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#111 A pill for the second clot I do not want


CLINICAL QUESTION
QUESTION CLINIQUE
Are novel anti-coagulants as effective as warfarin in treating acute venous thromboembolism (VTE)?


BOTTOM LINE
RÉSULTAT FINAL
Studies show novel anti-coagulants are non-inferior to warfarin in the treatment of VTE and generally have less major bleeding. Regulatory approval, patient values, and drug costs should help in deciding which therapy to use.  



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EVIDENCE
DONNÉES PROBANTES
Five large, industry-funded, non-inferiority randomized clinical trials compared available novel oral anticoagulants to warfarin. Patients’ mean age 55-58 years, ~60% men, ~20% with previous VTE, significant renal impairment excluded. 
  • Rivaroxaban: 15mg bid x three weeks, then 20mg qd for three, six, or 12 months for 3,449 deep vein thrombosis (DVT)1 and 4,832 pulmonary embolism (PE)2 patients had: 
    • Similar rates of: recurrent VTE (2-3%), major or clinically significant bleeding (8-11%), and death (2-3%). 
  • Dabigatran: 150mg bid for six months in 5,107 DVT or PE patients3,4 had: 
    • Similar rates of recurrent VTE: ~2-2.5%. 
    • Statistically significantly less major or clinically relevant bleeding: 5.3% vs. 8.5%, Number Needed to Treat (NNT) 32. 
    • More acute coronary syndromes (9 vs. 5) but statistics not reported. 
  • Apixaban: 10mg bid x seven days, then 5mg bid x six months in 5,395 DVT or PE patients5 had: 
    • Similar rates of recurrent VTE or VTE-related death: 2.2% vs. 2.6%. 
    • Statistically significantly less major or clinically significant bleeding: 4.3% vs. 9.7%, NNT 19. 
Most patients receiving rivaroxaban or apixaban had initial LMWH treatment for <2 days,1,2,5 while dabigatran-treated patients had LMWH for a median of nine days.3,4  Statistical issues: 
  • Non-inferiority margins set higher than clinically important differences: 
    • Rivaroxaban considered non-inferior to warfarin if had ≤twice the number of recurrent VTEs. Dabigatran margins set higher, apixaban lower.
Context:   
  • Warfarin time in therapeutic range ~60%lower earlier in studies.1-5 
  • Compared to placebo, extending novel oral anticoagulant therapy decreases VTE recurrence which is partially offset by increased bleeding.1,6,7 
    • Extending treatment with aspirin also decreases VTE recurrence.8  
  • LMWH is recommended for treating VTEs in cancer patients.9  
  • Only rivaroxaban is currently approved in Canada for VTE treatment.10 
    • Drug costs, six months (Alberta): rivaroxaban ~$625warfarin ~$40.11 


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Author(s)
Auteur(s)
  • Michael R Kolber BSc MD CCFP MSc
  • Tammy Bungard BSP PharmD

1. EINSTEIN Investigators. N Engl J Med. 2010; 363:2499-510.

2. EINSTEIN–PE Investigators. N Engl J Med. 2012; 366:1287-97.

3. Schulman S, Kearon C, Kakkar AK, et al. N Engl J Med. 2009; 361:2342-52.

4. Schulman S, Kakkar AK, Goldhaber SZ, et al. Circulation. 2014; 129(7):764-72.

5. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med. 2013; 369:799-808.

6. Schulman S, Kearon C, Kakkar AK, et al. N Engl J Med. 2013; 368:709-18.

7. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med. 2013; 368:699-708.

8. Ference J, Allan GM. Tools for Practice, Alberta College of Family Physicians 2013 July 22. http://www.acfp.ca/Portals/0/docs/TFP/20130722_060542.pdf. Accessed April 7, 2014.

9. Lyman GH, Khorana AA, Kuderer NM, et al. J Clin Oncol. 2013; 31:2189-2204.

10. Drugs and Health Products. Health Canada. Available at http://webprod5.hc-sc.gc.ca/noc-ac/info.do?no=14313&lang=eng. Accessed April 7, 2014.

11. Kolber MR, Lee J, Nickonchuk T. Price Comparison of Commonly Prescribed Pharmaceuticals 2014. Available at http://acfp.ca/Portals/0/docs/ACFPPricingDoc2014.pdf. Accessed April 7, 2014.

Tammy Bungard, speaker with honoraria (Bayer, Boehringer Ingelheim) in the past two calendar years.