1 Novel OACs: How should we use them?" Iqwal Mangat, MD FRCPC" Director, Arrhythmia Service, St. Michaelʼs Hospital" Assistant Professor of Medicine, University of Toronto"
2 Presenter Disclosure Dr. Iqwal Mangat Presenter Topic: Novel OAC s: How should we use them? Relationships with commercial interests: - Grants/Research Support: Bayer, Bristol Myers Squibb, St. Jude Medical - Speakers Bureau/Honoraria: AstraZeneca, Bayer, St. Jude Medical - Consulting Fees: AstraZeneca, Bayer, St. Jude Medical - Other: None
3 Disclosure of Commercial Support This program has received financial support from Merck Canada, Janssen and Valeant Canada in the form of an educational grant. Potential for conflict(s) of interest: Dr. Mangat has received consulting fees/honoraria/research grants from the organizations supporting this program and organizations whose product(s) are being discussed in this program. AstraZeneca, Bayer, Bristol Myers Squibb developed/licenses/ distributes/benefits from the sale of, etc. a product that will be discussed in this program:
5 Mi5ga5ng Poten5al Bias The Canadian Heart Research Centre assesses conflict of interest with its instructors, planners, managers and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by the CHRC for fair balance, scientific objectivity of studies utilized in this program, and patient care recommendations. The CHRC is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The speaker had provided his full disclosure in advance of the program. The scientific content of the program is evidence based and all content related to pharmacotherapy is within product label. The program has been peer reviewed. Dr. Mangat has provided his disclosure information at the start of this presentation.
6 The Perils of Warfarin"
7 We need something new!!" Ximelagatran 2001 x SPORTIF 2006 Dabigatran 2002 RELY 2009 Rivaroxaban 2005 ROCKET 2011 Apixaban 2006 ARISTOTLE 2011 Edoxaban 2008 ENGAGE-AF TIMI
8 A Little Bit About the Drugs..." Dabigatran! Rivaroxaban! Apixaban! Edoxaban! Target" IIa (thrombin)" Xa" Xa" Xa" Peak (hrs)" 1.5 to 3" 2 to 4" 1 to 3" 1 to 2" Half-life (hrs)" 12 to 17" 5 to 9" 9-14" 9-11" Protein Binding" Renal clearance" CYP3A4 substrate" 35%" 92-95%" 87%" 45%" 80%" 66% (of active drug)" 25%" 35%" No" Yes" Yes" Yes" Prodrug" Yes" No" No" No" Bioavailability" 6.5%" >80%" >50%" 45%" Must not be taken out of packaging until being consumed Must be taken with large evening meal 2013 Cabral, K. J Thromb Thrombolysis 36:
9 New Oral Anticoagulants for AF: Overview" Four major trials of New OACs" All studied non-valvular AF" Stroke and systemic embolism primary endpoint" Large, controlled, randomized trials with 2.5yr follow-up" - RELY (Dabigatran) - Non-Blinded, CrCl >30, no dose adjustment" - ROCKET (Rivaroxaban) highest risk patients, dose adjustment for CrCl 30-49" - ARISTOTLE (Apixaban) dose adjustment based on Cr, Age, weight; small mortality benefit, less bleeding" - ENGAGE AF TIMI-48 (Edoxaban) dose adjustment based on Cr, weight; small mortality benefit, less bleeding" Warfarin control in trials likely better than clinical practice"
10 RELY Study: Dabigatran Stroke or Systemic Embolism Connolly SJ, et al. NEJM 2009;361:
11 ROCKET Study: Rivaroxaban Stroke or Systemic Embolism" Patel et al, NEJM 2011;365:883-91
12 ARISTOTLE Study: Apixaban Stroke or Systemic Embolism" Granger et al, NEJM 2011;365:981-92
13 ENGAGE AF TIMI-48 : Edoxaban Stroke or Systemic Embolism" Giugliano et al, NEJM 2013;online before print
14 Recent Oral Anticoagulation Trials: Stroke or Systemic Embolism! Edoxaban 60mg OD Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Non-inferiority Margin P <.001 P =0.34 P <.001 P = 0.12 Apixaban 5 mg BID P = HR (95% CI) Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: Giugliano et al, NEJM 2013;online before print New Agent BeDer Warfarin BeDer
15 Recent Oral Anticoagulation Trials: Ischemic Stroke! Edoxaban 60mg OD Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID P = 0.97 P = 0.35 P =.03 P = 0.58 P = HR (95% CI) New Agent BeDer Warfarin BeDer Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: Giugliano et al, NEJM 2013;online before print
16 Recent Oral Anticoagulation Trials: Hemorrhagic Stroke! Edoxaban 60mg OD P < Dabigatran 110 mg BID Dabigatran 150 mg BID P < P < Rivaroxaban 20 mg QD P = 0.02 Apixaban 5 mg BID P < HR (95% CI) Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: Giugliano et al, NEJM 2013;online before print New Agent BeDer Warfarin BeDer
17 Recent Oral Anticoagulation Trials: Major Bleeding! Edoxaban 60mg OD Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID P < P = P = 0.31 P = 0.58 P < HR (95% CI) New Agent BeDer Warfarin BeDer Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: Giugliano et al, NEJM 2013;online before print
18 Cost of the new OACs" Dabigatran" Rivaroxaban" Apixaban" Approximately $4/day Edoxaban???" Warfarin much cheaper, but factor in costs of monitoring." What about ODB
19 Cost of the new OACs" 1. Anticoagulation is inadequate following a reasonable trial on warfarin; OR 2. Anticoagulation with warfarin is contraindicated or not possible due to inability to regularly monitor via International Normalized Ratio (INR) testing. LU Code Dabigatran Rivaroxaban Apixaban
20 How do monitor new OACs?" Explain to your patients the importance of taking the medication as prescribed" - Q12h for Dabigatran and Apixaban" - Dabigatran not to be removed from packaging until consumed" - With large meal of day for Rivaroxaban" No specific requirement for monitoring" PTT will be elevated for all 4 drugs" PT will be elevated for Xa inhibitors" Neither test useful to assess anticoagulant effect"
21 What about bleeding?" All 4 new OACs, when compared to warfarin, have:" - Less major bleeding " - Less bleeding related deaths" - Less hemorrhagic stroke and intracranial hemorrhage" GI Bleeding increased with" - Dabigatran 150mg BID (not 110mg BID)" - Edoxaban 60mg OD (not 30mg OD)" Less bleeding of EVERY kind with:" - Apixaban" - Edoxaban 30mg OD"
22 When bleeding happens" Supportive management" Dialysis may be useful for drugs" that are not highly protein bound:" - Dabigatran" - Edoxaban" Prothrombin complex concentrates, PCC (eg: Octaplex) have been shown to be useful for most of the new OACs" Novel antibodies in development:" - First human study with fragmented antibody (Fab) to dabigtran shown to be safe, well tolerated, and effective in healthy volunteers"
23 When itʼs time for surgery" Several factors to consider:" - Risk of bleeding with surgery" - Risk of thrombosis when withholding OAC" - Renal function" Generally, do not give any OAC on day before or day of surgery, restart OAC on post-op day 1 or 2 depending on risk of bleeding" If high risk of bleeding or renal impairment, may need to hold OAC for 2 to 4 days" - If holding OAC for this duration, may need to consider bridging if risk of thrombosis is high"
24 We still need warfarin." Mechanical valves" AF secondary to rheumatic heart disease" Patient has intermittent compliance (more of a problem when drug has short half life)" Severe renal impairment" - ALL new OACs are contraindicated"
25 Which new OAC should I use?" Largest RRR of ischemic stroke: dabigatran 150 BID! Once daily dosing: rivaroxaban and edoxaban! Demonstrated safety in modest renal impairment: rivaroxaban, apixaban and edoxaban! Significant reductions in major bleeding with possible mortality benefit: apixaban and edoxaban! Severe renal insufficiency, mechanical prosthetic valves: warfarin! Least expensive: warfarin!
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