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Anticoagulation duration after deep-vein thrombosis
associated with an ipsilateral deep-vein thrombosis and 1 with a contralateral deep-vein thrombosis).
Clinical outcomes after the study treatment period
During the 24-month follow up after study treatment discontinuation, the composite outcome occurred in 14 patients in the warfarin group (cumulative risk, 26.3%; 16.5 events per 100 person-years) and in one patient in the placebo group (cumulative risk, 2.0%; 1.0 events per 100 person-years) (Table 2). In the warfarin group, sympto- matic recurrent venous thromboembolism occurred in 14 patients, all in the absence of anticoagulation, and in 12 (86.0%) cases was unprovoked. Of these 14 recurrences 13 were non-fatal isolated deep-vein thrombosis (6 con- tralateral and 7 ipsilateral), and one was non-fatal pul- monary embolism. In the placebo group, symptomatic recurrent venous thromboembolism occurred in one patient as an isolated ipsilateral deep-vein thrombosis, in the absence of anticoagulation, and was unprovoked and non-fatal. In the warfarin group, one patient had non-fatal major bleeding on warfarin.
Clinical outcomes during the entire study period
Overall, the composite outcome of recurrent venous thromboembolism or major bleeding occurred in 14 war- farin-treated patients (cumulative risk, 36.8%; 11.2 events per 100 person-years) and 17 placebo-treated patients (cumulative risk, 31.5%; 12.9 events per 100 person- years), resulting in a non-significant difference (HR, 0.72; 95% CI: 0.35-1.46) (Table 2, Figure 2). Figure 2 shows the time course of the composite outcome. Results of pre- specified subgroup analyses on the composite outcome during the treatment and entire study periods were consis- tent with the overall treatment effect (Online Supplementary Figures S1A and S2B).
Meta-analysis
The combined results of the PADIS-DVT and PADIS-PE7 trials showed a significant reduction of 87% in the rate of the composite outcome and of 93% in the rate of recur- rent venous thromboembolism during the 18-month treat- ment period. A non-significant reduction of 27% in the rate of the composite outcome and of 32% in the rate of recurrent venous thromboembolism was observed over the 42-month study period (Figure 3).
Discussion
In this multicenter, randomized, double-blind trial in patients having completed 6 months of oral anticoagula- tion for a first episode of unprovoked proximal deep-vein thrombosis, an additional 18 months of warfarin therapy, as compared to placebo, was associated with a major 97% relative reduction in the risk of the composite endpoint of recurrent venous thromboembolism and major bleeding. However, this benefit was not maintained after anticoag- ulation was stopped.
In comparison with the PADIS-PE study,7 a similarly designed trial in patients with a first unprovoked pul- monary embolism, and other randomized studies having evaluated prolonged anticoagulation after unprovoked venous thromboembolism,4-6 we found an unexpectedly high risk of recurrent venous thromboembolism in the placebo group (cumulative risk of 37% at 18 months after
Table 1. Baseline characteristics of study participants according to random- ized assignment.a
Age, mean (SD), years >65 years, n. (%)
Warfarin (N=50)
59.0 (17.2) 19 (38.0)
19 (38.0)
26.8 (4.9) 11 (22.0)
1 (4.8) 5 (23.8) 15 (71.4)
2 (4.0) 6 (12.0)
3 (6.0) 7 (14.0)
19 (40.4) 15 (31.9) 13 (27.7)
27 (55.1) 1.0 (0.0-4.0) 43 (86.0) 6 (12.0)
1 (2.0)
Placebo (N=54)
61.5 (14.5) 29 (53.7)
15 (27.8)
26.4 (3.2) 6 (11.1)
0 (0.0)
1 (3.4)
28 (96.6)
4 (7.4) 7 (13.0)
0 (0.0) 9 (16.7)
15 (27.8) 23 (42.6) 16 (29.6)
32 (59.3) 1.0 (0.0-4.5) 39 (75.0) 10 (19.2) 2 (3.8)
Female, n. (%)
Body-mass index, mean (SD), kg/m2
≥30 kg/m2, n. (%)
b Creatinine clearance category, no. (%)
<30 mL/min
≥30 and <50 mL/min ≥50 mL/min
Medical conditions, n. (%) Previous cancerc Previous distal DVT
or superficial-vein thrombosis Chronic heart failure
Chronic respiratory failure
Extent of DVT at diagnosis Common femoral vein Superficial femoral vein Popliteal vein
Characteristics of DVT at inclusion Residual DVTd, n. (%)
Villalta score, median (IQR)
0-4 5-9 10-14 ≥15
D-dimer levele, mean (SD), ng/mL Minor thrombophiliaf, n. (%) Major thrombophiliaf,n. (%)
Treatment of DVT prior to randomization Warfarin, n. (%)
Fluindione, n. (%)
Acecoumarol, n. (%)
Duration of initial anticoagulation, mean (SD), months
Mean (SD) percentage time in therapeutic INR range
Use of compression stockings, n. (%)
Main concomitant treatments, n. (%) Antiplatelet agent
Statins
Estrogen-containing contraception
ACCP bleeding risk at inclusiong, n. (%) Low (no risk factor)
Moderate (1 risk factor)
High (≥2 risk factors)
0 1(1.9)
327.4 (315.3) 8 (16.0)
9 (18.0)
25 (50.0) 26 (52.0) 0
6.4 (0.7)
68.7 (26.4)
49 (98.0)
2 (4.0) 4 (8.0) 4 (8.0)
5 (26.3) 5 (26.3) 9 (47.4)
287.0 (227.5) 8 (15.4) 14 (26.9)
28 (51.9) 26 (48.1) 0
6.3 (0.5)
74.6 (21.0)
49 (90.7)
5 (9.3) 5 (9.3) 2 (3.7)
7 (26.9) 5 (19.2) 14 (53.8)
aDenominators may be lower than 50 and 54 due to missing data for some variables. Baseline characteristics of the two groups were compared using the Student t-test for quantitative vari- ables and Fisher exact test for qualitative variables. None of the resulting P values was <0.05. bCreatinine clearance was estimated by the Cockcroft-Gault method; creatinine clearance val- ues were available for only 21 patients in the warfarin group and 29 patients in the placebo group. cCancer resolved more than 2 years prior to the patients’ inclusion. dResidual deep-vein thrombosis, assessed using bilateral compression ultrasonography, was defined by the pres- ence of persistent,non-full compressibility of a proximal deep-vein that was initially non-com- pressible in one or two lower limbs.eD-dimer level was measured before randomization while patients were receiving vitamin K antagonist therapy. fScreening for thrombophilia was per- formed at the time of statistical analysis from centralized frozen blood samples taken on day 0.Thrombophilia was defined as minor if patients had either heterozygous factor V Leiden or heterozygous G20210A prothrombin gene variant or elevated factor VIII (90th percentile). Thrombophilia was defined as major if patients had antithrombin or protein C or protein S deficiency or lupus anticoagulant or anticardiolipin antibodies (99th percentile) or homozy- gous factor V Leiden or combined thrombophilia (details are provided in Online Supplementary Table S3). gThe American College of Chest Physicians (ACCP) score was cal- culated at the time of the statistical analysis, using the patients’ baseline characteristics. Definitions and references are provided in the Online Supplement. SD: standard deviation; DVT: deep-vein thrombosis; IQR: interquartile range; INR: International Normalized Ratio.
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