.0 (−21.7 to −0.7).044
      Bleeding Complications during 3 months treatment interval
      Patients were stratified as high risk for bleeding for the following reasons: surgery or trauma in past 14 days (25); history of peptic ulcer disease, gastrointestinal bleeding or genitourinary bleeding (37); platelet count ≤150,000 mm2 (41); stroke within the past 14 days (0); miscellaneous reasons for high risk of bleeding (23). Some patients had more than one risk factor: 78 patients had one risk factor only; 21 had 2 risk factors; and 2 patients had 3 risk factors. Stratified by risk of bleeding:All bleeding: High risk: (LMWH vs. usual-care) 18/49 (36.7) vs 15/52 (28.8); Low risk: 9/51 (17.7) vs 9/48 (18.8)Major bleeding: High risk: 7/49 (14.3) vs 6/52 (11.5); Low risk: 0/51 (0) vs 1/48 (2.1); P=.001Minor bleeding: High risk: 11/49 (22.5) vs 9/52 (17.3); Low risk: 9/51 (17.7) vs 8/48 (16.7)
       All27 (27)24 (24)−3.0 (−9.1 to 15.1)
       Major7 (7)7 (7)0.0 (−7.1 to 7.1)
       Minor20 (20)17 (17)3.0 (−7.8 to 13.8)
      Death
       At 3 months20 (20)19 (19)1.0 (−10.2 to 11.9)
       At 12 months47 (47)47 (47)0.0 (−14.6 to 13.2)
      Other findings
      Thrombocytopenia during 3 months treatment interval
      Thrombocytopenia: Low-molecular-weight heparin group: thrombocytopenia was associated with cancer or cancer therapy in 10 patients. Usual-care group: thrombocytopenia was associated with cancer or cancer therapy in 5 patients.
       Platelet count
       <100×109/L6 (6)4 (4)
       <150×109/L11 (11)7 (7)
      Bone fractures at 12 months3 (3)5 (5)
      low asterisk Unfractionated heparin and vitamin-K-antagonist therapy.
      At 3 months, 6 patients in the low-molecular-weight heparin group=1 pulmonary embolism (documented by: spiral CT); 5 recurrent deep-vein thrombosis (documented by: duplex ultrasonography). 10 patients in the heparin-warfarin group=3 pulmonary embolism (documented by: high-probability lung scan); 7 recurrent deep-vein thrombosis (documented by: venography, n=1; duplex ultrasonography, n=6).
      At 12 months, 7 patients in the low-molecular-weight heparin group=1 pulmonary embolism (documented by: lung scan); 6 deep-vein thrombosis (documented by: duplex ultrasonography). 16 patients in the heparin-warfarin group=8 pulmonary embolism (documented by: autopsy, n=3; high-probability lung scan, n=3; spiral CT scan, n=2); 8 deep-vein thrombosis (documented by: venography, n=1; duplex ultrasonography, n=7).
      § Long-term vitamin-K-antagonist therapy was administered by the primary-care physician, if indicated; in patients such as those with recurrent deep-vein thrombosis at entry, or who, in the physician’s judgment, remained at risk. The physician either instituted or continued vitamin-K-antagonist therapy long term in 37 patients assigned to low-molecular-weight heparin (mean duration 215 days, median duration 272) and in 57 patients assigned to intravenous heparin-warfarin (mean duration 165 days, median duration 152).
      Patients were stratified as high risk for bleeding for the following reasons: surgery or trauma in past 14 days (25); history of peptic ulcer disease, gastrointestinal bleeding or genitourinary bleeding (37); platelet count ≤150,000 mm2 (41); stroke within the past 14 days (0); miscellaneous reasons for high risk of bleeding (23). Some patients had more than one risk factor: 78 patients had one risk factor only; 21 had 2 risk factors; and 2 patients had 3 risk factors.Stratified by risk of bleeding:
      • All bleeding: High risk: (LMWH vs. usual-care) 18/49 (36.7) vs 15/52 (28.8); Low risk: 9/51 (17.7) vs 9/48 (18.8)
      • Major bleeding: High risk: 7/49 (14.3) vs 6/52 (11.5); Low risk: 0/51 (0) vs 1/48 (2.1); P=.001
      • Minor bleeding: High risk: 11/49 (22.5) vs 9/52 (17.3); Low risk: 9/51 (17.7) vs 8/48 (16.7)
      Thrombocytopenia: Low-molecular-weight heparin group: thrombocytopenia was associated with cancer or cancer therapy in 10 patients. Usual-care group: thrombocytopenia was associated with cancer or cancer therapy in 5 patients.
      Figure thumbnail gr2
      Figure 2Time to event analysis for patients who had recurrent venous thromboembolism.
      Among patients with recurrent venous thromboembolism in the usual-care vitamin-K-antagonist group, 1 patient had an INR of less than 2 at the time of the event.

      Bleeding Complications During the 3-month Study Treatment Interval

      The bleeding complications are shown in Table 4. Bleeding occurred in 27 of 100 patients (27%) receiving low-molecular-weight heparin and 24 of 100 (24%) receiving usual care (absolute difference −3%; 95% CI, −9.1 to 15.1).
      Among patients with major bleeding in the usual-care vitamin-K-antagonist group, 2 patients had an elevated INR (4.0 or greater on the day of bleeding); among patients with minor bleeding, 2 patients had an elevated INR (4.0 or greater).

      Risk of bleeding

      Patients at low risk for bleeding at the time of randomization suffered major bleeding infrequently in both treatment groups compared with the frequency of major bleeding in patients at high risk for bleeding at the time of randomization (P=.001) (Table 4).

      Deaths

      Mortality findings and causes of death are shown in Table 4, Table 5, and Figure 3.
      Table 5Causes of Death in the 2 Treatment Groups
      Cause of DeathLong-Term Low-Molecular-Weight HeparinUsual-Care—Vitamin-K-Antagonist Therapy
      Deaths (n=47)Days After Start of TherapyDeaths (n=47)Days After Start of Therapy
      Abrupt
      Patients were categorized according to whether they died abruptly or insidiously. Patients who died insidiously had progressive declines in their health, and their immediate death was anticipated, whereas most patients who died abruptly did so without warning.
      (n=2)(n=7)
       Pulmonary embolism (autopsy)03(Days 14, 87, 191)
       Possible pulmonary embolism2(Days 1, 6)4(Days 2, 23, 24, 279)
      Insidious
      Patients were categorized according to whether they died abruptly or insidiously. Patients who died insidiously had progressive declines in their health, and their immediate death was anticipated, whereas most patients who died abruptly did so without warning.
      (n=45)(n=40)
       Bleeding complications
        Intracranial hemorrhage1(Day 41)1(Day 114)
        Gastrointestinal bleeding1(Day 17)2(Days 81, 155)
      low asterisk Patients were categorized according to whether they died abruptly or insidiously. Patients who died insidiously had progressive declines in their health, and their immediate death was anticipated, whereas most patients who died abruptly did so without warning.
      Figure thumbnail gr3
      Figure 3Time to event analysis for patients who died.
      At 1 year, 47 patients (47%) in the low-molecular-weight heparin group and 47 patients (47%) in the unfractionated heparin-warfarin group had died (absolute difference 0.0%; 95% CI, −14.6 to 13.2). In the low-molecular-weight heparin group, 2 patients (2%) died abruptly compared with 7 patients (7%) in the unfractionated heparin-warfarin group; absolute difference −5%; 95% CI, −10.7% to 0.70%. Death was insidious due to progressive cancer for most patients who died in either group; for the low-molecular-weight heparin group, 45 of 47 (95.7%) of the deaths were insidious compared with 40 of 47 patients (85.1%) receiving usual-care vitamin-K-antagonist therapy.

      Other Findings

      The outcomes for thrombocytopenia and bone fractures are shown in Table 4.
      Occasional patients were diagnosed with new cancer during the study interval after randomization; inclusion of these patients, as well as analysis of patients with current cancer (present or actively undergoing treatment) did not affect our analysis.
      Our findings with respect to recurrent venous thromboembolism and hemorrhagic complications and the relationship of these findings to those reported by the other 3 trials cited to date is shown in Figure 4.
      Figure thumbnail gr4
      Figure 4Randomized clinical trials of long-term low-molecular-weight heparin therapy combined with vitamin-k-antagonist therapy in cancer patients with venous thromboembolism.
      Figure 4 shows the cited randomized clinical trials of long-term low-molecular-weight heparin therapy compared with vitamin-K-antagonist therapy in patients with venous thromboembolism. The summary treatment effect for recurrent venous thromboembolism favored long-term low-molecular-weight heparin therapy. Our study adds to the literature, as is shown by the displayed weights shown in Figure 4.

      Discussion

      Long-term therapeutic dose low-molecular-weight heparin, when compared with usual-care vitamin-K-antagonist therapy for cancer patients with acute proximal-vein thrombosis, offered improved efficacy against recurrent venous thromboembolism. The outcome measures were assessed during study therapy and at 1 year, because there is evidence that the impact of study therapy on outcome persists after therapy is discontinued.
      • Klerk C.P.
      • Smorenburg S.M.
      • Otten H.M.
      • et al.
      The effect of low molecular weight heparin on survival in patients with advanced malignancy.
      • Hull R.D.
      • Raskob G.E.
      • Brant R.F.
      • Pineo G.F.
      • Valentine K.A.
      The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy The emerging theme of delayed recurrence.
      Our results are consistent with those of a benchmark trial evaluating long-term low-molecular-weight heparin therapy in cancer patients with venous thromboembolism,
      • Lee A.Y.Y.
      • Levine M.N.
      • Baker R.I.
      • et al.
      CLOT Investigators
      Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
      which showed improved efficacy against venous thromboembolism without increased harm due to increased bleeding.
      The response to long-term vitamin-K-antagonist therapy against recurrent venous thromboembolism appears to differ among venous thromboembolism patients with or without cancer. The use of vitamin-K-antagonist therapy is associated with a similar efficacy against recurrent venous thromboembolism when compared with long-term low-molecular-weight heparin therapy in a broad spectrum of patients.
      • Hull R.D.
      • Pineo G.F.
      • Brant R.F.
      LITE Trial Investigators
      Self-managed long-term low-molecular-weight compared with usual-care anticoaguation for patients with proximal venous thrombosis: harm associated with bleeding.
      The consistent findings for improved efficacy against recurrent thromboembolism for long-term low-molecular-weight heparin (Figure 4) may reflect the fact that cancer patients are less responsive to vitamin-K-antagonist therapy than noncancer patients.
      It is apparent that cancer per se is, in its own right, a risk factor for bleeding.
      • Meyer G.
      • Marjanovic Z.
      • Valcke J.
      • et al.
      Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
      In addition, in our study many patients had additional factors at the time of randomization placing them at even greater risk for bleeding. The frequency of hemorrhagic complications, including major bleeding, observed in our trial is consistent with those reported by other investigators
      • Meyer G.
      • Marjanovic Z.
      • Valcke J.
      • et al.
      Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
      • Lee A.Y.Y.
      • Levine M.N.
      • Baker R.I.
      • et al.
      CLOT Investigators
      Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
      for such patients. Major bleeding was largely confined to those patients at high risk for bleeding; this also was true for patients receiving vitamin-K-antagonist therapy (INR control was successful). Indeed, our risk stratification for bleeding is of practical value, providing a prognostic predictor for major bleeding. Major bleeding occurred infrequently in both treatment groups for patients who were assigned a low risk for bleeding at the time of randomization.
      Our mortality findings are consistent with those reported by Lee and colleagues,
      • Lee A.Y.Y.
      • Levine M.N.
      • Baker R.I.
      • et al.
      CLOT Investigators
      Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
      but our findings should be interpreted with caution due to the modest sample size. The lack of a mortality advantage does not necessarily reflect a negative finding for the cancer field at large, as a high proportion of our patients had advanced metastatic cancer. Such patients have been shown to be nonresponsive, in terms of survival, to antithrombotic therapy.
      • Lee A.Y.Y.
      • Rickles F.R.
      • Julian J.A.
      • et al.
      Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism.
      The survival benefit appears to be limited to patients with solid tumors without metastatic disease.
      • Lee A.Y.Y.
      • Rickles F.R.
      • Julian J.A.
      • et al.
      Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism.
      Thrombocytopenia was infrequent in both treatment groups, and a common association was cancer therapy. Bone fractures potentially due to osteoporosis occurred infrequently in both treatment groups.
      The open-label design could be a potential source of bias in our trial. A double-blind design was not feasible due to the geographic location of many of the centers and the necessarily large number of primary care physicians providing anticoagulant monitoring. It is unlikely that a reporting bias explains the observed differences for the following reasons. Our protocol identified cancer patients at the onset of the study and these patients were randomized separately to test an a priori hypothesis; our cancer findings are not based on subgroup hypothesis-generating analysis or on retrospective analysis. Clinical characteristics of patients on entry were similar among groups. To avoid a selection bias, care was taken to ensure that participating physicians adhered to the protocol. To minimize reporting and diagnostic bias, we contacted patients at regular intervals using standardized follow-up assessments. We used objective testing to evaluate suspected events, and all suspected outcomes were evaluated by a central committee whose members were unaware of the patients’ treatment assignments. Internationally recognized objective documentation of venous thromboembolism and bleeding was carried out. Care was taken throughout the study that anticoagulant monitoring ensured adequate intravenous heparin using a heparin protocol and oral warfarin therapy. Also, an important bias related to treatment management is unlikely because the INR control achieved was similar to that reported in other studies.
      • Hull R.D.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Kearon C.
      • Ginsberg J.S.
      • Kovacs M.
      • et al.
      Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.
      • Hull R.
      • Delmore T.
      • Genton E.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      • Hull R.
      • Delmore T.
      • Carter C.
      • et al.
      Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.
      It is likely that our results are relevant to clinical practice and are not unduly influenced by bias.
      Patients assigned to vitamin-K-antagonist therapy received discretionary warfarin therapy more frequently (Table 4) after cessation of the 3-month interval of study therapy; a bias against the long-term low-molecular-weight heparin group, favoring usual care to patients with a potentially lower risk of recurrent venous thromboembolism. For this reason, the observed benefit of long-term low-molecular-weight heparin against recurrent venous thromboembolism may have been underestimated in our study. A rebound in the frequency of recurrent venous thromboembolism did not occur after cessation of low-molecular-weight heparin therapy (Figure 2).
      Long-term low-molecular-weight heparin offers an alternative strategy to usual care with vitamin-K-antagonist therapy without the need for anticoagulant monitoring. The improved efficacy in cancer patients is strongly supported by the literature and offers the hope of improved quality of life, particularly in patients without additional risk factors for bleeding.

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