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Novel OACs: How should we use them?"

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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

(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:

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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®)

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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.

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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 2013

x

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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

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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"

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Connolly SJ, et al. NEJM 2009;361:1139-51

RELY  Study:  Dabigatran  

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ROCKET Study: Rivaroxaban


Stroke or Systemic Embolism"

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ARISTOTLE Study: Apixaban


Stroke or Systemic Embolism"

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ENGAGE AF TIMI-48 : Edoxaban


Stroke or Systemic Embolism"

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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

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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  BeDer  

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  

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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  BeDer  

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  

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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  BeDer  

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  

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Cost of the new OACs"

•  Dabigatran"

•  Rivaroxaban"

•  Apixaban"

•  Edoxaban ???"

•  Warfarin – much cheaper, but factor in costs of monitoring…."

Approximately $4/day

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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

(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"

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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"

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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"

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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

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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"

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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!

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