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The American Journal of Medicine (2007) 120, 72-82

LINICAL RESEARCH STUDY

elf-Managed Long-Term Low-Molecular-Weight Heparinherapy: The Balance of Benefits and Harms

ussell D. Hull, MBBS, MSc,a Graham F. Pineo, MD,a Rollin F. Brant, PhD,b Andrew F. Mah, BSc,a

atasha Burke, BSc,a Richard Dear, MD,a Turnly Wong, MD,c Roy Cook, MD,a Susan Solymoss, MD,d

an-Chiu Poon, MD, MSc,a Gary Raskob, PhD,e for the LITE Trial InvestigatorsUniversity of Calgary, Calgary, AB, Canada; bUniversity of British Columbia, Vancouver, BC, Canada; cUniversity of Manitoba, Winnipeg,

AJM Theme Issue: Cardiology

N, Canada; dM e kla.

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E-mail address

002-9343/$ -see foi:10.1016/j.amjm

cGill University, Montreal, PQ, Canada; University of Oklahoma Health Sciences Center, Oklahoma City, O

ABSTRACT

URPOSE: A substantial clinical need exists for an alternate to vitamin K antagonists for treating deepein thrombosis in many patients. Long-term low-molecular-weight heparin (LMWH), body-weightdjusted, avoids anticoagulant monitoring and may be associated with less bleeding. We evaluated theffectiveness and safety of long-term LMWH compared with vitamin K antagonist therapy in a broadpectrum of patients with proximal vein thrombosis.ETHODS: We performed a multicenter, randomized, open-label clinical trial using objective outcomeeasures comparing therapy for 3 months. Outcomes were assessed at 3 and 12 months.ESULTS: Of 737 patients, 18 of 369 receiving tinzaparin (4.9%) had recurrent venous thromboembolism atmonths compared with 21 of 368 (5.7%) receiving usual care (absolute difference, �0.8%, 95% confidence

nterval �4.1-2.4). Hemorrhagic complications occurred less frequently in the LMWH group largely becausef less minor bleeding: 48 of 369 patients (13.0%) versus 73 of 368 patients (19.8%) receiving usual-carenticoagulation (absolute difference �6.8%; P � .011; risk ratio � 0.66). New major bleeding events ceasedarly (by day 23, P � .034) for patients receiving LMWH but persisted throughout the study treatment intervalor patients receiving vitamin K antagonist therapy. No mortality advantage was shown for LMWH.ONCLUSION: Our study shows that LMWH is similar in effectiveness to the usual-care vitamin Kntagonist treatment for preventing recurrent venous thromboembolism in a broad spectrum of patients. Itauses less harm and enhances the clinicians’ therapeutic options for patients with proximal deep veinhrombosis. Our findings reported here suggest the possibility of a broader role for long-term LMWH inelected patients. © 2007 Elsevier Inc. All rights reserved.

KEYWORDS: Long-term low-molecular-weight heparin; Broad spectrum of patients; Usual-care anticoagulation;Vitamin K antagonist therapy

Tvoubtwsira

The study was supported by a Medical Research Council (now Canadiannstitutes for Health Research) and Industry grant (Leo Pharmaceutical Prod-cts Ltd A/S of Denmark). Additional funding was provided by Pharmion andupont Pharmaceuticals. Leo provided study drug and drug safety monitoring.he funding organization(s) and sponsor(s) did not have a role in the designnd conduct of the study; collection, management, analysis, and interpretationf the data; and preparation or approval of the article.

Study design table and participating sites appendix available online.Requests for reprints should be addressed to Russell D. Hull, MBBS,

Sc, Thrombosis Research Unit, 601 South Tower, Foothills Hospital,403 29th Street NW, Calgary, Alberta, Canada T2N 2T9.

t: Jeanne.Sheldon@calgaryhealthregion.ca.

ront matter © 2007 Elsevier Inc. All rights reserved.ed.2006.03.030

he classic long-term treatment for deep vein thrombosis isitamin K antagonist therapy overlapped with initial heparinr low-molecular-weight heparin (LMWH) therapy.1 These of accurate objective tests to detect venous thromboem-olism has led to randomized trials evaluating short-termherapy or long-term anticoagulants for venous thrombosis,hich have advanced our therapeutic understanding. Initial

hort-term LMWH therapy is effective and preferred overntravenous heparin because anticoagulant monitoring is notequired, facilitating outpatient therapy.2,3 For vitamin Kntagonist therapy,1,4-6 the importance of maintaining a

herapeutic international normalized ratio (INR) (2.0-3.0)

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73Hull et al Long-term LMWH Therapy

s well documented; this necessitates frequent INRonitoring.There is a need for an effective and safe alternate therapy

o vitamin K antagonists in a broad spectrum of patientsith venous thrombosis. It is possible that long-termMWH, although administeredubcutaneously, is a viable optionn such patients. A key concernith long-term vitamin K antago-ists is harm resulting from hem-rrhagic complications.7,8 The ag-regate data,7,9-15 as reported byhe “Cochrane Database of Sys-ematic Reviews,” identify thatong-term LMWH may cause lessleeding, but further study is re-uired in the individual trial set-ing to determine whether safety isndeed improved. The Cochraneuthors also report uncertainty onhe efficacy of long-term LMWHor preventing recurrent venoushromboembolism, but the authors note that the prophylac-ic LMWH doses used in some of these trials may haveesulted in inadequate therapy. Subsequently, long-termMWH was shown to be more effective than vitamin Kntagonists for preventing recurrent venous thromboembo-ism in patients with cancer and venous thromboembolism16

ithout increased bleeding. Whether this benefit applies tother patient groups with deep vein thrombosis is uncertain;here are insufficient data in patients without cancer witheep vein thrombosis.7 Indeed, the authors of a recent re-iew article17 conclude that further clinical trials are nec-ssary, because LMWH may prove to be an appropriateong-term therapy.

We conducted a large multicenter, randomized, open-abel clinical trial in a broad spectrum of patients to evaluatehe effectiveness (benefits) and harm (safety) of long-termMWH, using a therapeutic dose of tinzaparin once dailyubcutaneously, compared with usual care consisting ofntravenous heparin and long-term vitamin K antagonistherapy.

ETHODS

tudy Designhe study design, patient eligibility and allocation, and

reatment regimens are shown in the table availablenline.1-5,18-25

urveillance and Follow-upatients were instructed to seek care immediately if theyad symptoms or signs of venous thromboembolism orleeding. Patients presenting with clinically suspected re-urrent venous thromboembolism underwent objective test-ng. Patients routinely attended the clinic at 12 weeks. At 1

CLINICAL SIGNIF

● During 3 monthvenous thrombostion of low-mowas equivalent tonism in preventhrombosis.

● The 2 therapiesspect to mortalitest period.

ear, all patients or their primary care physicians were (

ontacted, determining whether the patient had experiencedocumented recurrent venous thromboembolism and waslive.

Primary outcome measures were assessed at 3 monthsnd included objectively documented recurrent venous

thromboembolism or death. Pa-tients were then followed by tele-phone at 1 year and assessed forobjectively documented venousthromboembolism or death. Re-current venous thrombosis was di-agnosed when a previously com-pressible proximal vein segmentwas not compressible on ultra-sonography2,3,26,27 or by the pres-ence of a constant intraluminalfilling defect in the deep veins thatwas not present on the baselinevenogram.28,29 For patients withclinically suspected pulmonaryembolism, the diagnosis was con-firmed by high-probability lung

can findings;30,31 a nondiagnostic lung scan with docu-ented new deep vein thrombosis;30 spiral computed to-ography32 showing thrombus in the central pulmonary

rteries; pulmonary angiography30,33 revealing a constantntraluminal filling defect or cutoff of a vessel greater than.5 mm in diameter; or by pulmonary embolism found atutopsy.

The primary safety end point for assessing harm washe occurrence of bleeding (all, major, or minor) duringhe 12-week treatment interval. Bleeding was classifieds major if it was overt and associated with a decrease inemoglobin of 2 g/dL or more, if it led to the transfusionf 2 or more units of blood; and if it was retroperitoneal,ccurred into a major joint, or was intracranial.4,34-37

leeding was defined as minor if it was clinically overtut did not meet other criteria for major bleeding.4,34-37

hese criteria were used successfully in previoustudies.4,34-37

All suspected events, including recurrent deep veinhrombosis, pulmonary embolism, bleeding, or death,ere interpreted independently without knowledge of thether findings by a central, independent adjudicationommittee. Adjudication was made by 2 committee mem-ers not involved in the patient’s care, and disputes wereesolved independently by a third member. Members ofhe committee were unaware of the patients’ treatmentssignments.

tatistical Analysissample size of 455 patients in each treatment group was

nitially chosen to provide 80% power for a 2-sided test (�.05) to detect a 50% reduction in mortality from the 9.6%

xperienced in a previous trial suggesting a mortality ad-antage.35 The findings of a companion randomized trial

CE

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74 The American Journal of Medicine, Vol 120, No 1, January 2007

utcome suggested rebound recurrent venous thromboem-olism immediately after cessation of long-term LMWHherapy.18,38,39 Because of both safety and regulatory affairequirements, the trial reported here was terminated when37 patients were enrolled. Because our confidence intervalCI) for relative mortality risk excludes a 50% reductionfavoring either group), we conclude that the achieved sam-le size is sufficient for our primary aims.

The comparison of the frequency of events (recurrentenous thromboembolism, bleeding, death) between the 2roups in the first 12 weeks was based on the chi-squareest and associated CIs. Cumulative incidence estimateso 1 year were derived from Kaplan-Meier survivalurves and compared using the log-rank test after assess-ng the proportional hazard assumption.40 Proportionalazards test diagnostics were based on weighted residu-ls.40 CIs were derived from standard errors calculatedrom Greenwood’s formula. The meta-analysis was con-ucted following a fixed-effects approach based on theantel-Haenszel method as implemented in the metan

rocedure41 of Stata software, release 6.0 (Stata Corp,ollege Station, Tex).

The protocol was designed by 3 investigators. The steer-ng committee, central adjudication committee, and statis-ical analysis were independent of the sponsor. The Throm-osis Research Unit, University of Calgary, coordinated thetudy and carried out the data management and administra-ive duties. Statistical analysis was carried out indepen-ently of the industry sponsor by Rollin F. Brant, PhD,epartment of Community Health Sciences, University ofalgary.

369 Assigned to receive low-molecular-weight heparin

1 Lost to Follow-up at 3 months (+ 2 at 12 months)

1 withdrew consent at 3 months

369 Included in Analysis

2212 assessed for elig

737 randomized

Figure 1 Participa

ESULTS

tudy Populationtotal of 737 consecutive patients were recruited beginning

n 1994 at 30 centers across Canada (see Appendix availablenline) and randomized to tinzaparin (369 patients) or usual-are anticoagulants (368 patients). A broad spectrum ofatients were evaluated. Figure 1 shows the patient flow forhe eligible patients and those randomized to the treatmentroups. The tinzaparin and usual-care groups were compa-able at entry (Table 1). Because of difficulties with occa-ional patient follow-up, which were overcome, successfulatient follow-up was completed in July 2003.

ecurrent Venous Thromboembolismhe outcomes for recurrent venous thromboembolism arehown in Figure 2 and Table 2.

At 3 months, of 737 patients, 18 of 369 patientseceiving tinzaparin (4.9%) had recurrent venous throm-oembolism compared with 21 of 368 patients (5.7%)eceiving usual-care anticoagulation (absolute difference,0.8%, 95% CI, �4.1-2.4). Thus, LMWH was unlikely

o be more effective against recurrent venous thrombo-mbolism than usual-care anticoagulation by more than.1% (absolute risk difference), and usual-care anticoag-lation was unlikely to be more effective than LMWH byore than 2.4%.The activated partial thromboplastin time and INR val-

es for patients receiving usual-care anticoagulation arehown according to test sequence in the Appendix figureavailable online).

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

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

1 Lost to Follow-up at 3 months (+2 at 12 months)

3 Withdrew consent at 3 months (+2 at 12 months)

368 Included in Analysis

1475

ibility

nt flow chart.

Frd

75Hull et al Long-term LMWH Therapy

igure 2 Time to event analysis for patients who had recurrent venous thromboembolism At 3 months, of 737 patients, 18 of 369 patientseceiving tinzaparin (4.9%) had recurrent venous thromboembolism compared with 21 of 368 (5.7%) receiving usual care (absolute

Table 1 Clinical Characteristics of Patients with Proximal Vein Thrombosis Treated with Long-Term Low-Molecular-Weight Heparinor Oral Anticoagulant Therapy

Characteristic

LMWH N � 369Intravenous Heparin/WarfarinN � 368

No. of Patients (%)

Age �60 y, �60 y 187, 182 151, 217Sex (M, F) 207, 162 188, 180Status at entry

Symptomatic deep vein thrombosis 350 (94.9) 346 (94.0)Symptoms of pulmonary embolism 98 (26.6) 82 (22.3)

Previous venous thromboembolism 64 (17.3) 74 (20.1)Factor V Leiden gene mutation 56 (15.2) 51 (13.9)High risk for bleeding* 144 (39.0) 146 (39.7)Clinical measures at entry

Surgery and/or trauma in past 6 mo 162 (43.9) 167 (45.4)Cancer 100 (27.1) 100 (27.2)Coronary heart disease 65 (17.6) 91 (24.7)

Diabetes 41 (11.1) 45 (12.2)Chronic obstructive pulmonary disease 33 (8.9) 29 (7.9)Peripheral vascular disease 28 (7.6) 21 (5.7)Congestive heart disease 14 (3.8) 19 (5.2)Leg paralysis 21 (5.7) 16 (4.4)Liver disease 10 (2.7) 9 (2.4)

*With regard to the risk of bleeding, patients were stratified into groups according to the absence (low risk) or presence (high risk) of 1 or more riskfactors for bleeding including surgery or trauma within the previous 14 d, history of peptic ulcer disease, bleeding into the gastrointestinal orgenitourinary tract, thrombotic stroke within the previous 14 d, platelet count less than 150 � 109/L, or miscellaneous reasons (predisposing disorders)for a high risk of bleeding. In the LMWH group, 1 patient withdrew, 1 patient was lost to follow-up at 3 mo, and 1 patient was lost to follow-up at 1 y.In the usual-care group, 3 patients withdrew and 1 patient was lost to follow-up at 3 mo; 2 additional patients withdrew consent and 2 were lost tofollow-up at 1 year. Thus, 726 of the 737 patients (98.5%) randomized completed the 3-mo study interval and subsequent follow-up to 12 mo.

ifference, �0.8%, 95% CI, �4.1-2.4). IV � intravenous; LMWH � low-molecular-weight heparin.

76 The American Journal of Medicine, Vol 120, No 1, January 2007

Table 2 Outcomes at 3 Months

Tinzaparin N � 369 n (%) Usual Care* N � 368 n (%) Absolute Difference (95% CI) P Value

New episodes of venousthromboembolism†

At 3 mo 18 (4.9) 21 (5.7) �0.8 (�4.1-2.4)At 12 mo 33 (8.9) 36 (9.8) �0.8 (�5.5-3.5) At 12 mo

DeathAt 3 mo 25 (6.8) 24 (6.5) 0.3 (�3.4-3.9)At 12 mo 60 (16.3) 59 (16.0) 0.2 (�5.4-5.4) At 12 mo

Bleeding complicationsFrequency of bleeding

All 48 (13.0) 73 (19.8) �6.8 (�12.4-�1.5) P � .011Major 12 (3.3) 17 (4.6) �1.4 (�4.3-1.4)Minor 36 (9.8) 56 (15.2) �5.5 (�10.4-�0.6) P � .022

Stratified by risk of bleedingAll bleeding

High risk 31/144 (21.5%) 39/146 (26.7%) �5.2 (�15%-4.6%)Low risk 17/225 (7.6%)‡ 34/222 (15.3%)§ �7.8 (�13.6%-�1.9%) P � .01

Major bleedingHigh risk 10/144 (6.9%) 13/146 (8.9%) �2.0 (�8.2%-4.3%)Low risk 2/225 (0.9%)� 4/222 (1.8%)¶ �0.9 (�3.1%-1.2%)

Minor bleedingHigh risk 21/144 (14.6%) 26/146 (17.8%) �3.2 (�11.7%-5.3%)Low risk 15/225 (6.7%)** 30/222 (13.5%) �6.9 (�12.4%-�1.3%) P � .018

Other findingsThrombocytopenia††Platelet count

�100 � 109/L 10 (2.7%) 4 (1.1%) 1.6 (�3.6-0.3)�150 � 109/L 21 (5.7%) 9 (2.4%) 3.3 (�6.1-�0.4) P �.039

Bone fractures out to 12 mo‡‡ 4 (1.1%) 7 (1.9%) �0.8 (�0.9-2.6)

CI � confidence interval.*Unfractionated heparin and vitamin K antagonist therapy.†Recurrent venous thromboembolism at 3 mo: 18 patients in the LMWH group � 10 with pulmonary embolism (documented by autopsy, n � 1; high-probability

lung scan, n � 4; pulmonary angiography, n � 1; spiral computed tomography [CT], n � 3; pulmonary angiography and lung scan, n � 1); 8 with recurrent deep veinthrombosis (documented by duplex ultrasonography); 21 patients in the heparin/warfarin group � 6 with pulmonary embolism (documented by autopsy, n � 1;high-probability lung scan, n � 5); 15 with recurrent deep vein thrombosis (documented by venography, n � 3; duplex ultrasonography, n � 12). At 12 mo: 33 patientsin the LMWH group � 12 with pulmonary embolism (documented by autopsy, n � 2; lung scan, n � 5; spiral CT scan, n � 3, pulmonary angiography, n � 1; pulmonaryangiography and high-probability lung scan, n � 1); 21 with deep vein thrombosis (documented by venography, n � 1; duplex ultrasonography, n � 20); 36 patientsin the heparin/warfarin group � 11 with pulmonary embolism (documented by autopsy, n � 4; high-probability lung scan, n � 5; spiral CT scan, n � 2); 25 with deepvein thrombosis (documented by venography, n � 7; duplex ultrasonography, n � 18).

Long-term vitamin K antagonist therapy was administered by the primary care physician, if indicated, in patients such as those with recurrent or idiopathicdeep vein thrombosis at entry or who had a continuing risk factor. The physician instituted or continued vitamin K antagonist therapy long term in 146 patientsassigned to LMWH (mean duration 202 d, median duration 258 d) and in 250 patients assigned to intravenous heparin/warfarin (mean duration 156 d, medianduration 147 d). In patients with cancer, 37 were assigned to LMWH (mean duration 215 d, median duration 272 d), and 57 were assigned to intravenousheparin/warfarin (mean duration 165 d, median duration 152 d).

The presence of a predisposing factor for bleeding (high risk for bleeding) on entry overwhelmed any potentially significant bleeding outcomedifferences between the groups. In patients without a predisposing factor for bleeding on entry (low risk for bleeding), long-term LMWH therapy use wasassociated with significantly less overall bleeding.

High risk for bleeding stratum compared with low risk: ‡P � .001; §P � .007; �P � .001; ¶P � .002; **P � .012.A preponderance of bleeding from mucosal sites was observed in the usual-care group compared with the LMWH group: nasopharyngeal (epistaxis), 20

patients (5.4%) versus 9 patients (2.4%), respectively; hemoptysis, 8 patients (2.2%) versus 4 patients (1.1%), respectively; and upper and lower digestive tractbleeding, 23 patients (6.3%) versus 13 patients (3.5%), respectively. Thus, hemorrhagic complications involving mucosal sites (nasopharyngeal, upper and lowerdigestive tract, and bronchial) occurred in 51 of 368 patients (13.9%) receiving vitamin K antagonist therapy compared with 26 of 369 patients (7%) receivingLMWH (absolute difference 6.8%, P � .003).

Long-term LMWH use was associated with significantly less nasopharyngeal and upper and lower digestive tract bleeding (absolute difference �5.7%, P � .01).On diagnostic pursuit of the causes of bleeding (in the absence of known predisposing causes), a substantive cause for bleeding was frequently not established.Bleeding complications from other diverse sites were rare or similar between the LMWH and usual-care groups: intracranial bleeding, 2 patients and 1 patient,

respectively; genitourinary, 12 and 10 patients, respectively; hematomas, 5 and 8 patients, respectively; and miscellaneous, 3 and 3 patients, respectively.††Thrombocytopenia: LMWH group: Thrombocytopenia was associated with cancer or cancer therapy in 10 patients, 1 patient had systemic lupus

erythematosus, and 2 patients had heparin-associated thrombocytopenia. Usual-care group: Thrombocytopenia was associated with cancer or cancertherapy in 5 patients, and 1 patient had autoimmune pancytopenia.

‡‡Twelve-month data provided, because osteoporosis, if present, may have resulted in delayed fractures.

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77Hull et al Long-term LMWH Therapy

Among patients with recurrent venous thromboembolismn the usual-care vitamin K antagonist group, 4 patients hadn INR of less than 2 at the time of the event.

leeding Complicationsdetailed analysis of the harm caused by bleeding is

rovided to comply with the recent CONSORT agreementBetter Reporting of Harms in Randomized Trials.”21

requency of Bleeding and Time to Event Analysis.emorrhagic complications are shown in Figure 3 andable 2. Bleeding occurred in 48 of 369 patients (13.0%)

eceiving LMWH and 73 of 368 patients (19.8%) receiv-ng usual-care anticoagulation (P � .011; absolute dif-erence �6.8%, risk ratio � 0.66). Major bleeding oc-urred in 12 patients (3.3%) receiving LMWH and in 17atients (4.6%) receiving usual-care anticoagulation (ab-olute difference �1.4; risk ratio � 0.70). Minor bleed-ng occurred in 36 patients (9.8%) receiving LMWH andn 56 patients (15.2%) receiving unfractionated heparinnd warfarin (P � .022; absolute difference �5.5; riskatio � 0.64).

Among patients with major bleeding in the usual-careitamin K antagonist group, 1 patient had an INR between.1 and 3.9, and 2 patients had an INR of 4.0 or greater onhe day of bleeding; among patients with minor bleeding, 4atients had an INR between 3.1 and 3.9, and 6 patients hadn INR of 4.0 or greater.

iming of Bleeding Occurrence. The occurrence of bleed-ng according to time course of study therapy for each groups shown in Figure 4 for major and minor bleedingomplications.

isk of Bleeding. Patients were stratified according to thebsence (low risk) or presence (high risk) of risk factors forleeding. On entry, 290 of the 737 patients (39.3%) were atigh risk for bleeding and 447 patients (60.7%) were at lowisk for bleeding. The treatment groups were comparable atntry for the proportion of patients at high risk of bleedingTables 1 and 2). Major bleeding occurred in 23 of 290atients (7.9%) at high risk for bleeding compared with 6 of47 patients (1.3%) (P � .001) at low risk for bleeding.

redictive Nature of Risk Categorization for Bleedingnd Its Interaction Among the Treatment Groups. Riskategorization was predictive of bleeding, because patientst low risk for bleeding had significantly less hemorrhagicomplications receiving LMWH or usual care comparingigh- versus low-risk strata (Table 2). Bleeding complica-ions, either major or minor, by risk stratification for bleed-ng and their association with each treatment group areresented separately (Table 2).

ite of Bleeding. The site of bleeding is described in the

igure 3 Time to event analysis for patients who had hemorrhagicomplications. A: All bleeding. Bleeding occurred in 48 of 369atients (13.0%) receiving LMWH and 73 of 368 patients (19.8%)eceiving heparin and warfarin (P � .011; risk ratio � 0.66). B: Majorleeding. Major bleeding occurred in 12 of 369 patients (3.3%) in theMWH group and in 17 of 368 patients (4.6%) receiving heparin andarfarin (risk ratio � 0.70; absolute difference �1.4, 95% CI, �4.3-.4). C: Minor bleeding. Minor bleeding occurred in 36 of 369atients (9.8%) receiving LMWH and in 56 of 368 patients (15.2%)eceiving heparin and warfarin (P � .022; risk ratio � 0.64). IV �

egend of Table 2.

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78 The American Journal of Medicine, Vol 120, No 1, January 2007

eathso mortality advantage for LMWH was found (Table 2).ortality findings and causes of death are shown in Table 3.

atient Outcomes at 12-Month Follow-uphe findings for recurrent venous thromboembolism andeath are shown in Table 2.

A rebound in the frequency of recurrent venous throm-oembolic events was not seen in either group after cessa-ion of therapy at 3 months.

ther Findingshe frequencies for thrombocytopenia are shown in Table 2.or those patients with thrombocytopenia, the outcomesiffered between the treatment groups. Six of 9 patients withhrombocytopenia receiving usual care died (66.7%, 95%I, 29.9-92.5) versus 4 of 21 patients with thrombocytope-ia receiving LMWH (19%, 95% CI, 5.4-41.9) (absoluteifference 47.6%, 95% CI, 82.7-12.5, P � .03). Recurrentbjectively confirmed venous thromboembolism occurrednfrequently in patients with thrombocytopenia.

The frequencies for bone fractures are shown in Table 2.Figure 5 shows the summary treatment effects for the

utcomes of recurrent venous thromboembolism and hem-rrhagic complications. These favored long-term LMWHherapy. The test for heterogeneity was nonsignificant (re-urrent venous thromboembolism P � .34, hemorrhagic

igure 4 Prevalence of bleeding over time. The occurrence of blor major and minor bleeding complications. The pattern of the timP � .034). New major bleeding events occurred throughout studyot present after day 23 in the LMWH group (P � .034). New mor both treatment groups. LMWH � low-molecular-weight hepa

omplications P � .41). b

ISCUSSIONe did not find LMWH to be superior to usual therapy with

itamin K antagonists for the outcome of mortality, which isonsistent with the outcomes of other studies.7,8,16 In aroad spectrum of patients, long-term LMWH comparedith vitamin K antagonist therapy for 3 months shows

imilar efficacy against recurrent venous thromboembolism.f the 737 patients with proximal venous thrombosis on

ntry, 18 of 369 patients (4.9%) had recurrent venoushromboembolism in the LMWH group compared with 21f 368 patients (5.7%) in the usual-care group (absoluteifference, �0.9%, 95% CI, �4.1-2.4). Thus, LMWH isnlikely to be less effective than usual care by more than anbsolute difference of 2.4%. Such narrow margins for re-urrent venous thromboembolism have been accepted tostablish the non-inferiority of new antithrombotics com-ared with usual care for the initial treatment of venoushromboembolism.42,43

Our findings suggest improved safety for long-termMWH therapy because of less harm from bleeding comparedith usual care with vitamin K antagonist therapy (P � .011).ll bleeding and minor bleeding were less frequent in patients

eceiving LMWH. Minor bleeding clearly detracts from qual-ty of life and consumes health care resources. In the early980s, a trial evaluating vitamin K antagonist therapy4 that ledo less-intense oral anticoagulant therapy (INR: 2.0-3.0)howed improved safety, largely because of less minor bleed-ng. Subsequently, this safer vitamin K antagonist therapy

according to time course of study therapy for each group is shownesentation of major bleeding differed significantly between groupsent for patients in the usual-care group receiving warfarin but dideeding episodes occurred throughout the study treatment interval

eedinge of prtreatm

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79Hull et al Long-term LMWH Therapy

The timing of new major bleeding events differed amonghe treatment groups. New major bleeding events occurredhroughout the study treatment interval for patients in thesual-care group receiving warfarin but ceased early in theMWH group (P � .034) (Figure 4). This protective effectas previously observed using the same LMWH regimen35

or initial treatment, but the bleeding advantage was losturing subsequent long-term vitamin K antagonist therapy.he observation that major bleeding events ceased earlyith long-term LMWH may reflect the interplay between

reatment and the presence or absence of predisposing fac-ors for bleeding. Bleeding was significantly less likely foratients receiving LMWH compared with usual care in thebsence of predisposing factors for bleeding (low-risk pa-ients) (P � .01). For patients receiving usual care, the facthat hemorrhagic complications occurred more frequently inhe low-risk group suggests that long-term usual care wasnnately more hemorrhagic. Conversely, patients at highisk for bleeding had similar rates for bleeding with eitherherapy.

A clinically relevant finding is that usual care was associ-ted with significantly more bleeding from mucosal sites (P �003). This is clinically relevant because of the need to inter-

Table 3 Causes of Death in the Two Treatment Groups

Cause of Death

LMWH

Deaths(N � 25) Days After Start

Abrupt* (n � 4)Pulmonary embolism 1 5 (by autopsy)Possible pulmonary

embolism?2 1, 6

Suspected pulmonaryembolism/metastaticcancer?

0

Metastatic cancer 0Cerebrovascular 1 39

Insidious* (n � 20)Suspected pulmonary

embolism?/metastaticcancer

0

Metastatic cancer 18 7, 17, 17, 22, 241, 44, 45, 4667, 82 (2)

Pneumonia 1 35Cardiovascular 0Cerebrovascular 1 17Parkinson disease 0

Unknown if abrupt orinsidious

(n � 1)

Cardiovascular 1 29

*Patients were categorized according to whether they died abruptlyhealth, and their immediate death was anticipated, whereas most patie

In the LMWH group, death was complicated by intracranial hemorrhagK antagonist group, the cause of death was complicated by a gastrointe(1 patient).

ene diagnostically to resolve the bleeding complication. s

Our findings regarding bleeding are supported by the liter-ture.7 In addition, extended LMWH prophylaxis after total hipeplacement compared with vitamin K antagonists was signif-cantly less harmful because of avoidance of bleeding.44 Theeduced bleeding observed with LMWH is consistent witheduced bleeding found in animal models.45,46

Thrombocytopenia was uncommon in both groups. Goodlinical practice necessitated platelet count monitoring dur-ng the first 3 weeks of therapy with long-term LMWHompared with 1 week only for usual care. A higher pro-ortion of patients with thrombocytopenia in the usual-careroup died in comparison with those receiving LMWH whoad thrombocytopenia. The greater harm associated withsual-care thrombocytopenia requires further study.

Bone fractures potentially caused by concomitant osteo-orosis occurred infrequently in both treatment groups, buturther study of this complication is required.

Prior studies8-10,12-16,47 evaluating long-term LMWHherapy (Figure 5) were limited in size, used prophylacticoses of LMWH (which may have been insufficient torevent recurrent venous thromboembolism), or evaluatedelected patients, such as those with cancer. To date, all

Usual Care

rapyDeaths(N � 24) Days After Start of Therapy

(n � 6)2 13 (by autopsy), 142 2, 24

1 23

1 810

(n � 18)1 11

40 (2),52, 64,

14 9, 16, 19, 21, 30, 32 (2), 41 (2),61, 62, 76, 81, 84

1 701 3701 23

(n � 0)

0

diously. Patients who died insidiously had progressive declines in theirdied abruptly did so without warning.

tient) and a gastrointestinal bleed (1 patient). In the usual-care vitaminleed (2 patients) and a major bleed (intracerebral) at the time of death

of The

5, 35,, 48,

or insints whoe (1 pastinal b

tudies (Figure 5) evaluating long-term LMWH have had an

oi

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Fw

80 The American Journal of Medicine, Vol 120, No 1, January 2007

pen-label design because of the difficulty in double-blind-ng such studies.

The open-label design could be a potential source ofias in our trial. A double-blind design was not feasibleecause of the geographic location of many of the centersnd the necessarily large number of primary care physi-ians providing anticoagulant monitoring. It is unlikelyhat a reporting bias explains the observed differences forhe following reasons. Before the study, criteria for eli-ibility were specified and a representative sample ofligible patients were randomized. The clinical charac-eristics of patients on entry were similar among groups.o avoid a selection bias, care was taken to ensure thatarticipating physicians adhered to the protocol. To min-mize reporting and diagnostic bias, we contacted pa-ients at regular intervals using standardized follow-upssessments. We used objective testing to evaluate sus-ected events, and all suspected outcomes were evaluatedy a central committee whose members were unaware ofhe patients’ treatment assignments. Internationally rec-gnized objective documentation of venous thromboem-olism and bleeding was carried out. Care was takenhroughout the study that anticoagulant monitoring en-ured adequate intravenous heparin using a heparin pro-ocol and oral warfarin therapy (see Appendix). Also, anmportant bias related to treatment management is un-ikely because the INR control achieved was similar tohat reported in other studies.4,6,34,36 It is likely that ouresults are relevant to clinical practice and not undulynfluenced by bias.

A rebound in the frequency of recurrent venous throm-

Open-label Cancer Lee,16 2003 Multicentre Venous Thromboembolism T & M‡ 27/336 (8.0%) 53/336 (15.8%)

Study yr (ref) Design

Patients with Recurrent Venous

Patient population

LMWH

Regimen LMWH Vitamin-K-Antagonists

Das,9 1996 Single-centre

Open-label Broad-spectrum

Deep Vein Thrombosis P* 3/44 (6.8%) 1/42 (2.4%)

Lopaciuk,12 1999 Multicentre

Open-label Broad-spectrum

Deep Vein Thrombosis T* 2/98 (2.0%) 7/95 (7.4%)

Gonzalez-Fajardo,10

1999Single-centre

Open-label Broad-spectrum

Deep Vein Thrombosis P* 8/85 (9.4%) 19/80 (23.8%)

Veiga,15 2000 Single-centre

Open-label Over 75 yrs of age

Deep Vein Thrombosis P† 2/50 (4.0%) 1/50 (2.0%)

Lopez-Beret,13

2001Single-centre

Open-label Broad-spectrum

Deep Vein Thrombosis P† 2/81 (2.5%) 7/77 (9.1%)

Meyer,8 2002 Multicentre

Open-label Cancer

Venous Thromboembolism T* 3/75 (4.0%) 2/71 (2.8%)

Kakkar,47 2003 Multicentre

Open-label Broad-spectrum

Deep Vein Thrombosis T & M* 3/94 (3.2%) 4/98 (4.1%)

Overall (95% CI)

Results Favour LMWH

0.10 1.00

Pini,14 1994 Single-centre

Open-label

Deep Vein Thrombosis

Broad-spectrum

P* 6/93 (6.5%) 4/94 (4.3%)

Hull, Multicentre

Open-label Broad-spectrum

Proximal Vein Thrombosis T*

(current article)

18/369 (4.9%) 21/368 (5.7%)

igure 5 *Treatment duration 3 months. †Treatment duration 3eight heparin; CI � confidence interval; LMWH regimen: T � t

oembolic events was not seen in patients receiving n

MWH at cessation of therapy. The issue of potentialebound requires further study.18,48

Self-managed oral anticoagulant therapy comparedith anticoagulant clinic management resulted in im-roved patient outcomes.49 Although self-management ofral anticoagulant treatment achieved a similar level ofnticoagulant INR control, harm resulting from bleedingomplications, largely minor hemorrhage, occurred lessrequently in self-managed patients. The option of long-erm LMWH therapy offers an even simpler alternativey removing the need for anticoagulant monitoring andose adjustment. LMWH as evaluated in our study allowsore patient autonomy, uses less resources (eg, blood

tations and anticoagulant monitoring), and is safer thanhysician-managed oral anticoagulation.

An evaluation of the cost-effectiveness of long-termMWH is beyond the scope of this article, but it may beost-effective in patients at high risk of recurrence.48 These of long-term LMWH in individual patients with deepein thrombosis will depend on the clinical setting, pa-ient comorbidity, ability to self-inject (patient or familyembers), health care system resources, and availability

f reimbursement. Patient self-management, with the as-ociated independence from routine long-term anticoag-lant monitoring, may prove a powerful determinant forhoosing LMWH therapy for individual patients. Theelevance of this innovative regimen is considerableiven the ubiquitous nature and ongoing presentation ofeep vein thrombosis as an important health careroblem.

Our study shows that LMWH is similar in effective-

8.23)50.1 ,35.0( 57.0 )%0.41( 633/74 63/336 (18.8%) 51 (0.33, 0.79) 43.9

Patients with Hemorrhagic Complications olism

thgieW %)IC %59( oitaR ksiRHWML Vitamin-K-Antagonists Ratio (95% CI) % Weight

7.2)67.1 ,10.0( 01.0 0 5/55 (9.1%) 6 (0.31, 26.45) 0.8

7.3)38.1 ,71.0( 55.0 )%1.4( 89/4 7/95 (7.4%) 28 (0.06, 1.30) 5.9

1/85 (1.2%) 0.12 (0.02, 0.92) 4.3

8/80 (10.0%) 40 (0.18, 0.85) 16.2

1.3)33.1 ,20.0( 71.0 )%0.2( 05/1 6/50 (12.0%) 0 (0.19, 21.36) 0.8

1.2)76.3 ,52.0( 59.0 )%2.5( 77/4 4/77 (5.2%) 27 (0.06, 1.27) 5.9

1.6)91.1 ,61.0( 44.0 )%0.61( 57/215/71 (7.0%) 70 (0.12, 4.09) 2.4

0.1)52.7 ,51.0( 40.1 )%1.2( 49/2 2/98 (2.0%) 78 (0.18, 3.40) 3.2

Results Favour LMWH

Results Favour Vitamin-K-Antagonists

Overall (95% CI)

Results Favour Vitamin-K-Antagonists

1.000.01

0.61 (0.49, 0.75)

0.10

60 (0.46, 0.80)

10.0

4/93 (4.3%) 0.34 (0.11, 1.01) 6.212/94 (12.6%) 52 (0.44, 5.20) 3.3

0.83)29.0 ,74.0( 66.0 )%0.31( 963/84 73/368 (19.8%) 85 (0.46, 1.58) 17.4

onths. ‡Treatment duration 6 months. LMWH � low-molecular-nt dose; P � prophylactic dose; M � reduced maintenance dose.

0.

Thromboemb

Risk

2.8

0.

0.

2.0

0.

0.

0.

10.0

0.

1.

0.

to 6 mreatme

ess to the usual-care vitamin K antagonist treatment for

pstiLtip

ATt

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

81Hull et al Long-term LMWH Therapy

reventing recurrent venous thromboembolism in a broadpectrum of patients. It causes less harm and enhanceshe clinicians’ therapeutic options for patients with prox-mal deep vein thrombosis. The aggregate data show thatMWH is preferred in patients with cancer with venous

hromboembolism.16,50 Our findings suggest the possibil-ty of a broader role for long-term LMWH in selectedatients.

CKNOWLEDGMENThe authors thank Avneet Brar and Jeanne Sheldon, BA, for

heir assistance in the preparation of the article.

eferences1. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for

venous thromboembolic disease. Chest. 2001;119:176S-193S.2. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-

weight heparin administered primarily at home with unfractionatedheparin administered in the hospital for proximal deep-vein thrombo-sis. N Engl J Med. 1996;334:677-681.

3. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of ve-nous thrombosis with intravenous unfractionated heparin ad-ministered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med.1996;334:682-687.

4. Hull RD, Hirsh J, Jay R, et al. Different intensities of oral anticoag-ulant therapy in the treatment of proximal-vein thrombosis. N EnglJ Med. 1982;307:1676-1681.

5. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mecha-nism of action, clinical effectiveness, and optimal therapeutic range.Chest. 2001;119:8S-21S.

6. Kearon C, Ginsberg JS, Kovacs M, et al. Comparison of low-intensitywarfarin therapy with conventional-intensity warfarin therapy forlong-term prevention of recurrent venous thromboembolism. N EnglJ Med. 2003;349:631-639.

7. Van der Heijden JF, Hutten BA, Buller HR, Prins MH. Vitamin Kantagonist or low-molecular-weight heparin for the long-term treat-ment of venous thromboembolism. The Cochrane Database of Sys-tematic Reviews 2002: The Cochrane Library, 2002;(1):CD002001.Available at: www.cochrane.org.

8. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecu-lar-weight heparin and warfarin for the secondary prevention of ve-nous thromboembolism in patients with cancer: a randomized con-trolled study. Arch Intern Med. 2002;162:1729-1735.

9. Das SK, Cohen AT, Edmondson RA, Melissari E, Kakkar VV. Low-molecular-weight heparin versus warfarin for prevention of recurrentvenous thromboembolism: a randomized trial. World J Surg. 1996;20:521-526.

0. Gonzalez-Fajardo JA, Arreba E, Castrodeza J, et al. Venographiccomparison of subcutaneous low-molecular-weight heparin with oralanticoagulant therapy in the long-term treatment of deep venousthrombosis. J Vasc Surg. 1999;30:283-290.

1. Hamann H. Lrezidivporphylaxe nach phlebothrombose—orale antiko-agulation oder niedermolekulares heparin subkutan [Low molecularwith heparin versus coumarin in the prevention of recurrence afterdeep vein thrombosis]. VASOMED. 1998;10:133-136.

2. Lopaciuk S, Bielska-Falda H, Noszczyk W, et al. Low molecularweight heparin versus acenocoumarol in the secondary prophylaxis ofdeep vein thrombosis. Thromb Haemost. 1999;81:26-31.

3. Lopez-Beret P, Orgaz A, Fonteuberta J, et al. Low molecular weightheparin versus oral anticoagulants in the long-term treatment of deep

venous thrombosis. J Vasc Surg. 2001;33:77-90.

4. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparinversus warfarin in the prevention of recurrences after deep vein throm-bosis. Thromb Haemost. 1994;72:191-197.

5. Veiga F, Escriba A, Maluenda MP, et al. Low molecular weightheparin (enoxaparin) versus oral anticoagulant therapy (acenocou-marol) in the long-term treatment of deep venous thrombosis in theelderly: a randomized trial. Thromb Haemost. 2000;84:559-564.

6. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparinversus a coumarin for the prevention of recurrent venous thromboem-bolism in patients with cancer. N Engl J Med. 2003;349:146-153.

7. Kher A, Samama MM. Primary and secondary prophylaxis of venousthromboembolism with low-molecular-weight heparins: prolongedthromboprophylaxis, an alternative to vitamin K antagonists. J ThrombHaemost. 2005;3:473-481.

8. Hull RD, Pineo GF, Mah AF, Brant RF, for the LITE study investi-gators. Home-LITE: safety and efficacy results for a study investigat-ing the long-term out-of-hospital treatment of patients with proximalvenous thrombosis using subcutaneous low-molecular-weight heparinversus warfarin. Thromb Haemost. 2001;(Suppl):OC1647.

9. Altman DG, Schulz KF, Moher D, et al. The revised CONSORTstatement for reporting randomized trials: explanation and elabora-tions. Ann Intern Med. 2001;134:663-694.

0. Moher D, Schulz KF, Altman D. The CONSORT statement: revisedrecommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987-1991.

1. Ioannidis JPA, Evans SJW, Gotzsche PC, et al for the CONSORTGroup. Better reporting of harms in randomized trials: an extension ofthe CONSORT Statement. Ann Intern Med. 2004;141:781-788.

2. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days ascompared with 10 days in the initial treatment of proximal venousthrombosis. N Engl J Med. 1990;322:830-831.

3. Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic levelof heparin therapy in patients with venous thrombosis. Arch InternMed. 1992;152(8):1589-1595.

4. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparinnomogram compared with a ‘standard care’ nomogram: a randomizedcontrolled trial. Ann Intern Med. 1993;119:874-881.

5. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics,dosing, monitoring, efficacy, and safety. Chest. 2001;119:64S-94S.

6. Lensing AWA, Prandoni P, Brandjes D, et al. Detection of deep-veinthrombosis by real-time B-mode ultrasonography. N Engl J Med.1989;320:342-345.

7. The Columbus Investigators. Low-molecular-weight heparin in thetreatment of patients with venous thromboembolism. N Engl J Med.1997;337:657-662.

8. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in theleg. Arch Surg. 1972;104:134-144.

9. Hull RD, Carter CJ, Jay RM, et al. The diagnosis of acute, recurrent,deep-vein thrombosis: a diagnostic challenge. Circulation. 1983;67:901-906.

0. Hull RD, Hirsh J, Carter CJ, et al. Pulmonary angiography, ventilationlung scanning, and venography for clinically suspected pulmonaryembolism with abnormal perfusion lung scan. Ann Intern Med. 1983;98:891-899.

1. A collaborative study by the PIOPED investigators. Value of theventilation-perfusion scan in acute pulmonary embolism: results ofthe Prospective Investigation of Pulmonary Embolism Diagnosis(PIOPED). JAMA. 1990;263:2753-2759.

2. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specificity ofhelical computed tomography in the diagnosis of pulmonary embo-lism: a systematic review. Ann Intern Med. 2000;132:227-232.

3. Dalen JE, Brooks HL, Johnson LW, et al. Pulmonary angiography inacute pulmonary embolism: indications, techniques, and results in 367patients. Am Heart J. 1971;81:175-185.

4. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-doseheparin in the long-term treatment of venous thrombosis. N Engl

J Med. 1979;301:855-858.

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82 The American Journal of Medicine, Vol 120, No 1, January 2007

5. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in thetreatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975-982.

6. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparinversus warfarin sodium in the long-term treatment of venous throm-bosis. N Engl J Med. 1982;306:189-194.

7. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparincompared with intermittent subcutaneous heparin in the initial treatmentof proximal-vein thrombosis. N Engl J Med. 1986;315:1109-1114.

8. Hull RD, Pineo GF, Mah AF, Brant RF, for the LITE Study Investi-gators. Long-term out-of-hospital treatment with low-molecularweight heparin versus warfarin sodium: a randomized trial comparingthe quality of life associated with these antithrombotic therapies.Blood. 2001;98:267A.

9. Hull RD, Pineo GF, Mah AF, Brant RF, for the LITE StudyInvestigators. A randomized trial evaluating long-term low-molec-ular-weight heparin therapy out-of-hospital versus warfarin sodiumcomparing the post-phlebitic outcomes at three months. Blood.2001;98:447A.

0. Grambsch P, Therneau TM. Proportional hazards tests and diagnosticsbased on weighted residuals. Biometrika. 1994;81:515-526.

1. Bradburn MJ, Deeks JJ, Altman DG. Metan—an alternative meta-analysis command. Stata Tech Bull. 1998;44:4-15.

2. Matisse Investigators. Subcutaneous fondaparinux versus intravenousunfractionated heparin in the initial treatment of pulmonary embolism.

N Engl J Med. 2003;349:1695-1702.

3. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux orenoxaparin for the initial treatment of symptomatic deep venousthrombosis: a randomized trial. Ann Intern Med. 2004;140:867-873.

4. Samama CM, Vray M, Barre J, et al, for the SACRE Study Inves-tigators. Extended venous thromboembolism prophylaxis after totalhip replacement. Arch Intern Med. 2002;162:2191-2196.

5. Andriuoli G, Mastacchi R, Barnti M, et al. Comparison of the anti-thrombotic and hemorrhagic effects of heparin and a new low molec-ular weight heparin in the rat. Haemostasis. 1985;15:324-330.

6. Carter CJ, Kelton JG, Hirsh J, et al. The relationship between thehemorrhagic and antithrombotic properties of low molecular weightheparins and heparin. Blood. 1982;59:1239-1245.

7. Kakkar VV, Gebska M, Kadziola Z, Saba N, Carrasco P, for theBemiparin Investigators. Low-molecular-weight heparin in the acuteand long-term treatment of deep vein thrombosis. Thromb Haemost.2003;89:674-680.

8. Marchetti M, Pistorio A, Barone M, Serafini S, Barosi G. Low-molecular-weight heparin versus warfarin for secondary prophylaxisof venous thromboembolism: a cost-effectiveness analysis. Am J Med.2001;111:130-139.

9. Menendez-Jandula B, Souto JC, Oliver A, et al. Comparing self-management of oral anticoagulant therapy with clinic management: arandomized trial. Ann Intern Med. 2005;142:1-10.

0. Hull RD, Pineo GF, Brant RF, et al, for the LITE Trial Investigators.Long-term LMWH versus usual-care in proximal-vein thrombosis

patients with cancer. Am J Med. 2006;119:1062-1072.

Table Study Design, Patient Eligibility, and Allocation and Treatment Regimens

Study DesignPatient population: Patients with proximal vein thrombosisDesign Multicenter, open-label, randomized trialComparison: Long-term subcutaneous LMWH vs usual-care initial intravenous heparin and long-term oral warfarin

sodiumDuration of therapy: 3 moStudy rationale: This study is one of a set of studies using a randomized design with objective assessment of outcome.

The set of studies were performed under the auspices of the Long-term Innovations in TreatmEntprogram (LITE) funded by the Canadian Institutes of Health Research, formerly Medical ResearchCouncil, and industry.

Main-LITE, which is reported hereHome-LITE, a home treatment study evaluating quality of life and the postphlebitic syndrome, which is

reported separately18

An evaluation of patients with cancer and proximal deep vein thrombosis was also planned prospectivelyand performed because patients with cancer were randomized separately within the Main-LITEpopulation of patients. The findings in patients with cancer are reported separately.

Center participation: Thirty centers in Canada participated.Ethics: The protocol was approved by the institutional review board at each center. Written informed consent

was obtained from all patients.Compliance with

CONSORT:Our study and the reporting of the findings comply with the CONSORT statement19,20 and the more

recent updating of the agreement “Better reporting of harms in randomized trials: an extension of theCONSORT statement.”21

Patient Eligibility and AllocationConsecutive eligible patients 18 years of age or older with acute proximal vein thrombosis (popliteal,

femoral, or iliac vein thrombosis) documented by venography or compression ultrasonography wereenrolled in the study. Patients presenting with pulmonary embolism were eligible, providing they hadproximal vein thrombosis.

Patients were eligible ifthey had none of thefollowing:

A bleeding diathesis or bleeding contraindicating anticoagulation; pregnancy; breastfeeding; allergy toheparin or bisulfates; history of heparin-associated thrombocytopenia; malignant hypertension orblood pressure equal to or greater than 250 mm Hg systolic or 130 mm Hg diastolic; hepaticencephalopathy; renal failure necessitating dialysis; neurologic or ophthalmic surgery within 14 d;pulmonary embolism requiring thrombolysis, thrombectomy, or vena cava interruption; life expectancyless than 3 mo; lumbar puncture within 24 h; receiving oral anticoagulation for other conditions;unable to discontinue acetylsalicylic acid; eligible for home therapy with LMWH but could not beallocated to intravenous heparin, which requires hospitalization; participating in another trial; unableto inject (eg, arthritis or lack of family support); or geographic inaccessibility for follow-up

Eligible patients wereexcluded if they:

Received heparin, LMWH, or oral anticoagulant therapy for more than 2 d (575 patients) or were unableor declined to give written informed consent (900 patients). The excluded patient population as aproportion is less than that reported in other landmark cardiovascular trials.

Before randomization,patients werestratified according to:

Study center; whether primary or recurrent venous thrombosis, high or low risk for bleeding,22,23 andcancer

With regard to the riskof bleeding, patientswere stratified intogroups according to:

The absence (low risk) or presence (high risk) of one or more risk factors for bleeding including surgeryor trauma within the previous 14 d, history of peptic ulcer disease, bleeding into the gastrointestinalor genitourinary tract, thrombotic stroke within the previous 14 d, platelet count less than 150 �109/L, or miscellaneous reasons (predisposing disorders) for a high risk of bleeding.

Randomization: A computer-derived randomized treatment schedule was used; within each stratum, the randomizedschedule was balanced in blocks of two and four.

Treatment RegimensLMWH: Patients assigned to LMWH received tinzaparin (Innohep, Leo Pharmaceutical Products Ltd A/S of

Denmark) subcutaneously in a fixed dose of 175 International Factor Xa Inhibitory Units per kilogramof body weight once daily.

Patients were taught to self-administer injections; for some, family members administered the injection.Patients receiving LMWH underwent platelet counts at 14 and 21 d.

Unfractionated beparinand warfarin sodium:

Patients receiving unfractionated heparin and warfarin sodium were given an intravenous heparin bolusof 5000 units or 80 units per kilogram, followed by a continuous intravenous infusion.

The heparin infusion was administered according to one of two validated protocols for ensuringadequate heparin therapy.23,24

The heparin infusion was adjusted according to the results of laboratory monitoring using the activatedpartial thromboplastin time described elsewhere.25

82.e1Hull et al Long-term LMWH Therapy

Table Study Design, Patient Eligibility, and Allocation and Treatment Regimens (continued)

Warfarin sodium was commenced on day 1 at 5 to 10 mg, then adjusted daily to maintain the INRbetween 2.0 and 3.01,5 overlapping with heparin to day 6 when heparin was discontinued if the INRwas therapeutic. Thereafter, INR monitoring was performed every 1 to 2 wk until cessation of therapy.

Prohibited medications: Acetylsalicylic acid use was prohibited, and ticlopidine, sulfinpyrazone, dipyridamole, and nonsteroidalanti-inflammatory drugs were strongly discouraged.

On completion of study drug at 12 wk, therapy was discontinued unless oral anticoagulation was indicated; this was determined foreach patient by the primary care physician according to the standard of care.

LMWH � low-molecular-weight heparin; INR � international normalized ratio.

Appendix Participating Sites

Site Name, Location Principal Investigator(s), Coordinator(s)No. of PatientsEnrolled

Foothills Hospital, Calgary, AB R. Hull, D. Kimmett, K. Morrison, H. Hair,B. Sham

171

Peter Lougheed Centre, Calgary, AB R. Dear, T. Mooers, C. Dielissen, J. Gardner,D. Mckeage

106

St Boniface General Hospital, Winnipeg, MN T. Wong, S. Erickson-Nesmith 82Rockyview General Hospital, Calgary, AB R. Cook, D. Burnand, J. Dear, J. Davis,

M. McDonald64

Montreal General Hospital, Montreal, QU S. Solymoss, S. Finkenbine, B. St Jacques 49Royal Alexandra Hospital, Edmonton, AB C. Harley, E. Konopad, P. Nicholls, N. Whalen,

V. Troncoso32

Red Deer Regional Hospital, Red Deer, AB J. Singh, J. Glen 26Hotel Dieu de Hospital, Montreal, QC P. Nguyen, B. LeCours, S. Roy 25Kelowna General Hospital, Kelowna, BC J. Sutherland, M. Mantle, S. Shori 22University Hospital, London, ON M. Cruickshank (deceased), M. von Lewinski 21Grey Bruce Regional Health Centre, Owen Sound, ON J. Ostrander, S. St Croix 20Ottawa General Hospital, Ottawa, ON M. Rodger, A. M. Clement, B. Kearns 19University Hospital, Edmonton, AB M. Mant, P. Donahue, M. MacDonald 19St Paul’s Hospital, Vancouver, BC L. Vickars, L. Bachop, L. Wadup, D. Heinrich,

M. Rusak, D. Michaels, J. Poirier, S. Taylor18

Jewish General Hospital, Montreal, QC S. Kahn, C. Strulovitch 12St Joseph’s Health Centre, London, ON W. Brien, B. Palmer, M. von Lewinski 10Group Health Centre, Sault Ste Marie, ON H. Lee (deceased), S. McLean, K. Barban,

J. Sloss7

St Mary’s Hospital Centre, Montreal, QC S. Solymoss, S. Finkenbine, B. St Jacques,L. Porco, M. Iskander

7

Sudbury General Hospital, Sudbury, ON C. Bourdon, J. Bretzlaff-Michaud, H. Neilson,D. Cole, L. Fabris

6

Memorial University, St John’s, NF L. Whitman, J. Watson 5St Joseph’s General Hospital, Comox, BC R. Engman, B. Paulson 3St Michael’s Hospital, Toronto, ON J. Teitel, R. Tanzini 3Burnaby Hospital, Burnaby, BC T. Sparling, W. Leong, E. Asirvatham,

M. Bernard, L. Scoffield, L. Brown, D. Jay2

Centre Universitaire de Sante, Fleurimont, QC M. Lepine-Martin, L. Claprood, M. Grondin 2Greater Niagara General Hospital, Niagara Falls, ON M. Alexander, R. Shriver R. Rutherford, C. Gabriell 1Orthopaedic & Arthritic Hospital, Toronto, ON W. Cass, B. Goudie, S. Barnes, C. Bakuska 1Port Arthur General Hospital, Thunder Bay, ON A. Dhar, D. Martin, C. Elliott 1Saint John Regional Hospital, Saint John, NB S. Dolan, P. Cook 1Sunnybrook Health Science Centre, Toronto, ON W. Geerts, K. Code, K. Belisle 1Vancouver General Hospital, Vancouver, BC S. Nantel, L. Pringle, S. Rekker 1Adjudicators: G. Elliott, J. George, G. RaskobData Safety Monitoring: C. Carter, Chair

82.e2 The American Journal of Medicine, Vol 120, No 1, January 2007

Test 1 to 7 performed on day 1 through 7 Tests 8 to 18 performed on weeks 2 through 12

Activated partial-thromboplastin time (APTT) during initial

treatment for the study patients randomized to unfractionated

heparin, according to test sequence

International Normalized Ratios (INR) for the study patients

randomized to warfarin during the study interval

The top and bottom of each box represent the upper and lower quartiles of the values for the sample, and the centre line the

medians. Bars extend above and below each box to the maximal and minimal values in the sample or, if there are extreme

250

0

50

100

150

200

1 2 3 4 5 6 7 8 9 10 11

APTT(seconds)

Test Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1816 17

6

5

4

3

1

2

0

INR

Test Number

data points, to limits based on the interquartile range, defined as the distance from the lower quartile to the upper quartile.

Outliers beyond these limits are plotted separately.

The therapeutic ranges for both heparin and warfarin were successfully achieved (see median values).

82.e3Hull et al Long-term LMWH Therapy