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Anticoagulation duration after deep-vein thrombosis
in the patients’ care, before enrollment of the first patient. Patients were provided with numbered supplies of study drug containing either warfarin tablets of 2 mg and 5 mg or visually identical placebo tablets (packaged at the sponsor's central phar- macy). On day 0 (date of randomization), all patients underwent laboratory testing (including D-dimer measurement) and leg ultra- sound examination. Screening for thrombophilia was performed at the time of statistical analysis from centralized frozen blood
samples taken on day 0.
After written informed consent had been obtained, all study
INR values were determined at each patient’s usual local laborato- ry and were sent directly to the central anticoagulation clinic, with patients and investigators remaining unaware of the local results in order to maintain the double-blind condition. For patients assigned to warfarin, the clinic returned the true INR results to investigators for dose adjustments. For those assigned to placebo, the clinic substituted computer-generated sham INR results. The frequency of INR monitoring was left to the investigators’ discre- tion, but was mandatory at least monthly and after each change in dose or concomitant therapy.
After the end of the treatment period, all patients were followed for an additional period of 24 months without anticoagulant ther- apy. Visits were scheduled at 3, 6, 12, 18, 30 and 42 months, and phone call contacts at 24 and 36 months.
Outcome measures
The primary outcome was the composite of symptomatic recurrent venous thromboembolism (including objectively con- firmed non-fatal symptomatic pulmonary embolism or proximal deep-vein thrombosis or fatal venous thromboembolism) and non-fatal or fatal major bleeding, up to 18 months after inclusion. This composite outcome and its components were also assessed during the entire study period (i.e. up to 42 months). Other sec- ondary outcomes were death unrelated to pulmonary embolism or major bleeding during the 18-month treatment period and the entire 42-month study period. Secondary outcomes were speci- fied in the statistical analysis plan (see Online Supplement) after the protocol was finalized, but before the database was locked and any data were analyzed.
Symptomatic recurrent deep-vein thrombosis or pulmonary embolism was objectively confirmed by ultrasonography, ventila- tion/perfusion lung scanning, spiral computerized tomography angiography, or autopsy, or in the event of sudden death for which no cause other than pulmonary embolism could be identified.18-20 Bleeding was considered as major according to the International Society of Thrombosis and Haemostasis definition (see Online Supplement).21 The American College of Chest Physicians (ACCP) bleeding score, initially unplanned, was calculated at the time of statistical analyses using prospectively recorded variables.8 All out- comes were adjudicated blindly by an independent central critical events committee. This committee had full access to any relevant medical reports and images from objective tests to adjudicate sus- pected events notified by investigators or detected during routine site monitoring.
Sample size and statistical methods
The trial was designed to demonstrate superiority of warfarin over placebo in preventing the composite primary outcome during the 18-month study treatment. Based on previous studies,1-7 with placebo we assumed rates of 9% per year of recurrent venous thromboembolism and 1% per year of major bleeding, yielding a 15% rate of the composite outcome at 18 months; corresponding assumptions with warfarin were 1% per year and 3% per year, yielding a 6% rate of the composite outcome at 18 months. A sample size of 178 patients per group therefore had 80% power to
detect a statistically significant difference between groups (at a two-sided 5% level of significance). Taking into account an antic- ipated 5% rate of patients lost to follow-up, a total sample of 374 patients was required.
In October 2013, after inclusion of the first 104 patients, the steering committee decided to end enrollment of patients into the study, as recommended by the data and safety monitoring committee in view of the slow recruitment rate that made reach- ing the expected sample size unfeasible. It is important to note that this recommendation was not prompted by any efficacy or safety issue. The data and safety monitoring committee also rec- ommended that all included patients be followed until the last visit at 42 months, as originally planned in the protocol. These decisions were renewed every year and confirmed until the last included patient attended the last pre-planned visit at 42 months of follow up.
All analyses were performed on the intention-to-treat popula- tion, i.e. all randomized patients. Time-to-event outcomes were estimated by the Kaplan-Meier method, and between-group com- parisons were performed using the log-rank test. The hazard ratio (HR) and corresponding 95% confidence interval (CI) were calcu- lated. If any baseline characteristic was differently distributed between the two groups (P<0.05 by the Fisher exact test, or Student t-test where appropriate), the comparisons were adjusted on the variables concerned using a Cox proportional hazards regression model. Time within the therapeutic INR range was cal- culated using standard methods,22 with corrections for planned interruptions of study drug. Finally, we combined the results from the PADIS-PE7 and PADIS-DVT studies by performing a meta- analysis of the log hazard ratios for the treatment effect on out- come from each study weighted by their inverse variances. All tests were two-sided and a P-value of less than 0.05 was consid- ered to be statistically significant. Statistical analyses were per- formed using SAS V9.4 software (SAS Institute, Cary, NC, USA).
Results
Between July 2007 and October 2013, 104 patients were enrolled, 50 being randomized to warfarin and 54 to place- bo. Of these patients, 102 (98.1%) attended the 18-month visit and 100 (96.2%) the 42-month visit; no patient was lost to follow up (Figure 1 and Online Supplementary Table S1). The median follow up (interquartile range) was 23.6 (23.2-24.1) months after the treatment period, and 41.2 (40.9-41.6) months overall. Baseline characteristics were similar between the two groups (Table 1).
Treatment and evaluation of International Normalized Ratios
The median study treatment duration was similar in the two groups (warfarin: 17.5 months; placebo: 17.2 months). Double-blind treatment was permanently dis- continued in six warfarin-treated patients (none with recurrent venous thromboembolism or major bleeding, all 6 discontinuing for other reasons), and 21 placebo-treated patients (16 with confirmed recurrent venous throm- boembolism, none experiencing major bleeding and 5 dis- continuing for other reasons). Of the six patients on war- farin who discontinued the study treatment for reasons other than major bleeding, two continued to receive anti- coagulant therapy; of the five patients on placebo who discontinued for other reasons, two started anticoagulant therapy. The median interval between INR measurements was 19.5 days and 20.5 days for warfarin- and placebo-
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