Oral Apixaban For The Treatment of Acute Venous Thromboembolism

1. Oral Apixaban For The Treatment of AcuteVenous Thromboembolism Done by :Fatimah Al-Shehri Pharm.D Candidate King Abdul-Aziz university. Supervised by : Dr.SherineEsmail. Clinical pharmacist .  Internal medicine/ Nephrology.               August 29, 2013Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808

2. Introduction to Apixaban : • Pharmacological class. • Indications:(FDA & non-FDA ) • Mechanism of action. • Pharmacokinetics. • Contraindications. • Advantages and disadvantages comparing to warfarin .

3. Introduction : • Apixaban: is an oral anticoagulant . • pharmacological class: Factor Xa inhibitor. • Uses : • Labeled Uses(FDA approved): 1-Stroke prophylaxis. Systemic embolism prophylaxis in patients with non-valvular atrial fibrillation.In 28 December, 2012. • Unlabeled Uses(non-FDA approved): 1-To reduce the risk of recurrent DVT and/or PE (in patients completing 6-12 months of standard anticoagulation for venous thromboembolism). 2- Postoperative DVT prophylaxis for arthroplasty of the knee. 3- Postoperative DVT prophylaxis for total hip replacement.

4. Mechanism of action : Oral anticoagulants in the management of venous thromboembolism John N. Makaryus, Jonathan L. Halperin & Joe F. Lau Nature Reviews Cardiology 10, 397-409 (July 2013) doi:10.1038/nrcardio.2013.73

5. Introduction:pharmacokinetics: • Absorption: - The bioavailability is 50%. -(C max) appear 3 to 4 hours. -Apixaban is absorbed throughout the GIT with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. • Distribution: Plasma protein binding in humans is 87%. The Vd is 21 liters. • Metabolism: Approximately 25% is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4. • Elimination: Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.

6. Introduction: • Contraindications: • Active pathological bleeding. • Severe hypersensitivity reaction to Apixaban. • Liver diseases. • With other anticoagulants. • Prosthetic valves. • Mitral stenosis.

7. Introduction: Comparison between Apixaban and Warfarin :

8. Previous studies: 1-Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement: Among patients undergoing hip replacement, thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with lower rates of venous thromboembolism, without increased bleeding. N Engl J Med 2010;363:2487-98 ,december 23, 2010 vol. 363 no. 26

9. Previous studies: 2- Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients. In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. N Engl J Med 2011;365:2167-77.

10. The Study of The Journal Club: Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808

11. Study overview: • Aim of the study :to compare the efficacy and safety of apixaban with the efficacy and safety of conventional therapy in patients with DVT,PE or both. • PICOT:

12. Study overview : • Null hypothesis: Apixaban would be inferior to conventional therapy with respect of the primary outcomes . • Trial design: Randomized, double-blind ,double dummy trial. • Funding: (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

13. Method: • Randomization : Usage of an interactive voice-response system and was stratified according to the qualifying diagnosis of either: 1-Symptomatic proximal deep-vein thrombosis. 2- Symptomatic pulmonary embolism (with or without deep-vein thrombosis).

14. Method: Allocation and blinding: Double blinded , double dummy study , used blinded INR monitoring with a point-of-care device that generated an encrypted code for INR results.

15. Methods :Inclusion criteria : • Patients were eligible for inclusion in the study if they were: -18 years of age or older and had objectively confirmed, symptomatic proximal deep-vein thrombosis or pulmonary embolism (with or without deep-vein thrombosis).

16. Methods :Exclusion criteria : • Active bleeding OR a high risk of bleeding. • Contraindications to treatment with enoxaparin &warfarin. • If they had cancer and long-term treatment with LMWH was planned. • If their DVT or PE was provoked in the absence of a persistent • risk factor for recurrence. • If < 6 months of anticoagulant treatment was planned. • If they had another indication for long-term anticoagulation therapy, dual antiplatelet therapy, treatment with aspirin at a dose of more than 165 mg daily, or treatment with potent inhibitors of cytochrome P-450 3A4.

17. Methods :Exclusion criteria : • If they had received more than two doses of a once-daily LMWH regimen, fondaparinux, or a vitamin K antagonist. more than three doses of a twice-daily LMWH regimen; or more than 36 hours of continuous intravenous heparin. • A hemoglobin level of < 9 mg/dl. • A platelet count of <100,000 per cubic millimeter, • A serum creatinine level of >2.5 mg/dl, or a calculated • CrCl of < 25 ml/min.

18. Method: • Statistical analysis: • Intention to treat analysis . • The 95% confidence interval for the relative risk was calculated with the use of the Mantel–Haenszel method. • The 95% confidence interval for the difference in risk was calculated for the primary outcome with the use of the inverse-variance method. • Statistical testing for non-inferiority was performed with the method of Farrington and Manning. • Time-to-event curves were calculated with the Kaplan–Meier method

19. Results:

20. Primary efficacy and safety outcomes :

21. Results:Kaplan –Meier cumulative event risk .

22. Results :Kaplan –Meier cumulative event risk .

23. Primary efficacy and safety outcomes:

24. Results: Adverse effects : The rates of adverse events, including elevations in liver-function tests, were similar in the two treatment groups .

25. Rates of adverse events :

26. Subgroup analysis:

27. Subgroup analysis :

28. Study Conclusion : • On the basis of the results of this study, together with those of the Apixaban for the Extended Treatment of Deep Vein Thrombosis and Pulmonary Embolism trials , apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism.

29. Critical Appraisal of The Topic:

30. Validity :

31. Baseline characteristics:

32. Baseline characteristics:

33. Validity :

34. Validity:

35. Results :

36. Results :

38. Results: • How are the results expressed ? • FOR MAJOR BLEEDING : • EER=(Events in E group/total in E-group)=15/2691= 0.005=(0.6 %). • CER=(Events in C group/total in C group)=49/2704= 0.018(1.8 %). • RR=EER/CER= (0.33) • RRR=1-RR=(1-0.33)= (0.67) • ARR=CER-EER=(1.2) NNH=[100/ARR=100/ 1.2]=83 For every 83 patients treated by apixaban 1 of them will experience MAJOR BLEEDING .

39. Results:Kaplan –Meier cumulative event risk .

40. Results :Kaplan –Meier cumulative event risk .

41. Applicability: .

42. Applicability:

43. Costs :

44. Over all Conclusion: • Limitations : • This study was funded by Bristol-Myers Squibb and Pfizer. Many of the authors were affiliated with or employed by Bristol-Myers Squibb, which introduces a potential for bias. • The compliance was mentioned but it wasn't assessed .

45. Over all conclusion: • Strength : • Minimization of bias with the double-blind design. • Identical follow-up of all patients. • Central adjudication of all outcome events. • Study execution was rigorous, with minimal loss to follow-up, few patients withdrawing consent, good adherence to study medication, and well-managed warfarin therapy.