Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE (RE-SONATE)

• Centrally Confirmed Symptomatic Recurrent Venous Thrombotic Events (VTE) Excluding Unexplained Death During the Intended Treatment Period [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Symptomatic recurrent VTE is the composite of recurrent deep vein thrombosis (DVT) , fatal or non-fatal pulmonary embolism (PE). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event.
• Centrally Confirmed Symptomatic Recurrent Deep Venous Thrombotic (DVT) Events During the Intended Treatment Period [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• Centrally Confirmed Symptomatic Pulmonary Embolism (PE) Events During the Intended Treatment Period [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• Centrally Confirmed Unexplained Deaths During the Intended Treatment Period [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• First Centrally Confirmed Major Bleeding Event (MBE) During the Treatment Period [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  A bleeding event was considered to be major if it was fatal, associated with a fall in haemoglobin of ≥2 g/dL, led to the transfusion of ≥2 units packed cells or whole blood, or occurred in a critical site (intracranial, intraspinal, intraocular, pericardial or intra-articular, intramuscular with compartment syndrome or retroperitoneal). Whilst the endpoint is time to event, the measured values present the number of participant with event and the hazard ratio presents the time to event. However as the Cox model did not converge due to too few events, hazard ratios are not estimable.

The primary efficacy objective is to evaluate whether dabigatran etexilate is superior to placebo in the long-term prevention of recurrent symptomatic venous thrombo-embolism (VTE) in patients with symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE) who completed 6 to 18 months of treatment with vitamin K antagonist (VKA).

• Drug: dabigatran etexilate 150 mg twice daily (BID)
  dabigatran etexilate capsules 150 mg BID
• Drug: matching placebo twice daily (BID)
  Matching placebo BID

• Experimental: dabigatran etexilate 150 mg BID
  Patient to receive dabigatran etexilatate capsules 150 mg twice daily
  Intervention: Drug: dabigatran etexilate 150 mg twice daily (BID)
• Placebo Comparator: matching placebo twice daily (BID)
  Patient to receive dabigatran extexilate matching placebo capsules twice daily
  Intervention: Drug: matching placebo twice daily (BID)

Inclusion criteria:

1. Patients with confirmed symptomatic PE or proximal DVT of the leg(s) who have been treated for 6 to 18 months with therapeutic dosages (intended INR between 2-3) of an oral VKA (e.g. warfarin, acenocoumarol, phenprocoumon, or fluindione) or RE-COVER study medication up to the moment of screening for the current study.
2. Written informed consent

Exclusion criteria:

1. Younger then 18 years of age
2. Indication for VKA other than DVT and/or PE
3. Patients in whom anticoagulant treatment for their index PE or DVT should be continued
4. Active liver disease or liver disease decreasing survival (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT > 3 x ULN
5. Creatinine clearance < 30 ml/min
6. Acute bacterial endocarditis
7. Active bleeding or high risk for bleeding.
8. Uncontrolled hypertension (investigators judgement)
9. Intake of another experimental drug within the 30 days prior to randomization into the study
10. Life expectancy <6 months
11. Childbearing potential without proper contraceptive measures*, pregnancy or breast feeding