| | Home Therapy of Venous Thrombosis with Long-term LMWH versus Usual Care: Patient Satisfaction and Post-thrombotic SyndromeAbstract PurposeHome-LITE compared long-term treatment at home with tinzaparin or usual care in terms of efficacy, safety, patients' treatment satisfaction, incidence of post-thrombotic syndrome, and associated venous leg ulcers. MethodsThis multicenter, randomized, controlled trial enrolled 480 patients with documented, acute, proximal deep vein thrombosis. Patients received tinzaparin 175 IU/kg subcutaneously once daily for 12 weeks, or tinzaparin for ≥5 days plus oral warfarin, commenced on day 1, international normalized ratio-adjusted, and continued for ≥12 weeks (“usual care”). Patients received 1 in-clinic injection, then home treatment. ResultsThe rate of recurrent venous thromboembolism at 12 weeks was 3.3% in both groups (absolute difference 0%; 95% confidence interval −3.2-3.2), and at 1 year was 10.4%/8.3% in the tinzaparin/usual-care groups, respectively (difference 2.1%; 95% confidence interval −3.1-7.3). There were no between-group differences in deaths at 12 weeks or 1 year, or bleeding at 12 weeks. Patients in the tinzaparin group expressed significantly greater treatment satisfaction (P = .0024), particularly regarding freedom from the inconvenience of blood monitoring; were less likely to report signs/symptoms of post-thrombotic syndrome (individual odds ratios 0.66 to 0.91, overall odds ratio 0.77, P = .001); and reported fewer leg ulcers at 12 weeks: 1 (0.5%) versus 8 (4.1%) (P = .02) with usual care. ConclusionsLong-term home treatment with tinzaparin or usual care resulted in similar rates of recurrent venous thromboembolism, death, and bleeding. The significantly lower incidence of post-thrombotic syndrome and leg ulcers observed in the tinzaparin group is a potentially important benefit and deserves further study. Patients with proximal deep vein thrombosis require long-term anticoagulant treatment to prevent symptomatic extension and/or recurrent venous thromboembolism.1 Earlier guidelines for therapy of deep vein thrombosis and/or pulmonary embolism recommended unfractionated heparin or low-molecular-weight heparin for 5-7 days, initiating a vitamin K antagonist on day 1 and continuing for at least 3 months.1 More recent guidelines recommend subcutaneous low-molecular-weight heparin, rather than unfractionated heparin, for initial treatment for deep vein thrombosis,2 as it is at least as safe and effective as unfractionated heparin, and more convenient, not requiring intravenous infusion or frequent monitoring. Clinical Significance•Efficacy and safety were similar when patients with deep vein thrombosis were treated out of hospital with either once-daily subcutaneous tinzaparin 175 IU/kg, or tinzaparin for ≥5 days followed by warfarin, for 12 weeks. •The occurrence of symptoms of the post-thrombotic syndrome and of leg ulcers was significantly lower with tinzaparin relative to Usual Care. •Patients receiving long-term treatment with tinzaparin had significantly less interruption of work. Home-LITE is one of 3 trials in the Long-term Innovations in TreatmEnt (LITE) program of studies, which were designed to evaluate long-term treatment of proximal deep vein thrombosis with low-molecular-weight heparin, at a time when few data were available to support this approach. The first 2 studies in the LITE series compared the efficacy and safety of the treatment of deep vein thrombosis using either the low-molecular-weight heparin tinzaparin (Innohep, LEO Pharma A/S Ltd., Ballerup, Denmark) given long-term, or unfractionated heparin therapy followed by vitamin K antagonist.3, 4 Long-term once-daily tinzaparin showed similar efficacy, but caused less bleeding than unfractionated heparin/vitamin K antagonist in a broad spectrum of patients (the Main-LITE study).4 In cancer patients with deep vein thrombosis, long-term tinzaparin was more effective than unfractionated heparin/vitamin K antagonist in preventing recurrent venous thromboembolism, and bleeding was similar with both regimens (the Main-LITE Cancer study).3 In these 2 studies, patients were hospitalized for as long as clinically required. The current study, Home-LITE, examined whether there are benefits to long-term once-daily low-molecular-weight heparin in patients with proximal deep vein thrombosis when treated at home from the outset, compared with low-molecular-weight heparin/warfarin. Home-LITE also addressed patients' satisfaction with their treatment, and the incidence of post-thrombotic syndrome. Post-thrombotic syndrome is a common sequela of deep vein thrombosis, occurring in 20%-60% of patients.2, 5, 6, 7, 8, 9 The pathophysiology of post-thrombotic syndrome is incompletely understood, but its development post deep vein thrombosis is believed to be related to the presence of persistent venous obstruction and/or reflux. It causes chronic lifestyle-limiting symptoms such as venous insufficiency, limb swelling, and pain. Post-thrombotic syndrome impacts negatively on patients' quality of life, can progress to leg ulcers, and is a large economic burden on society.5, 9 Adequate anticoagulation after a deep vein thrombosis is believed to reduce the development and severity of post-thrombotic syndrome.5, 7, 9 The objectives of Home-LITE were to compare long-term treatment at home with tinzaparin or usual care using the following outcomes: efficacy (venous thromboembolism recurrence, mortality), safety (bleeding, thrombocytopenia, bone fractures), patients' satisfaction; and the incidence of post-thrombotic syndrome and venous leg ulcers. Methods  Study Design The study design, patient eligibility and allocation, treatment regimens, and procedures for surveillance and follow-up are shown in Table 3 (available online).1, 3, 4, 10, 11, 12 Assessment of Outcomes The primary efficacy outcome measure was the occurrence of objectively documented, symptomatic, recurrent venous thromboembolism at 12 weeks and 1 year. Other efficacy outcomes were: death rates at 12 weeks and 1 year; patients' self-reported treatment satisfaction during the treatment period; symptoms of post-thrombotic syndrome; and the incidence of venous leg ulcers as reported by patients. The primary safety outcome measure was the occurrence of bleeding (all, major or minor) during the 12-week treatment period. Additional safety outcomes were the incidence of thrombocytopenia and of bone fractures. The methods to assess venous thromboembolism and bleeding have been reported previously3, 4 and also are shown in the table available online. Suspected recurrent deep vein thrombosis, pulmonary embolism, or bleeding was interpreted by a central, independent, adjudication committee without knowledge of the patient's treatment or the other outcome results. Adjudication was made by 2 committee members, and disputes were resolved independently by a third member. Patients' quality of life was assessed using the Medical Outcome Study Short Form-20 (MOS-SF-20)13, 14 at baseline, and at 6 and 12 weeks. A questionnaire about parameters likely to affect the treatment satisfaction of post-thrombotic patients15, 16, 17 also was administered at 12 weeks. The questionnaires for the 2 groups differed slightly but contained 11 questions in common, which could be compared between the groups. Responses were made on a 5-point Likert scale. At 12 weeks, patients also completed a third questionnaire recording 8 symptoms or signs whose presence in combination is commonly used to diagnose the presence and severity of post-thrombotic syndrome,6, 7, 18, 19 additionally asking if an ulcer was present in the skin above the patient's ankle on the affected leg. All questionnaires were completed by the patients independently. Statistical Analysis The statistical analysis section can be found in the online table. Results Study Population Of 797 consecutive patients screened for eligibility between April 1997 and November 1998, 480 were randomized to long-term subcutaneous tinzaparin (240 patients) or to initial tinzaparin and long-term warfarin (240 patients). Excluded patients had received anticoagulant therapy for >2 days at time of referral (n = 104) or did not give consent (n = 213). The number of patients lost to follow-up was 0 at 3 months and 3 at 12 months (1 tinzaparin, 2 usual care). The groups were comparable at entry (Table 1), and 468 patients (97.5%) completed the 12-month protocol. Recurrent Venous Thromboembolism and Deaths Rates of recurrent venous thromboembolism are shown in Table 2. Eight patients (3.3%) in each group had symptomatic, new, documented venous thromboembolism during the 12-week treatment period (difference 0%; 95% confidence interval [CI], −3.2-3.2). At 1 year, 25 patients in the tinzaparin group (10.4%) and 20 patients in the usual-care group (8.3%) had documented new episodes of symptomatic venous thromboembolism (difference 2.1%; 95% CI, −3.1-7.3). | | |  | | Tinzaparin n = 240 n (%) | Usual Care n = 240 n (%) | Absolute Difference⁎ (%) (95% CI) | P Value | |
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| New episodes of venous thromboembolism | | | | | | |  At 84 days† | 8(3.3) | 8(3.3) | 0(−3.2-3.2) | 1 | | | Cumulative incidence at 365 days‡ | 25(10.4) | 20(8.3) | 2.1(−3.1-7.3) | .43 | | | 85 to 112 days | 12(5.0) | 1(0.4) | 4.6(1.7-7.5) | .002 | | | 113 to 365 days | 5(2.1) | 11(4.6) | −2.5(−5.7-0.7) | .20 | | | 85 to 365 days | 17(7.1) | 12(5) | 2.1(−2.2-6.3) | .34 | | | Death | | | | | | | At 84 days | 9(3.8) | 9(3.8) | 0(−3.4-3.4) | 1 | | | Cumulative incidence at 365 days | 22(9.2) | 21(8.8) | 0.4(−4.7-5.5) | .87 | | | 85 to 112 days | 2(0.8) | 1(0.4) | 0.4(−1.0-1.8) | .56 | | | 113 to 365 days | 11(4.6) | 11(4.6) | 0(−3.7-3.7) | 1 | | | Occurrence of bleeding during the 12-week treatment period | | | | | | | All | 22(9.2) | 22(9.2) | 0(−5.2-5.2) | 1 | | | Major | 1(0.4) | 3(1.2) | −0.8(−2.5-0.8) | .32 | | | Minor | 21(8.8) | 19(7.9) | 0.9(−4.1-5.8) | .74 | | | Other findings | | | | | | | Thrombocytopenia at 12 weeks§‖ | | | | | | | Platelet count | | | | | | | <100×109/L | 3(1.3) | 1(0.4) | 0.8(−0.8-2.5) | .32 | | | <150×109/L | 14(5.8) | 3(1.3) | 4.6(1.3-7.9) | .01 | | | Bone fractures at 12 months¶ | 2(0.8) | 5(2.1) | −1.3(−3.4-0.9) | .25 | | | Venous ulcers at 12 months⁎⁎ | 1(0.5) | 8(4.1) | Odds ratio 0.12 (0.01-0.97) | .02 | | | | |
| ⁎ Tinzaparin minus Usual Care. †Recurrent venous thromboembolism at 84 days: of 8 patients in the tinzaparin group, 4 had pulmonary embolism and 4 had recurrent deep vein thrombosis; of 8 patients in the usual-care group, 4 had pulmonary embolism and 4 had recurrent deep vein thrombosis. ‡Recurrent venous thromboembolism from 85 days to 1 year: of 17 patients in the tinzaparin group, 3 had pulmonary embolism and 14 had recurrent deep vein thrombosis; of 12 patients in the usual-care group, 4 had pulmonary embolism and 8 had recurrent deep vein thrombosis. §Causes of thrombocytopenia: Among the patients receiving tinzaparin, thrombocytopenia was associated with cancer or cancer therapy in 7 patients; 1 patient had parvovirus B19; 1 thrombocytopenia was alcohol-induced; and 1 patient had heparin-induced thrombocytopenia. Among patients in the usual-care group, thrombocytopenia was associated with cancer or cancer therapy in 3 patients. ‖Outcomes: 5 of the 14 patients with thrombocytopenia in the tinzaparin group, and 2 of the 3 patients with thrombocytopenia in the usual-care group, died. One patient in the usual-care group had a minor bleed. ¶Twelve-month data are provided because osteoporosis, if present, may have resulted in delayed fractures. ⁎⁎n = 198 Tinzaparin; 197 usual care. |
For the overall period of 85 to 365 days following cessation of study treatment, the rates of recurrent venous thromboembolism did not differ significantly between treatment groups (Table 2). There were more recurrent venous thromboembolic events in the tinzaparin group from days 85-112 (P = .002) and numerically more recurrent venous thromboembolic events in the usual-care group from days 113-365 (difference −2.5%; 95% CI, −5.7-0.7). After the 3-month study period, anticoagulant therapy could be continued at the discretion of the physician, and was not evenly distributed between groups: long-term oral anticoagulant treatment was prescribed to 106 patients (44.2%) in the tinzaparin group (mean duration 173 days, median 232 days) and 151 patients (62.9%) in the usual-care group (mean duration 161 days, median 159 days) (P <.001). Deaths occurred at similar rates in the 2 groups (Table 2). Most deaths were due to cancer (15/22 and 16/21 patients in the tinzaparin and usual-care groups, respectively). In each treatment group, 4 of the patients who died were diagnosed with pulmonary embolism or probable pulmonary embolism as contributing to the cause of death. Safety Outcomes There were no significant differences between groups with respect to overall, major, or minor bleeding (Table 2). The number of patients with a platelet count <150× 109/L during therapy was 14 (5.8%) in the tinzaparin group (1 with documented heparin-induced thrombocytopenia) and 3 (1.3%) in the usual-care group. Among these, 3 patients (1.3%) in the tinzaparin group and 1 patient (0.4%) in the usual-care group had a platelet count <100×109/L. Bone fractures occurred in 2 patients receiving tinzaparin (0.8%) and 5 patients receiving warfarin (2.1%). Treatment Satisfaction The 12-week scores for the MOS-SF-20 did not differ significantly between groups. In the questionnaire for patient-reported satisfaction with treatment, most items were in favor of tinzaparin (Figure 1). The overall score for the 11 questions showed a significant advantage for tinzaparin (P = .0024). Presence of Post-thrombotic Syndrome and/or Ulcers All 8 assessments of the presence of symptoms of post-thrombotic syndrome showed a trend favoring the tinzaparin group over the usual-care group, with individual odds ratios from 0.66 to 0.91 (Figure 2). The overall odds ratio of 0.77 (95% CI, 0.67-0.90) favored tinzaparin (P = .001). During the 12-week study period, leg ulcers occurred in 1 patient (0.5%) in the tinzaparin group (n = 198) and in 8 (4.1%) in the usual-care group (n = 197; P = .02), yielding an odds ratio of 0.12 (95% CI, 0.01-0.97) for tinzaparin relative to usual care. Discussion In Home-LITE, patients with proximal deep vein thrombosis not requiring hospitalization successfully received long-term treatment with tinzaparin or tinzaparin followed by warfarin (“usual care”). Rates of recurrent venous thromboembolism and deaths were similar in the 2 groups at 12 weeks and 1 year, and bleeding rates were similar during the 12-week study period. The patients treated with tinzaparin for 12 weeks expressed significantly greater satisfaction with their treatment, had a lower risk of developing symptoms of post-thrombotic syndrome, and had fewer leg ulcers after 12 weeks, compared with the usual-care group. When Home-LITE was planned (1996), only 1 study was available on the long-term treatment of venous thromboembolism with low-molecular-weight heparin versus oral anticoagulation.20 Since then, several studies have shown that long-term low-molecular-weight heparin is as effective as oral anticoagulation for the treatment of patients with deep vein thrombosis, with similar or lower rates of bleeding,2, 4, 21, 22, 23, 24, 25, 26, 27 and long-term low-molecular-weight heparin is now recommended for patients with cancer, in whom it appears to be more effective than oral anticoagulation.2 In the Main-LITE study, long-term once-daily tinzaparin showed similar efficacy but caused less bleeding than unfractionated heparin/vitamin K antagonist,4 whereas in Home-LITE, bleeding was similar in the 2 treatment groups. All patients in Home-LITE were considered suitable for home therapy, without needing hospital stay, and may therefore represent a lower-risk group for bleeding in whom differences between treatments would not readily be evident. Home-LITE is, to our knowledge, the first study to compare long-term treatment with a low-molecular-weight heparin or usual care in patients treated at home from the outset. Patients in the CLOT (Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial were treated at home “whenever possible,” but hospitalization was permitted as required.28 Several cost-effectiveness analyses have demonstrated that home treatment with low-molecular-weight heparin from the outset of therapy is cost-saving or cost-effective versus the use of heparin for a few days in hospital.16, 27 Home-LITE was a large trial of home therapy with fewer exclusion criteria than previous trials, and thus enrolled a population closer to the mix of patients likely to be seen in routine clinical practice. For example, patients with renal impairment not requiring dialysis were included. About 25% of the patients in Home-LITE had cancer at baseline, but sub-analyses were not performed on these patients. In Home-LITE, significantly more recurrent venous thromboembolic events occurred in the tinzaparin group between days 85 and 112, and more occurred in the usual-care groups between days 112 and 365. Neither of these increases are considered a “rebound effect,” but probably represent an ongoing prothrombotic state evidenced when therapy is discontinued, as reported in other trials.29, 30, 31 With true rebound, the number of events in the comparator group never catches up with those in the group experiencing rebound; in our study, the cumulative rates of recurrent venous thromboembolism or death did not differ between the groups at 1 year. The patients in our 2 groups were not treated identically after 12 weeks, with fewer patients in the tinzaparin group receiving ongoing warfarin after 12 weeks. Among the 12 tinzaparin patients who experienced recurrent venous thromboembolism between 84 and 112 days, 8 did not receive ongoing anticoagulation after day 84. Analysis of patient characteristics has not revealed any factors predictive of the earlier recurrence of venous thromboembolism, although there was an increased trend for absolute recurrence in males, as witnessed in other trials.30, 32 Recurrence rates in the 2 groups (3.3% at 12 weeks and 8-10% at 1 year) were as expected based on earlier studies, and death rates for days 84-112 did not differ between the groups. An examination of earlier trials shows that in the Main-LITE study, recurrence did not occur earlier in the tinzaparin group versus usual care.4 Similarly, in a study of tinzaparin versus unfractionated heparin/acenocoumarol given for 6 months, there was no clear difference in recurrent venous thromboembolism in the period after treatment cessation.27 However, in patients treated with enoxaparin or warfarin for 3 months, Meyer reported recurrences in 3/71 (4.2%) enoxaparin patients and 0/75 warfarin patients from day 90 to 180;33 none of the 3 patients received ongoing anticoagulation therapy after 90 days, and all were cancer patients. The study was open label, as were previous trials comparing low-molecular-weight heparin and warfarin, because of the difficulties of double-blinding the treatment regimens. However, all suspected thromboembolic outcomes or bleeding were evaluated by a central committee unaware of patients' treatment. The MOS-SF-20 did not reveal quality-of-life differences between the 2 home treatments. Generic instruments are useful for comparing results across studies, but disease-specific instruments are more responsive to treatment effects.34, 35 Therefore, Home-LITE incorporated a treatment satisfaction questionnaire targeted to anticoagulation therapy. Patients in the tinzaparin group were significantly more satisfied with their treatment as assessed by this questionnaire (P = .0024), particularly regarding the lack of interference with daily activities/work. Our questionnaire used Likert scales, which are easy to complete and frequently used in psychometric surveys.36 Their structured scale of responses conveniently quantifies attitudes. The questions, based on those in a previous study,15 addressed practical aspects of treatment likely to influence patients' satisfaction with therapy. The questions were defined before the study began, and patients completed the questionnaire independently at a uniform time-point at the end of therapy (12 weeks). Therefore, the results are unlikely to be because of bias, and provide clinically relevant information on the patients' perceived treatment satisfaction. A shortcoming of the comparison is that the responses to some questions, specifically those on injections or changes in drug dosage, could not be directly compared between groups as they applied to only one group (tinzaparin or usual care, respectively). A striking outcome from Home-LITE was the lower incidence of post-thrombotic syndrome symptoms at 3 months (P = .001), and the lower incidence of leg ulcers (P = .02) in the tinzaparin group. Although symptoms were patient-reported, it is still of interest to note that recent investigations using the Villalta scale and combinations of physical examination findings demonstrate that post-thrombotic syndrome assessments are reliable, reproducible, and have good to excellent inter-observer reliability.37 Patients recorded whether an ulcer was present in the skin above their ankle on the affected leg—wording chosen to ensure that patients would report only genuine venous ulcers. In the various adapted scoring systems, a venous ulcer indicates severe post-thrombotic syndrome regardless of other signs and symptoms.7 The frequency and chronic nature of post-thrombotic syndrome make it burdensome to patients and costly to society. Options for management are limited, involving thrombolysis6 or the use of elastic compression stockings.7, 19 Adequate thromboprophylaxis to prevent recurrence of the deep vein thrombosis is important, because recurrent venous thromboembolism has been shown to predict development of post-thrombotic syndrome,5, 9 and a recent cohort study confirmed that post-thrombotic syndrome occurs frequently after deep vein thrombosis.38 Home-LITE confirms findings by Daskalopoulos (not yet published in full) that patients treated with long-term tinzaparin have a reduced risk of developing post-thrombotic syndrome and leg ulcers, at follow-up of up to 42 months.39, 40 If the observed reduction in post-thrombotic syndrome is confirmed in further studies, this would be an important reason to use low-molecular-weight heparin rather than oral anticoagulation, particularly in the light of a recent trial which suggested that the occurrence of post-thrombotic syndrome after 5-7 months of oral anticoagulant therapy is the strongest predictor of recurrent venous thromboembolism.30 The mechanism is unknown, but low-molecular-weight heparins have multiple effects, including anti-inflammatory as well as antithrombotic effects. These effects depend in part on the chain length of the particular low-molecular-weight heparin, and different low-molecular-weight heparins are not necessarily clinically interchangeable.41 For example, low-molecular-weight heparins such as tinzaparin, which have a longer average chain length, are known to result in greater release of tissue factor pathway inhibitor, a molecule with anticoagulant, anti-inflammatory, and anti-angiogenic effects.42 The low-molecular-weight heparin dalteparin has been shown to improve healing of diabetic foot ulcers, presumably by its nonanticoagulant effects.43 Conclusions Home-LITE is the first reported trial comparing long-term treatment of deep vein thrombosis with either a low-molecular-weight heparin or usual care in patients treated at home from the outset. The results add to the evidence showing similar efficacy and safety for the 2 regimens, and confirm the effectiveness of once-daily tinzaparin. Patients treated with tinzaparin expressed significantly greater satisfaction with their treatment. The occurrence of symptoms of post-thrombotic syndrome and of leg ulcers was significantly lower in the tinzaparin group. This finding is potentially of great clinical and economic benefit and deserves to be studied further. Acknowledgement LEO Pharma A/S Ltd. provided an unrestricted educational grant for the preparation of this article. Editorial assistance was provided by Watermeadow Medical. Appendix [Online] | Alberta: Foothills Hospital, Calgary, R. Hull; Peter Lougheed Centre, Calgary, R. Dear; Rockyview General Hospital, Calgary, R. Cook; University Hospital, Edmonton, M. Mant; Red Deer Regional Hospital, Red Deer, J. Singh. | | | Quebec: Montreal General Hospital, Montreal, S. Solymoss; Jewish General Hospital, Montreal, S. Kahn; St Mary's Hospital Centre, Montreal, S. Solymoss; Centre Universitaire de Santé, Fleurimont, M. Lepine-Martin. | | | Ontario: St Joseph's Health Centre, London, W. Brien; University Hospital, London, M. Cruickshank (deceased); Sudbury General Hospital, Sudbury, C. Bourdon; Sunnybrook Health Science Centre, Toronto, W. Geerts; Group Health Centre, Sault Ste Marie, H. Lee (deceased); Port Arthur General Hospital, Thunder Bay, A. Dhar; Greater Niagara General Hospital, Niagara Falls, M. Alexander. | | | Manitoba: St Boniface General Hospital, Winnipeg, T. Wong. | | | British Columbia: St Paul's Hospital, Vancouver, L. Vickars; Kelowna General Hospital, Kelowna, J. Sutherland; Vancouver General Hospital, Vancouver, S. Nantel; St Joseph's General Hospital, Comox, R. Engman; Burnaby Hospital, Burnaby, T. Sparling. | | | Adjudicators: G. Elliott, J. George, G. Raskob; Data Safety Monitoring: C. Carter, Chair. | | | | |
Table 3 [Online] | | | | Study Design | | |
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| Patient population | Patients with acute proximal deep vein thrombosis | | | Design | Multicenter, open-label, randomized, controlled trial | | | Comparison | Home long-term use of the subcutaneous low-molecular-weight heparin tinzaparin(Innohep, LEO Pharma A/S Ltd., Ballerup, Denmark) versus initial tinzaparin for 5 or more days, overlapped with, and followed by, long-term oral warfarin sodium (“usual care”). | | | Duration of therapy | 12 weeks | | | Study 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 TreatmEnt program (LITE) funded by the Canadian Institutes of Health Research, formerly Medical Research Council, and industry, and are as follows:– Home-LITE, which is reported here – Main-LITE, in a broad spectrum of patients4 – Main-LITE Cancer, in patients with cancer and deep vein thrombosis3 | | | Center participation | 22 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 statement44, 45 and the “Better reporting of harms in randomized trials: an extension of the CONSORT statement.”46 | | | Patient eligibility and allocation | Consecutive eligible patients, 18 years of age or older, with a first or recurrent episode of acute proximal deep 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 objectively proven proximal deep vein thrombosis and did not have any condition precluding out-of-hospital treatment. | | | Patients were eligible if they had none of the following: | A bleeding diathesis or bleeding contraindicating anticoagulation; pregnancy; breastfeeding; allergy to heparin, warfarin or bisulfites; history of heparin-associated thrombocytopenia; malignant hypertension or blood pressure ≥250 mm Hg systolic or 130 mm Hg diastolic; hepatic encephalopathy; renal failure necessitating dialysis; neurologic or ophthalmic surgery within 14 days; pulmonary embolism requiring thrombolysis, thrombectomy, or vena cava interruption; life expectancy <3 months; lumbar puncture within 24 h; receiving oral anticoagulation for other conditions; unable to discontinue acetylsalicylic acid; or geographic inaccessibility for follow-up. | | | Eligible patients were excluded if they: | Had received heparin, low-molecular-weight heparin, or oral anticoagulant therapy for more than 2 days at the time of referral, or were unable or declined to give written informed consent. | | | Before randomization, patients were stratified according to: | Study center; whether primary or recurrent proximal deep vein thrombosis; and presence or absence of cancer. | | | Randomization | A computer-derived randomized treatment schedule was used; within each stratum, the randomized schedule was balanced in blocks of 4. | | | Treatment regimens | | | | Tinzaparin | Patients assigned to long-term tinzaparin received a fixed dose of 175 international anti-Xa units per kilogram subcutaneously, injected once daily. Patients received the first injection in the clinic and were sent home; patients who required hospitalization were not included in the study. Injections were self-administered by the patients or a family member or visiting nurse. Treatment with tinzaparin was continued for 12 weeks. Platelet counts were performed at 5, 14, and 21 days, to check for possible thrombocytopenia. | | | Tinzaparin and warfarin sodium | Patients assigned to the usual-care group received tinzaparin as above for a minimum of 5 days and also oral warfarin, commenced at a dose of 5-10 mg daily within 24 h of referral. The INR was measured daily and the warfarin dose adjusted until the patient's response had stabilized. Tinzaparin was stopped when an INR value of 2.0-3.0 was reached for 2 consecutive days. INR monitoring was subsequently performed every 1-2 weeks, by a laboratory convenient for the patient, until completion of therapy at 12 weeks. As with the tinzaparin group, patients were sent home after their first injection. | | | Prohibited medications | Acetylsalicylic acid use was prohibited, and ticlopidine, sulfinpyrazone, dipyridamole, and nonsteroidal anti-inflammatory drugs were strongly discouraged. | | | Poststudy therapy | On completion of the study drug at 12 weeks, continued oral anticoagulant therapy was indicated for patients with recurrent deep vein thrombosis at entry. In other patients, further oral anticoagulant therapy was given or not given, at the discretion of the patient's primary care physician and in line with treatment recommendations at the time.10 During the course of the study the standard of care changed, so that patients with idiopathic deep vein thrombosis who entered the study later were crossed over onto warfarin or continued on warfarin for a total treatment period of at least 6 months.1 | | | Assessment of clinical outcomes | | | | Surveillance and follow-up | During the initial consultation, patients were reviewed by the consultant physician or study nurse for symptoms or signs of recurrent deep vein thrombosis, PE, or bleeding. At discharge, patients were instructed to seek care immediately if they had any such symptoms or signs. Patients who presented with clinically suspected recurrent venous thromboembolism underwent objective testing. Patients attended a routine clinic visit 12 weeks after entry and were asked about any relevant symptoms and clinically examined. Serious adverse events (symptomatic recurrent venous thromboembolism, PE, death, bleeding) were reported for up to 28 days following completion of treatment. At 1 year, all patients or their primary physicians were contacted to determine whether the patients were alive and whether they had experienced a documented recurrent venous thromboembolism. | | | Diagnosis of venous thrombosis | Recurrent venous thrombosis was diagnosed when one or more previously compressible proximal vein segments were no longer compressible on ultrasonography or by the presence of a constant intraluminal filling defect (or a vessel cut-off) in the deep veins that was not present on the baseline venogram. In patients with clinically suspected pulmonary embolism, the diagnosis was confirmed by one of the following: a high-probability lung scan finding (following the methods described by PIOPED Investigators11 or Freitas et al,12 according to local preference); abnormal non-diagnostic perfusion scan with documented new deep vein thrombosis; spiral CT scan showing thrombus in the central pulmonary arteries; pulmonary angiography revealing a constant intraluminal filling defect or cut-off of a vessel >2.5 mm in diameter; or pulmonary embolism found at autopsy. | | | Bleeding | Bleeding was classified as major if it was overt and associated with a fall in the hemoglobin level 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; and as minor if it was clinically overt, but did not meet other criteria for major bleeding. These criteria have been used successfully in other studies, including the previously published LITE trials.3, 4 | | | Statistical analysis | | | | Sample size | The study sample size was chosen based on anticipated equivalence in efficacy and bleeding rates with the 2 regimens. Assuming a rate of recurrent venous thromboembolism at 12 weeks of 3% in both treatment groups, 180 patients per group were required to provide an 80% probability of excluding a true difference in recurrence rates of 5%. Allowing for dropouts, a total sample size of 400 was needed. Based on previous results,14 this also was considered to be adequate to detect a clinically significant difference in mean QoL outcomes. | | | Analysis of results | The uncorrected chi-squared test (or Fisher's exact test when indicated) was used to compare the incidences of death, recurrent venous thromboembolism, and bleeding between the 2 treatment groups. Cox proportional hazards regression analysis was used to analyze cumulative hazard ratios. Scores for the MOS-SF-20 were compared using analysis of covariance, adjusting for baseline values. Responses to the treatment satisfaction questionnaire were reported as odds ratios (OR) for greater satisfaction (tinzaparin group versus usual-care group), derived from fitting a proportional odds model to the Likert scale responses. Scores were summed for each subject, yielding an overall QoL score per individual and these were compared between groups using the Wilcoxon rank sum test with continuity correction. The presence of symptoms of PTS was compared for the 2 groups using the Wilcoxon rank-sum test, and the incidence of leg ulcers at 3 months was compared by Fisher's exact test. | | | | |
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46. 46Ioannidis JPA, Evans SJW, Gotzsche PC, et al.CONSORT Group Better reporting of harms in randomized trials: an extension of the CONSORT Statement. Ann Intern Med. 2004;141:781–788. a University of Calgary, Calgary, AB, Canada b University of British Columbia, Vancouver, BC, Canada c McGill University, Montreal, QC, Canada d College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City  Requests for reprints should be addressed to Russell D. Hull, MBBS, MSc, Thrombosis Research Unit, 601 South Tower, Foothills Hospital, 1403-29th Street NW, Calgary, AB T2N 2T9, Canada
Funding: The study was supported by grants from the Medical Research Council (now Canadian Institutes for Health Research) and industry (LEO Pharma A/S Ltd., Ballerup, Denmark). Additional funding was provided by Pharmion and Dupont Pharmaceuticals. LEO Pharma provided the study drug and drug safety monitoring. The industry sponsors did not have any influence on the design or analysis of the study. The protocol was designed by 3 investigators. 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 sponsors by Rollin F. Brant, PhD, Department of Community Health Sciences, University of Calgary, Canada. Conflict of Interest: R. Hull has received grants/research support from Bayer Pharmaceuticals Corporation, LEO Pharma Inc., and sanofi-aventis; been a consultant for LEO Pharma, Inc., Pfizer Inc., and GlaxoSmithKline, and sat on advisory boards for Pfizer Inc. and sanofi-aventis. Graham Pineo is a consultant or advisory board member (or both): sanofi-aventis, Pfizer, and steering committee member for sanofi-aventis. Susan Solymoss has received honoraria from Pfizer and LEO-Pharma. Jane Liang, Man-Chiu Poon, Roy Cook, and Rollin Brant have no conflict of interest to declare. Gary Raskob receives consultant income or honoraria (or both) from the following companies: GlaxoSmithKline, Pfizer, and sanofi-aventis. Authorship: All authors had access to the data and contributed to/critically reviewed drafts of the manuscript. PII: S0002-9343(09)00330-1 doi:10.1016/j.amjmed.2008.12.023 © 2009 Elsevier Inc. All rights reserved. | |
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