Self-Managed Long-Term Low-Molecular-Weight Heparin Therapy: The Balance of Benefits and Harms

Article Outline

• Abstract
• Methods
  • Study Design
  • Surveillance and Follow-up
  • Statistical Analysis
• Results
  • Study Population
  • Recurrent Venous Thromboembolism
  • Bleeding Complications
    • Frequency of Bleeding and Time to Event Analysis
    • Timing of Bleeding Occurrence
    • Risk of Bleeding
    • Predictive Nature of Risk Categorization for Bleeding and Its Interaction Among the Treatment Groups
    • Site of Bleeding
  • Deaths
  • Patient Outcomes at 12-Month Follow-up
  • Other Findings
• Discussion
• Acknowledgment
• Appendix. 
• References
• Copyright

Abstract 

Purpose

A substantial clinical need exists for an alternate to vitamin K antagonists for treating deep vein thrombosis in many patients. Long-term low-molecular-weight heparin (LMWH), body-weight adjusted, avoids anticoagulant monitoring and may be associated with less bleeding. We evaluated the effectiveness and safety of long-term LMWH compared with vitamin K antagonist therapy in a broad spectrum of patients with proximal vein thrombosis.

Methods

We performed a multicenter, randomized, open-label clinical trial using objective outcome measures comparing therapy for 3 months. Outcomes were assessed at 3 and 12 months.

Results

Of 737 patients, 18 of 369 receiving tinzaparin (4.9%) had recurrent venous thromboembolism at 3 months compared with 21 of 368 (5.7%) receiving usual care (absolute difference, −0.8%, 95% confidence interval −4.1-2.4). Hemorrhagic complications occurred less frequently in the LMWH group largely because of less minor bleeding: 48 of 369 patients (13.0%) versus 73 of 368 patients (19.8%) receiving usual-care anticoagulation (absolute difference −6.8%; P = .011; risk ratio = 0.66). New major bleeding events ceased early (by day 23, P = .034) for patients receiving LMWH but persisted throughout the study treatment interval for patients receiving vitamin K antagonist therapy. No mortality advantage was shown for LMWH.

Conclusion

Our study shows that LMWH is similar in effectiveness to the usual-care vitamin K antagonist treatment for preventing recurrent venous thromboembolism in a broad spectrum of patients. It causes less harm and enhances the clinicians’ therapeutic options for patients with proximal deep vein thrombosis. Our findings reported here suggest the possibility of a broader role for long-term LMWH in selected patients.

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

The classic long-term treatment for deep vein thrombosis is vitamin K antagonist therapy overlapped with initial heparin or low-molecular-weight heparin (LMWH) therapy.¹ The use of accurate objective tests to detect venous thromboembolism has led to randomized trials evaluating short-term therapy or long-term anticoagulants for venous thrombosis, which have advanced our therapeutic understanding. Initial short-term LMWH therapy is effective and preferred over intravenous heparin because anticoagulant monitoring is not required, facilitating outpatient therapy.², ³ For vitamin K antagonist therapy,¹, ⁴, ⁵, ⁶ the importance of maintaining a therapeutic international normalized ratio (INR) (2.0-3.0) is well documented; this necessitates frequent INR monitoring.

There is a need for an effective and safe alternate therapy to vitamin K antagonists in a broad spectrum of patients with venous thrombosis. It is possible that long-term LMWH, although administered subcutaneously, is a viable option in such patients. A key concern with long-term vitamin K antagonists is harm resulting from hemorrhagic complications.⁷, ⁸ The aggregate data,⁷, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ as reported by the “Cochrane Database of Systematic Reviews,” identify that long-term LMWH may cause less bleeding, but further study is required in the individual trial setting to determine whether safety is indeed improved. The Cochrane authors also report uncertainty on the efficacy of long-term LMWH for preventing recurrent venous thromboembolism, but the authors note that the prophylactic LMWH doses used in some of these trials may have resulted in inadequate therapy. Subsequently, long-term LMWH was shown to be more effective than vitamin K antagonists for preventing recurrent venous thromboembolism in patients with cancer and venous thromboembolism¹⁶ without increased bleeding. Whether this benefit applies to other patient groups with deep vein thrombosis is uncertain; there are insufficient data in patients without cancer with deep vein thrombosis.⁷ Indeed, the authors of a recent review article¹⁷ conclude that further clinical trials are necessary, because LMWH may prove to be an appropriate long-term therapy.

We conducted a large multicenter, randomized, open-label clinical trial in a broad spectrum of patients to evaluate the effectiveness (benefits) and harm (safety) of long-term LMWH, using a therapeutic dose of tinzaparin once daily subcutaneously, compared with usual care consisting of intravenous heparin and long-term vitamin K antagonist therapy.

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Methods 

Study Design 

The study design, patient eligibility and allocation, and treatment regimens are shown in the table available online.¹, ², ³, ⁴, ⁵, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵

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

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

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, determining whether the patient had experienced 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 ultrasonography², ³, 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 by pulmonary embolism found at autopsy.

The primary safety end point 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 decrease in hemoglobin of 2 g/dL 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.⁴, ³⁴, ³⁵, ³⁶, ³⁷ Bleeding was defined as minor if it was clinically overt but did not meet other criteria for major bleeding.⁴, ³⁴, ³⁵, ³⁶, ³⁷ These criteria were used successfully in previous studies.⁴, ³⁴, ³⁵, ³⁶, 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 involved in the patient’s care, and disputes were resolved independently by a third member. Members of the committee were unaware of the patients’ treatment assignments.

Statistical Analysis 

A sample size of 455 patients in each treatment group was initially chosen to provide 80% power for a 2-sided test (α = .05) to detect a 50% reduction in mortality from the 9.6% experienced in a previous trial suggesting a mortality advantage.³⁵ The findings of a companion randomized trial (Home-LITE) evaluating quality of life and postphlebitic outcome suggested rebound recurrent venous thromboembolism immediately after cessation of long-term LMWH therapy.¹⁸, ³⁸, ³⁹ Because of both safety and regulatory affair requirements, the trial reported here was terminated when 737 patients were enrolled. Because our confidence interval (CI) for relative mortality risk excludes a 50% reduction (favoring either group), we conclude that the achieved sample size is sufficient for our primary aims.

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-square test and associated CIs. 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.⁴⁰ Proportional hazards test diagnostics were based on weighted residuals.⁴⁰ CIs were derived from standard errors calculated from Greenwood’s formula. The meta-analysis was conducted following a fixed-effects approach based on the Mantel-Haenszel method as implemented in the metan procedure⁴¹ of Stata software, release 6.0 (Stata Corp, College Station, Tex).

The protocol was designed by 3 investigators. The steering committee, central adjudication committee, and statistical analysis were independent of the sponsor. The Thrombosis Research Unit, University of Calgary, coordinated the study and carried out the data management and administrative duties. Statistical analysis was carried out independently of the industry sponsor by Rollin F. Brant, PhD, Department of Community Health Sciences, University of Calgary.

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Results 

Study Population 

A total of 737 consecutive patients were recruited beginning in 1994 at 30 centers across Canada (see Appendix available online) and randomized to tinzaparin (369 patients) or usual-care anticoagulants (368 patients). A broad spectrum of patients were evaluated. Figure 1 shows the patient flow for the eligible patients and those randomized to the treatment groups. The tinzaparin and usual-care groups were comparable at entry (Table 1). Because of difficulties with occasional patient follow-up, which were overcome, successful patient follow-up was completed in July 2003.

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• Figure 1. 

  Participant flow chart.

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

Characteristic	LMWH N = 369	Intravenous Heparin/Warfarin N = 368
	No. of Patients (%)
Age <60 y, ≥60 y	187, 182	151, 217
Sex (M, F)	207, 162	188, 180
Status 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)

Recurrent Venous Thromboembolism 

The outcomes for recurrent venous thromboembolism are shown in Figure 2 and Table 2.

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• Figure 2. 

  Time to event analysis for patients who had recurrent venous thromboembolism At 3 months, of 737 patients, 18 of 369 patients receiving tinzaparin (4.9%) had recurrent venous thromboembolism compared with 21 of 368 (5.7%) receiving usual care (absolute difference, −0.8%, 95% CI, −4.1-2.4). IV = intravenous; LMWH = low-molecular-weight heparin.

Table 2. Outcomes at 3 Months

	Tinzaparin N = 369 n (%)	Usual Care⁎ N = 368 n (%)	Absolute Difference (95% CI)	P Value
New episodes of venous thromboembolism†
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
Death
At 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 complications
Frequency of bleeding
All	48(13.0)	73(19.8)	−6.8(−12.4-−1.5)	P = .011
Major	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 bleeding
All 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 bleeding
High 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 bleeding
High 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 findings
Thrombocytopenia††
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.

Long-term vitamin K antagonist therapy was administered by the primary care physician, if indicated, in patients such as those with recurrent or idiopathic deep vein thrombosis at entry or who had a continuing risk factor. The physician instituted or continued vitamin K antagonist therapy long term in 146 patients assigned to LMWH (mean duration 202 d, median duration 258 d) and in 250 patients assigned to intravenous heparin/warfarin (mean duration 156 d, median duration 147 d). In patients with cancer, 37 were assigned to LMWH (mean duration 215 d, median duration 272 d), and 57 were assigned to intravenous heparin/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 outcome differences between the groups. In patients without a predisposing factor for bleeding on entry (low risk for bleeding), long-term LMWH therapy use was associated with significantly less overall bleeding.

High risk for bleeding stratum compared with low risk:

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 tract bleeding, 23 patients (6.3%) versus 13 patients (3.5%), respectively. Thus, hemorrhagic complications involving mucosal sites (nasopharyngeal, upper and lower digestive tract, and bronchial) occurred in 51 of 368 patients (13.9%) receiving vitamin K antagonist therapy compared with 26 of 369 patients (7%) receiving LMWH (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.

At 3 months, of 737 patients, 18 of 369 patients receiving tinzaparin (4.9%) had recurrent venous thromboembolism compared with 21 of 368 patients (5.7%) receiving usual-care anticoagulation (absolute difference, −0.8%, 95% CI, −4.1-2.4). Thus, LMWH was unlikely to be more effective against recurrent venous thromboembolism than usual-care anticoagulation by more than 4.1% (absolute risk difference), and usual-care anticoagulation was unlikely to be more effective than LMWH by more than 2.4%.

The activated partial thromboplastin time and INR values for patients receiving usual-care anticoagulation are shown according to test sequence in the Appendix figure (available online).

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

Bleeding Complications 

A detailed analysis of the harm caused by bleeding is provided to comply with the recent CONSORT agreement “Better Reporting of Harms in Randomized Trials.”²¹

Hemorrhagic complications are shown in Figure 3 and Table 2. Bleeding occurred in 48 of 369 patients (13.0%) receiving LMWH and 73 of 368 patients (19.8%) receiving usual-care anticoagulation (P = .011; absolute difference −6.8%, risk ratio = 0.66). Major bleeding occurred in 12 patients (3.3%) receiving LMWH and in 17 patients (4.6%) receiving usual-care anticoagulation (absolute difference −1.4; risk ratio = 0.70). Minor bleeding occurred in 36 patients (9.8%) receiving LMWH and in 56 patients (15.2%) receiving unfractionated heparin and warfarin (P = .022; absolute difference −5.5; risk ratio = 0.64).

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• Figure 3. 

  Time to event analysis for patients who had hemorrhagic complications. A: All bleeding. Bleeding occurred in 48 of 369 patients (13.0%) receiving LMWH and 73 of 368 patients (19.8%) receiving heparin and warfarin (P = .011; risk ratio = 0.66). B: Major bleeding. Major bleeding occurred in 12 of 369 patients (3.3%) in the LMWH group and in 17 of 368 patients (4.6%) receiving heparin and warfarin (risk ratio = 0.70; absolute difference −1.4, 95% CI, −4.3-1.4). C: Minor bleeding. Minor bleeding occurred in 36 of 369 patients (9.8%) receiving LMWH and in 56 of 368 patients (15.2%) receiving heparin and warfarin (P = .022; risk ratio = 0.64). IV = intravenous; LMWH = low-molecular-weight heparin.

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

The occurrence of bleeding according to time course of study therapy for each group is shown in Figure 4 for major and minor bleeding complications.

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• Figure 4. 

  Prevalence of bleeding over time. The occurrence of bleeding according to time course of study therapy for each group is shown for major and minor bleeding complications. The pattern of the time of presentation of major bleeding differed significantly between groups (P = .034). New major bleeding events occurred throughout study treatment for patients in the usual-care group receiving warfarin but did not present after day 23 in the LMWH group (P = .034). New minor bleeding episodes occurred throughout the study treatment interval for both treatment groups. LMWH = low-molecular-weight heparin.

Patients were stratified according to the absence (low risk) or presence (high risk) of risk factors for bleeding. On entry, 290 of the 737 patients (39.3%) were at high risk for bleeding and 447 patients (60.7%) were at low risk for bleeding. The treatment groups were comparable at entry for the proportion of patients at high risk of bleeding (Table 1, Table 2). Major bleeding occurred in 23 of 290 patients (7.9%) at high risk for bleeding compared with 6 of 447 patients (1.3%) (P < .001) at low risk for bleeding.

Risk categorization was predictive of bleeding, because patients at low risk for bleeding had significantly less hemorrhagic complications receiving LMWH or usual care comparing high- versus low-risk strata (Table 2). Bleeding complications, either major or minor, by risk stratification for bleeding and their association with each treatment group are presented separately (Table 2).

The site of bleeding is described in the legend of Table 2.

Deaths 

No mortality advantage for LMWH was found (Table 2). Mortality findings and causes of death are shown in Table 3.

Table 3. Causes of Death in the Two Treatment Groups

Cause of Death	LMWH		Usual Care
	Deaths (N = 25)	Days After Start of Therapy	Deaths (N = 24)	Days After Start of Therapy
Abrupt⁎	(n = 4)		(n = 6)
Pulmonary embolism	1	5 (by autopsy)	2	13 (by autopsy), 14
Possible pulmonary embolism?	2	1, 6	2	2, 24
Suspected pulmonary embolism/metastatic cancer?	0		1	23
Metastatic cancer	0		1	81
Cerebrovascular	1	39	0
Insidious⁎	(n = 20)		(n = 18)
Suspected pulmonary embolism?/metastatic cancer	0		1	11
Metastatic cancer	18	7, 17, 17, 22, 25, 35, 40 (2), 41, 44, 45, 46, 48, 52, 64, 67, 82 (2)	14	9, 16, 19, 21, 30, 32 (2), 41 (2), 61, 62, 76, 81, 84
Pneumonia	1	35	1	70
Cardiovascular	0		1	37
Cerebrovascular	1	17	0
Parkinson disease	0		1	23
Unknown if abrupt or insidious	(n = 1)		(n = 0)
Cardiovascular	1	29	0

In the LMWH group, death was complicated by intracranial hemorrhage (1 patient) and a gastrointestinal bleed (1 patient). In the usual-care vitamin K antagonist group, the cause of death was complicated by a gastrointestinal bleed (2 patients) and a major bleed (intracerebral) at the time of death (1 patient).

Patient Outcomes at 12-Month Follow-up 

The findings for recurrent venous thromboembolism and death are shown in Table 2.

A rebound in the frequency of recurrent venous thromboembolic events was not seen in either group after cessation of therapy at 3 months.

Other Findings 

The frequencies for thrombocytopenia are shown in Table 2. For those patients with thrombocytopenia, the outcomes differed between the treatment groups. Six of 9 patients with thrombocytopenia receiving usual care died (66.7%, 95% CI, 29.9-92.5) versus 4 of 21 patients with thrombocytopenia receiving LMWH (19%, 95% CI, 5.4-41.9) (absolute difference 47.6%, 95% CI, 82.7-12.5, P = .03). Recurrent objectively confirmed venous thromboembolism occurred infrequently in patients with thrombocytopenia.

The frequencies for bone fractures are shown in Table 2.

Figure 5 shows the summary treatment effects for the outcomes of recurrent venous thromboembolism and hemorrhagic complications. These favored long-term LMWH therapy. The test for heterogeneity was nonsignificant (recurrent venous thromboembolism P = .34, hemorrhagic complications P = .41).

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• Figure 5. 

  *Treatment duration 3 months. †Treatment duration 3 to 6 months. ‡Treatment duration 6 months. LMWH = low-molecular-weight heparin; CI = confidence interval; LMWH regimen: T = treatment dose; P = prophylactic dose; M = reduced maintenance dose.

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Discussion 

We did not find LMWH to be superior to usual therapy with vitamin K antagonists for the outcome of mortality, which is consistent with the outcomes of other studies.⁷, ⁸, ¹⁶ In a broad spectrum of patients, long-term LMWH compared with vitamin K antagonist therapy for 3 months shows similar efficacy against recurrent venous thromboembolism. Of the 737 patients with proximal venous thrombosis on entry, 18 of 369 patients (4.9%) had recurrent venous thromboembolism in the LMWH group compared with 21 of 368 patients (5.7%) in the usual-care group (absolute difference, −0.9%, 95% CI, −4.1-2.4). Thus, LMWH is unlikely to be less effective than usual care by more than an absolute difference of 2.4%. Such narrow margins for recurrent venous thromboembolism have been accepted to establish the non-inferiority of new antithrombotics compared with usual care for the initial treatment of venous thromboembolism.⁴², ⁴³

Our findings suggest improved safety for long-term LMWH therapy because of less harm from bleeding compared with usual care with vitamin K antagonist therapy (P = .011). All bleeding and minor bleeding were less frequent in patients receiving LMWH. Minor bleeding clearly detracts from quality of life and consumes health care resources. In the early 1980s, a trial evaluating vitamin K antagonist therapy⁴ that led to less-intense oral anticoagulant therapy (INR: 2.0-3.0) showed improved safety, largely because of less minor bleeding. Subsequently, this safer vitamin K antagonist therapy became the standard of care.¹, ⁴, ⁶

The timing of new major bleeding events differed among the treatment groups. New major bleeding events occurred throughout the study treatment interval for patients in the usual-care group receiving warfarin but ceased early in the LMWH group (P = .034) (Figure 4). This protective effect was previously observed using the same LMWH regimen³⁵ for initial treatment, but the bleeding advantage was lost during subsequent long-term vitamin K antagonist therapy. The observation that major bleeding events ceased early with long-term LMWH may reflect the interplay between treatment and the presence or absence of predisposing factors for bleeding. Bleeding was significantly less likely for patients receiving LMWH compared with usual care in the absence of predisposing factors for bleeding (low-risk patients) (P = .01). For patients receiving usual care, the fact that hemorrhagic complications occurred more frequently in the low-risk group suggests that long-term usual care was innately more hemorrhagic. Conversely, patients at high risk for bleeding had similar rates for bleeding with either therapy.

A clinically relevant finding is that usual care was associated with significantly more bleeding from mucosal sites (P = .003). This is clinically relevant because of the need to intervene diagnostically to resolve the bleeding complication.

Our findings regarding bleeding are supported by the literature.⁷ In addition, extended LMWH prophylaxis after total hip replacement compared with vitamin K antagonists was significantly less harmful because of avoidance of bleeding.⁴⁴ The reduced bleeding observed with LMWH is consistent with reduced bleeding found in animal models.⁴⁵, ⁴⁶

Thrombocytopenia was uncommon in both groups. Good clinical practice necessitated platelet count monitoring during the first 3 weeks of therapy with long-term LMWH compared with 1 week only for usual care. A higher proportion of patients with thrombocytopenia in the usual-care group died in comparison with those receiving LMWH who had thrombocytopenia. The greater harm associated with usual-care thrombocytopenia requires further study.

Bone fractures potentially caused by concomitant osteoporosis occurred infrequently in both treatment groups, but further study of this complication is required.

Prior studies⁸, ⁹, ¹⁰, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ⁴⁷ evaluating long-term LMWH therapy (Figure 5) were limited in size, used prophylactic doses of LMWH (which may have been insufficient to prevent recurrent venous thromboembolism), or evaluated selected patients, such as those with cancer. To date, all studies (Figure 5) evaluating long-term LMWH have had an open-label design because of the difficulty in double-blinding such studies.

The open-label design could be a potential source of bias in our trial. A double-blind design was not feasible because of 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. Before the study, criteria for eligibility were specified and a representative sample of eligible patients were randomized. The 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 (see Appendix). Also, an important bias related to treatment management is unlikely because the INR control achieved was similar to that reported in other studies.⁴, ⁶, ³⁴, ³⁶ It is likely that our results are relevant to clinical practice and not unduly influenced by bias.

A rebound in the frequency of recurrent venous thromboembolic events was not seen in patients receiving LMWH at cessation of therapy. The issue of potential rebound requires further study.¹⁸, ⁴⁸

Self-managed oral anticoagulant therapy compared with anticoagulant clinic management resulted in improved patient outcomes.⁴⁹ Although self-management of oral anticoagulant treatment achieved a similar level of anticoagulant INR control, harm resulting from bleeding complications, largely minor hemorrhage, occurred less frequently in self-managed patients. The option of long-term LMWH therapy offers an even simpler alternative by removing the need for anticoagulant monitoring and dose adjustment. LMWH as evaluated in our study allows more patient autonomy, uses less resources (eg, blood stations and anticoagulant monitoring), and is safer than physician-managed oral anticoagulation.

An evaluation of the cost-effectiveness of long-term LMWH is beyond the scope of this article, but it may be cost-effective in patients at high risk of recurrence.⁴⁸ The use of long-term LMWH in individual patients with deep vein thrombosis will depend on the clinical setting, patient comorbidity, ability to self-inject (patient or family members), health care system resources, and availability of reimbursement. Patient self-management, with the associated independence from routine long-term anticoagulant monitoring, may prove a powerful determinant for choosing LMWH therapy for individual patients. The relevance of this innovative regimen is considerable given the ubiquitous nature and ongoing presentation of deep vein thrombosis as an important health care problem.

Our study shows that LMWH is similar in effectiveness to the usual-care vitamin K antagonist treatment for preventing recurrent venous thromboembolism in a broad spectrum of patients. It causes less harm and enhances the clinicians’ therapeutic options for patients with proximal deep vein thrombosis. The aggregate data show that LMWH is preferred in patients with cancer with venous thromboembolism.¹⁶, ⁵⁰ Our findings suggest the possibility of a broader role for long-term LMWH in selected patients.

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Acknowledgment 

The authors thank Avneet Brar and Jeanne Sheldon, BA, for their assistance in the preparation of the article.

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Appendix. 

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Appendix. Participating Sites

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References 

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