Pradaxa: That's 19 years old in dog years * Seth D

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PradaxaThat's 19 years old in dog years

• Tuesday, June 18, 2013
• Seth D Bilazarian, MD
• DrSeth_at_pmaonline.com

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Disclosure

• Nothing to disclose
• I am a clinical investigator in several AF trials
  (RE-LY, ARISTOTLE, AVERROES, ENGAGE)

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When will a generic version be available?

• The first patent for Pradaxa is currently set to
  expire in February 2018. This is the earliest
  predictable date that a generic version could
  become available.
• There are other circumstances that could come up
  to extend or shorten this exclusivity period.
  This could include such things as lawsuits or
  other patents for specific uses.

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19 years in a dog's life

• According to www.pedigree.com (a calculator based
  on breed) at two years old a standard poodle or
  flat-coated retriever is the equivalent of a
  19-year-old human and is considered an adult.
• Considered a senior dog at six years old (in
  human years, that's 47 years old)

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Cardiomyogenesis in the aging and failing human
heart

• Report that the human heart is characterized by a
  significant turnover of ventricular myocytes,
  endothelial cells, and fibroblasts,
  physiologically and pathologically.
• Renewal is very high shortly after birth,
  decreases during postnatal maturation, remains
  relatively constant in the adult organ, and
  increases dramatically with age.
• From 20 to 78 years of age, the adult human heart
  entirely replaces its myocyte, endothelial-cell,
  and fibroblast compartment eight, six, and eight
  times, respectively.
• Myocyte, endothelial-cell, and fibroblast
  regeneration is further enhanced with chronic
  heart failure.

(Circulation 2012 12618691881)
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All new agents compared with warfarin

• Advantages
• No monitoring required
• No variability
• Fast onset of action
• Fast offset
• Lower intracranial hemorrhage rates (about 50
  lower for all)

• Disadvantages
• No reversibility
• No monitoring
• Expensive (higher tier by pharmacy benefit
  management)
• Not once daily in AM
• Less clinical experience
• No data for cardiac issues other than nonvalvular
  AF

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Anticoagulants

• Warfarin
• FOR
• Cheap
• Long history
• AGAINST
• Variability with food, drugs
• Frequent monitoring

• Dabigatran
• FOR
• First mover
• More effective
• AGAINST
• Higher MI rate
• Higher GI bleeding

• Rivaroxaban
• FOR
• Once daily
• AGAINST
• Not superior efficacy
• Boxed warnings
• Higher GI bleeding
• Different doses

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2011 ACCF/AHA/HRS focused update on the
management of patients with atrial fibrillation
(update on dabigatran)

• Table 2. Recommendation for Emerging
  Antithrombotic Agents
• 2011 focused update recommendation comments
• Class I
• Dabigatran is useful as an alternative to
  warfarin for the prevention of stroke and
  systemic thromboembolism in patients with
  paroxysmal to permanent AF and risk factors for
  stroke or systemic embolization who do not have a
  prosthetic heart valve or hemodynamically
  significant valve disease, severe renal failure
  (creatinine clearance 15 mL/min), or advanced
  liver disease (impaired baseline clotting
  function). (Level of evidence B)

(Circulation 2011 12311441150)
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Periprocedural bleeding and thromboembolic events
with dabigatran compared with warfarin results
from RE-LY

• Bleeding rates were evaluated from seven days
  before until 30 days after invasive procedures,
  considering only the first procedure for each
  patient. A total of 4591 patients underwent at
  least one invasive procedure 25.4 received
  dabigatran 150 mg and 25.9 received warfarin.
• Procedures included
• pacemaker/defibrillator insertion (10.3)
• dental procedures (10.0)
• diagnostic procedures (10.0)
• cataract removal (9.3)
• colonoscopy (8.6)
• joint replacement (6.2)
• Among patients assigned to either dabigatran
  dose, the last dose of study drug was given 49
  (35 85) hours before the procedure on comparison
  with 114 hours in patients receiving warfarin.
• There was no significant difference in the rates
  of periprocedural major bleeding between patients
  receiving dabigatran 150 mg (5.1) or warfarin
  (4.6) dabigatran 150 mg vs warfarin relative
  risk 1.09 ( 95 CI 0.801.49 p0.58). Among
  patients having urgent surgery, major bleeding
  occurred in 17.7 with dabigatran 150 mg and
  21.6 with warfarin dabigatran 150 mg relative
  risk 0.82 (95 CI 0.501.35 p0.4).
• ConclusionsDabigatran and warfarin were
  associated with similar rates of periprocedural
  bleeding, including patients having urgent
  surgery. Dabigatran facilitated a shorter
  interruption of oral anticoagulation.

(Circulation 2012 126343-348)
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Slow adoption

•  

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Is the patient a good candidate for a new
anticoagulant? (CRAB-I)

• C Good prescription coverage?
• R Normal renal function?
• A Are you an early adopter willing to take a
  new drug with one large trial in AF?
• B No history of GI bleeding?
• I For patients on warfarin, has there been INR
  instability requiring frequent dose changes?

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Novel anticoagulants Pradaxa/dabigatran
adoption issues

• Over 90 of cardiologists have used Pradaxa and
  only about 10 of internists
• Some internists hesitant to use novel
  anticoagulants novelty? Reversibility? Not
  understanding the new term nonvalvular AF?
• Issues with the elements of CRAB-I?
• Coverage hassles?
• GFR calculation hassles?
• Bleeding concerns?
• Instability? Someone else is managing the
  warfarin so may not even know
• Bad drug commercials

NVAF No prosthetic heart valve or valvular
disease that does not require surgical repair
(RE-LY had 21 with valvular heart disease that
met nonvalvular-AF criteria)
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Conclusion

• Pleased with adoption in my practice
• Heartburn is a problem in some patients
• Drug has superior efficacy, and I feel
  comfortable quoting that data to patients (FDA
  approved that in the label)
• Evaluating renal function initially and at
  follow-upI avoid it in GFR lt40
• Clearly advantages for patient and practice
  reduced burden and ease of transition for surgery

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