Pradaxa:
That's 19 years old in dog years
Monday, April 13, 2015
Seth D Bilazarian, MD
DrSeth@pmaonline.com
Disclosure
• Nothing to disclose
• I am a clinical investigator in several AF
trials (RE-LY, ARISTOTLE,
AVERROES, ENGAGE)
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.
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-yearold human and is considered an adult.
- Considered a senior dog at six years old
(in human years, that's 47 years old)
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; 126:1869–1881)
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
Anticoagulants
Warfarin
FOR:
1. Cheap
2. Long history
Dabigatran
FOR:
1. First mover
2. More
effective
Rivaroxaban
FOR:
1. Once daily
AGAINST:
1. Variability
with food,
drugs
2. Frequent
monitoring
AGAINST:
AGAINST:
1. Not superior
efficacy
2. Boxed warnings
3. Higher GI
bleeding
4. Different doses
1.
2.
Higher MI
rate
Higher GI
bleeding
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; 123:1144–1150)
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 0.80–1.49; p=0.58). 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 0.50–1.35; p=0.4).
Conclusions—Dabigatran 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; 126:343-348)
Slow adoption
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?
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)
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 followup—I avoid it in GFR <40
• Clearly advantages for patient and practice
reduced burden and ease of transition for surgery