Novel OACs:
How should we use them?"
Iqwal Mangat, MD FRCPC"
Director, Arrhythmia Service, St. Michaelʼs Hospital" Assistant Professor of Medicine, University of Toronto"
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
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:
Disclosure of Commercial Support
AstraZeneca Bayer Bristol Myers Squibb
Rosuvastatin (Crestor®) Acarbose (Glucobay™) Apixaban (Eliquis®) Saxagliptin (Onglyza®) Bayer A1CNOW® and A1CNOW® Clopidogrel (Plavix®) Saxagliptin (Onglyza™) Bayer Blood Glucose Meters / Testing Strips Exenitide (Byetta®)
Ticagrelor (Brilinta®) Bayer's MICROLET®2
Metformin hydrochloride / Metformin hydrochloride and Glyburide (Glucophage®
Glucophage ® XR Extended Release, Glucovance®)
Ketostix® Saxagliptin (Onglyza®) Nifedipine (Adalat XL®, Adalat®XL® PLUS) Warfarin (Coumadin®)
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.
We need something new!!"
Ximelagatran Dabigatran Rivaroxaban Apixaban Edoxaban 2001 2002 2006 2005 2008 SPORTIF RELY ROCKET ARISTOTLE ENGAGE-AF TIMI-48 2006 2009 2011 2011 2013x
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" 35%" 92-95%" 87%" 45%" Renal clearance" 80%" 66% (of active drug)" 25%" 35%" CYP3A4 substrate"
No" Yes" Yes" Yes" Prodrug" Yes" No" No" No" Bioavailability" 6.5%" >80%" >50%" 45%"
A Little Bit About the Drugs..."
Must not be taken out of packaging until being consumed Must be taken with large evening meal
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"
Connolly SJ, et al. NEJM 2009;361:1139-51
RELY Study: Dabigatran
ROCKET Study: Rivaroxaban
Stroke or Systemic Embolism"
ARISTOTLE Study: Apixaban
Stroke or Systemic Embolism"
ENGAGE AF TIMI-48 : Edoxaban
Stroke or Systemic Embolism"
Recent Oral Anticoagulation Trials:
Stroke or Systemic Embolism!
Warfarin BeDer New Agent BeDer
Edoxaban 60mg OD P <.001 Dabigatran 110 mg BID P =0 .34 Dabigatran 150 mg BID P < .001 Rivaroxaban 20 mg QD P = 0.12 Apixaban 5 mg BID P = 0.01 HR (95% CI) 0.50 0.75 1.00 1.25 1.50
Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151. Patel MR, et al. N Engl J Med. 2011;365:883–891. Granger C, et al. N Eng J Med. 2011;365:981–992. Giugliano et al, NEJM 2013;online before print
N on -in fe rio rit y Ma rg in
Recent Oral Anticoagulation Trials:
Ischemic Stroke!
Edoxaban 60mg OD P = 0.97 Dabigatran 110 mg BID P = 0.35 Dabigatran 150 mg BID P = .03 Rivaroxaban 20 mg QD P = 0.58 Apixaban 5 mg BID P = 0.42 HR (95% CI) 0.50 0.75 1.00 1.25 1.50 Warfarin BeDer New Agent BeDerConnolly SJ, et al. N Engl J Med. 2009;361:1139–1151. Patel MR, et al. N Engl J Med. 2011;365:883–891. Granger C, et al. N Eng J Med. 2011;365:981–992. Giugliano et al, NEJM 2013;online before print
Recent Oral Anticoagulation Trials:
Hemorrhagic Stroke!
Edoxaban 60mg OD P < 0.001 Dabigatran 110 mg BID P < 0.001 Dabigatran 150 mg BID P < 0.001 Rivaroxaban 20 mg QD P = 0.02 Apixaban 5 mg BID P < 0.001 HR (95% CI) 0.00 0.25 0.50 0.75 1.00 1.25 Warfarin BeDer New Agent BeDerConnolly SJ, et al. N Engl J Med. 2009;361:1139–1151. Patel MR, et al. N Engl J Med. 2011;365:883–891. Granger C, et al. N Eng J Med. 2011;365:981–992. Giugliano et al, NEJM 2013;online before print
Recent Oral Anticoagulation Trials:
Major Bleeding!
Edoxaban 60mg OD P < 0.001 Dabigatran 110 mg BID P = 0.003 Dabigatran 150 mg BID P = 0.31 Rivaroxaban 20 mg QD P = 0.58 Apixaban 5 mg BID P < 0.001 HR (95% CI) 0.50 0.75 1.00 1.25 1.50 Warfarin BeDer New Agent BeDerConnolly SJ, et al. N Engl J Med. 2009;361:1139–1151. Patel MR, et al. N Engl J Med. 2011;365:883–891. Granger C, et al. N Eng J Med. 2011;365:981–992. Giugliano et al, NEJM 2013;online before print
Cost of the new OACs"
• Dabigatran"
• Rivaroxaban"
• Apixaban"
• Edoxaban ???"
• Warfarin – much cheaper, but factor in costs of monitoring…."
Approximately $4/day
Cost of the new OACs"
Dabigatran
Rivaroxaban
Apixaban
LU Code
431
435
448
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
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"
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"
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"
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