Venous thromboembolism: indefinite warfarin decreased recurrence.

Clinical bottom line (level 1b)

  1. Patients with a second episode of a deep vein thrombosis or pulmonary embolism who took oral anticoagulant therapy indefinitely had fewer recurrences of venous thromboembolism compared with those on six months of therapy (NNT = 6 at 4 years) .
  2. The effect on mortality and major haemorrhage was unclear.
Schulman et al: New England Journal of Medicine 1997; 336 (6): 393-398
Expires September 2003

The study

Unblinded concealed randomised trial with intention-to-treat
Setting: sixteen centres, Sweden

227 patients (aged mean 65 years, 70% male) second episode of deep vein thrombosis in the leg or ileac vessels in both, or pulmonary embolism. DVT confirmed by venography. PE confirmed by angiography or by chest radiography and perfusion-ventilation lung scanning.

Excluded if
  • <15 yeas old
  • pregnancy
  • allergy to warfarin or dicumarol
  • indication for continuous oral anticoagulation
  • paralysis of the affected leg
  • contraindication to compression stocking use
  • current or previous venous ulcer
  • cancer
  • congenital deficiency of antithrombin, protein C or protein S


Note:
  • Antithrombin III, protein C and protein S levels measured in patients <50 years old or with a family history.
  • INR was repeated weekly for the first three weeks, then once every four weeks. Patients were advised to avoid aspirin and other NSAIDs, and to use only ibuprofen.


Control Group: (n = 111, 111 analysed): warfarin for six months
Experimental Group: (n = 116, 116 analysed): warfarin indefinitely
All patients received heparin iv or LMWH subcutaneously for at least five days until PT in range for two days, then oral anticoagulation with warfarin sodium or dicumarol, targeted to an INR of 2.0 to 2.85. Patients with DVT were given and instructed to wear graduated compression stockings during the day for at least one year.
100% followed for 4 years
Outcome notes:
  • recurrent pulmonary embolism/deep vein thrombosis : DVT diagnosed if thrombus in contralateral leg, in another deep vein in the same leg as previous episode, thrombus in same vein in proximal extension >5cm. PE diagnosed by ventilation perfusion scan.
  • major haemorrhage : episodes of bleeding causing death, hospitalisation or treatment with blood products or vitamin K

The evidence

Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
recurrent pulmonary embolism/deep vein thrombosis 4 years 23
(20.7%)		 3
(2.59%)		 88%
(60% to 96%)		 18.1%
(10.1% to 26.2%)		 6
(4 to 10)
major haemorrhage 4 years 3
(2.70%)		 10
(8.62%)		 -219%
(-1000% to 10%)		 -5.92%
(-11.9% to 0.01%)		 -17
(NNT = 7100 to infinity;
NNH = 8 to infinity)
death 4 years 16
(14.4%)		 10
(8.62%)		 40%
(-26% to 72%)		 5.79%
(-2.50% to 14.1%)		 17
(NNT = 7 to infinity;
NNH = 40 to infinity)
fatal haemorrhage 4 years 1
(0.90%)		 2
(1.72%)		 -91%
(-2000% to 82%)		 -0.82%
(-3.77% to 2.13%)		 -121
(NNT = 47 to infinity;
NNH = 27 to infinity)

Comments

  1. Patients were randomised in groups of ten.
  2. 20% of patients had temporary risk factors (surgery, trauma, immobilisation, oestrogen medication, infection, Baker's cyst, pregnancy).
  3. All recurrences in indefinite group occurred on stopping anticoagulation (within 1 to 10 months).
  4. No patients had a fatal pulmonary embolism.
  5. Note major haemorrhage is tending to significance for indefinite anticoagulation (as might be expected).
  6. In the future, genotyping may help optimise individual dosing of warfarin.

Citation

  1. Schulman S, Granqvist S, Holmstrom M, et al: The duration of oral anticoagulant after a second episode of venous thromboembolism.. New England Journal of Medicine 1997; 336 (6): 393-398
Contributor: Chris Ball and Clare Wotton, May 2000
Reviewer: Deepak L Bhatt

Clinical Question.
Patient second episode of DVT
Intervention or Exposure warfarin for six months
Comparison warfarin indefinitely
Outcome recurrent DVT/PE