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New Oral Anticoagulants: A Review

New Oral Anticoagulants: A Review . Babak Moini, MD Veterans Affairs Hospital Noon Lecture S eries. Acknowledgment: . Some of the slides were borrowed from Amanda Miller Phar.D. Case1.

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New Oral Anticoagulants: A Review

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  1. New Oral Anticoagulants: A Review Babak Moini, MD Veterans Affairs Hospital Noon Lecture Series

  2. Acknowledgment: • Some of the slides were borrowed from Amanda Miller Phar.D.

  3. Case1 • 68 male with hx of DM, CHF and prior ischemic CVA admitted for new afib. He has a hx of non-compliance. • CHADs2: 4. • Which anticoagulant to send him home with?

  4. Oral Anticoagulants Available in US

  5. Mechanism of Action

  6. rivaroxaban apixaban dabigatran http://www.healio.com/~/media/Images/News/Online/Orthopedics/2009/12_December/01/79_fig_400_307_57368.gif

  7. Pharmacology:

  8. Indications: US Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients (MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days.

  9. Usual Dosing (A fib)

  10. Usual Dosing (VTE) • Only FDA-approved agent = rivaroxaban • VTE Prophylaxis (knee/hip surgery) • 10mg once daily (up to 35 days) • No renal dose (CrCl < 30 ml/min  avoid) • VTE Treatment: • 15 mg BID x 3 weeks then 20mg daily • No renal dose (CrCl < 30 ml/min  avoid)

  11. Perioperative Recommendations Dabigatran PI, Blood 2012;119:3016-23

  12. Major Side Effects: • Bleeding: varied definition in each study. • GI • ICH • Major (drop in Hgb by 2, life threatening). • Dabigatran: • Pills are made in acidic content, hence has 20% rate of GI side effects. • ? Observed increase risk of GI bleeding.

  13. Monitoring Levels: • Coumadin: INR • New Oral anticoagulants: no standardized studies. No accurate quantitative measures. • Dabigatran: ECT, Thrombin clotting time • Rivaroxaban: special anti-Xa activity • Abixaban special anti-Xa activity

  14. Drug-Drug Interactions: • No where as severe as with Warfarin. • Dabigatran: P-glycoprotein, pro-drug. • Needs acidic environment, avoid co-administration with PPI. • Rivaroxaban: CYP-450 and P-glycoprotein. • Caution with dual inhibitors (Ketoconazole, Itroconazole, Clarithromycin). • No dose adjustments needed. • Abixaban: CYP3A4 and P-glycoprotein. • Decrease dose to 2.5mg bid in dual inhibitors.

  15. Switching To/From Warfarin

  16. Treatment of Bleeding: • No evidence based guidelines. • Remember that unlike Coumadin, the new OAC will continuously bind to factor Xa or thrombin, hence making FFP less useful. • Current available Rx for life threatening active bleeding: based on case reports. • Factor VII • PCC: 3 and 4 factor concentrates. • HD: only for Dabigatran. Large volume of distribution. • Charcoal Gonsalves Et al. Mayo Clinic Proc. 5-2013

  17. Trials vs Warfarin for A Fib * Dose reductions for renal impairment

  18. Trials vs Warfarin for A fib

  19. Major Findings: • RELY • Dabigatran110mg NI to Warfarin (1.53% vs 1.69%). • Dabigatran150mg superior to Warfarin ONLY if compared with sub-optimal INR subgroup (1.11 % vs 1.69%). • Major bleeding less with 110mg (2.71 vs 3.11%). • ROCKET-AF • Rivaroxaban NI to Warfarin (2.1% vs 2.4%) • Less ICH or fatal bleeding (0.4% vs 0.8% ) • ARISTOTLE: • Abixaban Superior to Warfarin (1.27% vs 1.6% ) • Less Major bleeding (1.4% vs 2.1% )

  20. Key Safety Endpoints (% per year) • *: Primary safety endpoint: • RE-LY  major hemorrhage • ROCKET-AF  major + non-major clinically relevant bleeding • ARISTOTLE  ISTH (Int Soc Thromosis & Hemostasis) major bleeding

  21. Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF. http://dx.doi.org/10.1016/j.amjcard.2012.03.049

  22. Quick Review of Evidence- Based Medicine: • I • A: Systemic review of multiple RCTs / multiple RTCs • B: High quality single RTC • II: • A: Systemic review of cohort studies • B: High quality cohort studie(s) • III: • Systemic review of Case/Control studies / Case Control studies • IV • Case reports • IV • Expert opinion

  23. Chest 2012; 141:e531S-e575S Stroke 2012;43: 3442-3453 OAC = oral anticoagulation

  24. New OAC: • Pros: • Easy administration • Immediate effect • Much less food and drug interactions • One dose fits all • The names sound so much cooler than WARFARIN. • Cons: • Expensive • Inability to monitor compliance • Short duration: loss of effect with a single missed dose • No safe/reliable antidotes • ? Bleeding. Observational bias vs real difference. • Renal dosing

  25. Take home message: • Coumadin still remains the drug of choice for many patients due to cost, past experience and known side effects. • Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects. • Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile. • Watch out for recall bias with the new OAC among your own colleagues. • Patient compliance is a major factor: remember with the new OAC one missed dose means a lot!

  26. The End!

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