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

The American Journal of Medicine (2006) 119, 1062-1072

CLINICAL RESEARCH STUDY

Long-term Low-Molecular-Weight Heparin versus Usual Care in Proximal-Vein Thrombosis Patients with Cancer Russell D. Hull, MBBS, MSc,a Graham F. Pineo, MD,a Rollin F. Brant, PhD,b Andrew F. Mah, BSc,a Natasha Burke, BSc,a Richard Dear, MD,a Turnly Wong, MD,c Roy Cook, MD,a Susan Solymoss, MD,d Man-Chiu Poon, MD, MSc,a Gary Raskob, PhD,e for the LITE Trial Investigators a

University of Calgary, Calgary, Alta, Canada; bUniversity of British Columbia, Vancouver, BC, Canada; cUniversity of Manitoba, Winnipeg, Man, Canada; dMcGill University, Montreal, Que, Canada; eUniversity of Oklahoma Health Sciences Center, Oklahoma City, Okla. 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. © 2006 Elsevier Inc. All rights reserved. KEYWORDS: Deep-vein thrombosis; Cancer; Anticoagulation; Long-term low-molecular weight heparin

The classic long-term treatment for deep-vein thrombosis is vitamin-K-antagonist therapy overlapped with initial heparin or low-molecular-weight heparin therapy.1 There is a need for effective and safe alternate therapy to vitamin-Kantagonists in cancer patients with venous thrombosis. The aggregate data2-7 for patients receiving vitamin-K-antagoRequests for reprints should be addressed to Russell D. Hull, MBBS, MSc, Thrombosis Research Unit, 601 South Tower, Foothills Hospital, 1403 29th Street N.W., Calgary, AB T2N 2T9, Canada. E-mail address: [email protected]

0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.02.022

nist therapy show that recurrent venous thromboembolism occurs more frequently in cancer patients than in 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.8,9 For vitamin-K-antagonist therapy,1,10-12 the impor-

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tity. Accordingly, we report our unpublished data concerntance of maintaining a therapeutic international normalized ing our cancer trial, which assessed the benefits and potenratio (INR) (2.0-3.0) is well documented; this necessitates tial harms of long-term low-molecular-weight heparin frequent INR monitoring. therapy compared with usual-care vitamin-K-antagonist Renewed interest in the interaction of antithrombotic regitherapy in cancer patients with proximal venous thrombosis. mens on the survival of cancer patients resulted from the findings of randomized trials evaluating low-molecular-weight heparin treatment of deep-vein thrombosis, METHODS CLINICAL SIGNIFICANCE which revealed a reduction in canStudy Design cer mortality.13 Subsequently, this ● Long-term low-molecular-weight hepaWe used a multicenter, open-label revived interest in antithrombotic rin offers an alternative strategy to virandomized design and compared therapy in cancer patients has been tamin-K-antagonist therapy without relong-term subcutaneous low-molecreinforced by the outcomes of sevquiring anticoagulant monitoring. ular-weight heparin against usualeral trials evaluating long-term lowcare initial intravenous heparin and molecular-weight heparin therapy. ● Cancer is a risk factor for bleeding. long-term oral warfarin sodium for Vitamin-K-antagonist therapy was ● Long-term low-molecular-weight hepaa therapy duration of 3 months in associated with an excess of major rin offers the hope of improved quality cancer patients with proximal-vein bleeding compared with long-term of life, particularly in patients without thrombosis. An evaluation of palow-molecular-weight heparin in tients with cancer and proximal additional risk factors for bleeding. the secondary prevention of venous deep-vein thrombosis was planned thromboembolism in patients with ● The improved efficacy against recurrent prospectively as cancer patients cancer and venous thromboembothromboembolism for long-term low-mowere randomized separately within lism; bleeding was in part associlecular-weight heparin may reflect the the Main-LITE population of paated with supratherapeutic INR valfact that cancer patients are less respontients. Patients with cancer and ues.14 Subsequently, a benchmark sive to vitamin-K-antagonist therapy deep-vein thrombosis were identistudy showed that long-term lowfied a priori and randomized as a than noncancer patients. molecular-weight heparin was more separate population within the overeffective than vitamin-K-antagonist all Main-LITE population; the findtreatment for preventing recurrent ings for cancer patients only have venous thromboembolism in cancer 15 not been reported previously. patients with venous thromboembolism. Most recently, a Our cancer study is one of a set of studies using a brief course of subcutaneous low-molecular-weight heparin randomized design with objective assessment of outcome. was shown to favorably influence survival in patients with 16 The set of studies was performed under the auspices of the advanced malignancy. Long-term Innovations in TreatmEnt program (LITE) There is a clear need for ongoing study to further our funded by the Canadian Institutes of Health Research, forunderstanding of the role of low-molecular-weight heparin merly Medical Research Council, and industry. The inditherapy in cancer patients with venous thromboembolism. vidual studies included Main-LITE cancer, Main-LITE The difficulty of successfully completing clinical trials evalbroad spectrum of patients (which is reported separately), uating antithrombotic therapy in patients with cancer and and Home-LITE, a home treatment study evaluating quality deep-vein thrombosis is illustrated by the fact that, of the 3 of life and the postphlebitic syndrome, which is reported trials (enrolling 146 patients, 672 patients and 88 patients, 14,15,17 separately. The Main-LITE studies differed in their design respectively) reported to date, 2 trials had to close 14,17 from the Home-LITE study with regards to the treatment early due to poor enrollment. groups, and are entirely separate studies. For the Main-LITE We had the opportunity to address the effectiveness and studies, a consecutive population of hospitalized patients safety of differing long-term antithrombotic therapies in was entered and the comparison group was given intravepatients with cancer suffering proximal-vein thrombosis unnous heparin and vitamin-K-antagonist therapy, whereas der the auspices of our “long-term innovations in treatment patients randomized to Home-LITE received initial lowprogram.” We performed a multicenter, randomized openmolecular-weight heparin therapy and either continued lowlabel clinical trial to evaluate the effectiveness and safety of molecular-weight heparin therapy or crossed over to vitathe low-molecular-weight heparin, tinzaparin, versus usual min-K-antagonist therapy for 3 months. The requirement heparin care and vitamin-K-antagonist therapy in preventfor intravenous heparin in the comparison group mandated ing recurrent venous thromboembolism in a broad spectrum that patients participating in Main-LITE be hospitalized of patients; these findings are reported elsewhere.18 A priori, should they be randomized to receive intravenous heparin. cancer patients were randomized as a separate category with Cancer patients with proximal venous thrombosis who were the intent to evaluate and report the findings for cancer patients with proximal venous thrombosis as a distinct eneligible for home treatment could not be randomized to

1064 Table 1

The American Journal of Medicine, Vol 119, No 12, December 2006 Patient Eligibility and Allocation

Patients were eligible if they had none of the following:

Eligible patients were excluded if they: Before randomization, cancer patients were stratified according to: With regard to the risk of bleeding, patients were stratified into groups according to:

Randomization

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. 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 ⱖ250 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 followup. 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). Study center; whether primary or recurrent venous thrombosis and high or low risk for bleeding.22,23 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. A computer-derived randomized treatment schedule was used; within each stratum, the randomized schedule was balanced in blocks of 2 and 4.

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) statement19,20 and the more recent updating of the agreement “Better reporting of harms in randomized trials: an extension of the CONSORT statement.”21

Patients Patient eligibility and allocation are shown in Table 1.

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 contin-

uous intravenous infusion. The heparin infusion was administered according to 1 of 2 validated protocols for ensuring adequate heparin therapy.23,24 The heparin infusion was adjusted according to the results of laboratory monitoring using the activated partial thromboplastin time (APTT) described elsewhere.25 Warfarin sodium was commenced on day 1 at 5-10 mg then adjusted daily to maintain the INR between 2.0 and 3.0,1,11 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

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2212 patients assessed for eligibility

1475 patients were excluded: 575 received heparin, low-molecularweight heparin or oral anticoagulant therapy for more than 2 days 900 were unable or declined to give written consent

737 randomized to Main LITE Broad-spectrum

200 randomized to Main LITE Cancer

100 Assigned to receive low-molecular-weight heparin

100 Assigned to receive usual-care with intravenous heparin and warfarin

1 Withdrew consent at 12 months

1 Withdrew consent at 3 months

100 Included in Analysis

100 Included in Analysis

Figure 1

Participant flow chart.

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,8,9,26,27 or by the presence of a constant intraluminal filling defect in the deep veins that was not present on the baseline venogram.28,29 For patients with clinically suspected pulmonary embolism, the diagnosis was confirmed by: high probability lung scan findings;30,31 a nondiagnostic lung scan with documented new deep-vein thrombosis;30 spiral computed tomography32 showing thrombus in the central pulmonary arteries; pulmonary angiography30,33 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.10,34-37 Bleeding was defined as minor if it was clinically overt, but did not meet other criteria for major bleeding.10,34-37 These criteria were used successfully in previous studies.10,34-37 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 in-

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Table 2 Clinical Characteristics of Cancer Patients with Proximal-Vein Thrombosis Treated with Long-Term Low-Molecular-Weight Heparin or Oral Anticoagulant Therapy No. of Patients (%) Characteristic

Low-molecular-weight heparin n ⫽ 100

Intravenous heparin/warfarin n ⫽ 100

Age (years) ⬍60, ⱖ60 Sex (M, F) Status at entry Symptomatic deep-vein thrombosis Symptoms of pulmonary embolism Previous venous thromboembolism Factor V Leiden gene mutation Clinical measures at entry Surgery or trauma in past 6 months Coronary heart disease Diabetes Chronic obstructive pulmonary disease Peripheral vascular disease Congestive heart disease Leg paralysis Liver disease High risk of bleeding Cancer Solid tumor Nonmetastatic Metastatic Hematologic

38, 62 52, 48

24, 76 50, 50

92 21 18 10

(92) (21) (18) (10)

94 21 20 8

(94) (21) (20) (8)

53 16 15 8 9 8 7 5 49

(53) (16) (15) (8) (9) (8) (7) (5) (49)

49 29 14 10 3 8 3 6 52

(49) (29) (14) (10) (3) (8) (3) (6) (52)

43 47 10

volved in the patient’s care, and disputes were resolved independently by a third. Members of the committee were unaware of the patients’ treatment assignments.

51 36 13

ordinated 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.

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.38 Proportional hazards test diagnostics were based on weighted residuals.38 Confidence intervals were derived from standard errors calculated from Greenwood’s formula. The metaanalysis was conducted following a fixed-effects approach based on the Mantel-Haenszel method as implemented in the metan procedure39 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 co-

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. 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

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Participating Sites No. of Patients Enrolled

Site Name, Location

Principal Investigator(s), Coordinator(s)

Foothills Hospital, Calgary, AB St. Boniface General Hospital, Winnipeg, MB Peter Lougheed Centre, Calgary, AB Montreal General Hospital, Montreal, QC Rockyview General Hospital, Calgary, AB Hotel Dieu de Hospital, Montreal, QC Ottawa General Hospital, Ottawa, ON Jewish General Hospital, Montreal, QC Royal Alexandra Hospital, Edmonton, AB Kelowna General Hospital, Kelowna, BC University Hospital, London, ON St. Paul’s Hospital, Vancouver, BC

R. Hull, D. Kimmett, K. Morrison, H. Hair, B. Sham; 54 T. Wong, S. Erickson-Nesmith; 24 R. Dear, T. Mooers, C. Dielissen, J. Gardner, D. Mckeage; 23 S. Solymoss, S. Finkenbine, B. St. Jacques 20 R. Cook, D. Burnand, J. Dear, J. Davis, M. McDonald 13 P. Nguyen, B. LeCours, S. Roy; 9 M. Rodger, A.M. Clement, B. Kearns 8 S. Kahn, C. Strulovitch 7 C. Harley, E. Konopad, P. Nicholls, N. Whalen, V. Troncoso 6 J. Sutherland, M. Mantle, S. Shori 6 M. Cruickshank (deceased), M. von Lewinski 5 L. Vickars, L. Bachop, L. Wadup, D. Heinrich, M. Rusak, D. 5 Michaels, J. Poirier, S. Taylor H. Lee (deceased), S. McLean, K. Barban, J. Sloss 3 S. Solymoss, S. Finkenbine, B. St. Jacques, L. Porco, M. 3 Iskander J. Singh, J. Glen 2 J. Ostrander, S. St. Croix 2 M. Mant, P. Donahue, M. MacDonald 2 R. Engman, B. Paulson 2 M. Lepine-Martin, L. Claprood, M. Grondin 2 W. Brien, B. Palmer, M. von Lewinski 1 L. Whitman, J. Watson 1 J. Teitel, R. Tanzini 1 T. Sparling, W. Leong, E Asirvatham, M. Bernard, L. 1 Scoffield, L. Brown, D. Jay G. Elliott, J. George, G. Raskob C. Carter, Chair. The authors thank Jeanne Sheldon, BA for her assistance in the preparation of the manuscript. 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.

Group Health Centre, Sault Ste. Marie, ON St. Mary’s Hospital Centre, Montreal, QC Red Deer Regional Hospital, Red Deer, AB Grey Bruce Regional Health Centre, Owen Sound, ON University Hospital, Edmonton, AB St. Joseph’s General Hospital, Comox, BC Centre Universitaire de Sante, Fleurimont, QC St. Joseph’s Health Centre, London, ON Memorial University, St. John’s, NF St. Michael’s Hospital, Toronto, ON Burnaby Hospital, Burnaby, BC Adjudicators: Data Safety Monitoring: Acknowledgments: Sponsorship:

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-molecularweight heparin (P ⫽ .044; risk ratio ⫽ 0.44; absolute difference ⫺9.0%, 95% confidence interval [CI], ⫺21.7% to ⫺0.7%). 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.

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).

Bleeding Complications During the 3-month Study Treatment Interval

Deaths

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).

Mortality findings and causes of death are shown in Tables 4 and 5, and Figure 3. At 1 year, 47 patients (47%) in the low-molecular-weight heparin group and 47 patients (47%) in the unfractionated

1068 Table 4

The American Journal of Medicine, Vol 119, No 12, December 2006 Outcomes at 3 and 12 Months Tinzaparin n ⫽ 100 n (%)

New episodes of venous thromboembolism At 3 months† At 12 months‡§ Bleeding Complications during 3 months treatment interval储 All Major Minor Death At 3 months At 12 months Other findings Thrombocytopenia during 3 months treatment interval¶ Platelet count ⬍100 ⫻ 109/L ⬍150 ⫻ 109/L Bone fractures at 12 months

Usual Care* n ⫽ 100 n (%)

Difference, (95% CI)

P-Value

6 (6) 7 (7)

10 (10) 16 (16)

⫺4.0 (⫺12.0 to 4.1) ⫺9.0 (⫺21.7 to ⫺0.7)

.044

27 (27) 7 (7) 20 (20)

24 (24) 7 (7) 17 (17)

⫺3.0 (⫺9.1 to 15.1) 0.0 (⫺7.1 to 7.1) 3.0 (⫺7.8 to 13.8)

20 (20) 47 (47)

19 (19) 47 (47)

6 (6) 11 (11) 3 (3)

4 (4) 7 (7) 5 (5)

1.0 (⫺10.2 to 11.9) 0.0 (⫺14.6 to 13.2)

*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: highprobability 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). 储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 ⱕ150,000 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.

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-molecularweight 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.

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 4 shows the cited randomized clinical trials of longterm 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-molecularweight heparin therapy. Our study adds to the literature, as is shown by the displayed weights shown in Figure 4.

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.

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

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Long-Term LMWH in Proximal-Vein Thrombosis Patients

Figure 2

Time to event analysis for patients who had recurrent venous thromboembolism.

that the impact of study therapy on outcome persists after therapy is discontinued.16,40 Our results are consistent with those of a benchmark trial evaluating long-term low-molecular-weight heparin therapy in cancer patients with venous thromboembolism,15 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-molecu-

Table 5

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lar-weight heparin therapy in a broad spectrum of patients.18 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.14 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 investigators14,15 for such patients. Major bleeding was

Causes of Death in the 2 Treatment Groups Long-Term Low-Molecular-Weight Heparin

Cause of Death

Deaths (n ⫽ 47)

Abrupt* Pulmonary embolism (autopsy) Possible pulmonary embolism

(n⫽2) 0 2

Insidious* Bleeding complications Intracranial hemorrhage Gastrointestinal bleeding

(n ⫽ 45) 1 1

Usual-Care—Vitamin-K-Antagonist Therapy

Days After Start of Therapy

Deaths (n ⫽ 47)

(Days 1, 6)

(n ⫽ 7) 3 4 (n ⫽ 40)

(Day 41) (Day 17)

1 2

Days After Start of Therapy (Days 14, 87, 191) (Days 2, 23, 24, 279) (Day 114) (Days 81, 155)

*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.

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Figure 3

Time to event analysis for patients who died.

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,15 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.41 The survival benefit appears to be limited to patients with solid tumors without metastatic disease.41 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.10,12,34,36 It is likely that our results are relevant to clinical practice and are not unduly influenced by bias.

Hull et al

Long-Term LMWH in Proximal-Vein Thrombosis Patients

1071

Patients with Recurrent Venous Thromboembo Study yr (ref)

Meyer,

Design

14

2002

Deitcher,

17

2003

Patient population

Multicentre

Venous

Open-label

Thromboembolism Cancer

LMWH Regimen

T

*

Multicentre

Venous

T&M

Open-label

Thromboembolism

T

†

LMWH

Vitamin-KAntagonists

2/71 (2.8%)

3/75 (4.0%)

2/28 (7.1%)

3/29 (10.3%)

lism

Risk Ratio (95% CI)

Patients with Hemorrhagic Complications

% Weight

LMWH

Vitamin-KAntagonists

3.8

5/71 (7.0%)

12/75 (16.0%)

0.44 (0.16, 1.19)

11.8

47/336 (14.0%)

63/336 (18.8%)

0.75 (0.53, 1.05)

63.8

0.70 (0.12, 4.09)

Risk Ratio (95% CI)

% Weight

5.3

1/31 (3.2%)

0.49 (0.11, 2.29)

Cancer 15

Lee, 2003

Multicentre Open-label

Hull, (current article)

Multicentre Proximal Vein Thrombosis Open-label Broad-spectrum

Venous Thromboembolism Cancer

T

†

27/336 (8.0%)

53/336 (15.8%)

* ‡

6/100 (6.0%)

10/100 (10.0%)

§

7/100 (7.0%)

16/100 (16.0%)

T&M

0.51 (0.33, 0.79)

69.8

27/100 (27.0%) 0.44 (0.19, 1.02)

24/100 (24.0%)

21.1

1.12 (0.70, 1.81)

0.50 (0.35, 0.72)

0.10 Results Favor LMWH

1.00

0.80 (0.61, 1.05)

0.10

10.0 Results Favor Vitamin-K-Antagonists

Legend: ‡ § † 3 months; 12 months. * treatment duration 3 months; treatment duration 6 months; Follow-up: LMWH=low-molecular-weight heparin; CI=confi dence interval; LMWH regimen: T=treatm ent dose; P=prophylactic dose; M=reduced main

24.3

Results Favor LMWH

1.00

10.0 Results Favor Vitamin-K-Antagonists

tenance dose.

Deitcher: Low-molecular-weight heparin treatm ent groups pooled; bleeding proportions not reported.

Figure 4 Randomized clinical trials of long-term low-molecular-weight heparin therapy combined with vitamin-k-antagonist therapy in cancer patients with venous thromboembolism.

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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5. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160:769-774. 6. Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost. 2000;84:805-810. 7. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999;78:285-291. 8. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecularweight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334:677-681. 9. Koopman MMW, 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. N Engl J Med. 1996;334:682-687. 10. Hull RD, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med. 1982;307:1676-1681. 11. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8S-21S. 12. Kearon C, Ginsberg JS, Kovacs M, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639. 13. Green D, Hull RD, Brant RF, Pineo GF. Lower mortality in cancer patients treated with low-molecular-weight heparin versus standard heparin. Lancet. 1992;339:1476. 14. 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. Arch Intern Med. 2002;162:1729-1735.

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28. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 1972;104:134-144. 29. Hull RD, Carter CJ, Jay RM, et al. The diagnosis of acute, recurrent, deep-vein thrombosis: a diagnostic challenge. Circulation. 1983;67: 901-906. 30. Hull RD, Hirsh J, Carter CJ, et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med. 1983; 98:891-899. 31. The PIOPED investigators. Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;263:2753-2759. 32. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review. Ann Intern Med. 2000;132:227-232. 33. Dalen JE, Brooks HL, Johnson LW, et al. Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients. Am Heart J. 1971;81:175-185. 34. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-858. 35. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecularweight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975982. 36. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med. 1982;306:189-194. 37. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:11091114. 38. Kalbfleish JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY: John Wiley; 1980:70. 39. Bradburn MJ, Deeks JJ, Altman DG. Metan—an alternative metaanalysis command. Stata Tech Bull. 1998;44:4-15. 40. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. The emerging theme of delayed recurrence. Arch Intern Med. 1997;157:2371–2321. 41. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129.