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The New Oral Anticoagulants: Handle with Care. Philip C. Comp, M.D., Ph.D. October 18, 2013. Speaker for dabigatran (Pradaxa®) and rivaroxaban (Xarelto®). Anticoagulant Quiz. Which commonly used anticoagulant does not require laboratory monitoring? Which anticoagulant has no antidote? - PowerPoint PPT Presentation
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The New Oral Anticoagulants:
Handle with CarePhilip C. Comp, M.D., Ph.D.
October 18, 2013
Speaker for dabigatran (Pradaxa®) and rivaroxaban (Xarelto®)
Anticoagulant Quiz• Which commonly used anticoagulant does
not require laboratory monitoring? • Which anticoagulant has no antidote?• The dose of which anticoagulant depends on
renal function?
(Enoxaparin, Lovenox®)
Edoxaban
The New Oral Anticoagulants
Dabigatran (Pradaxa®)Inhibits thrombinTwice a dayAtrial fibrillation
Apixaban (Eliquis®)Inhibits factor XaTwice a dayAtrial fibrillation
Rivaroxaban (Xarelto®)Inhibits factor XaOnce a dayAtrial fibrillation; DVT/PE treatment;Reduction in risk of DVT/PE (after 6 mn Tx);Hip/Knee prophylaxis;
Canine Model of Blood Coagulation
Factor IX Factor X PROTHROMBIN
Canine Model of Blood CoagulationEffect of Warfarin
Factor IXa Factor Xa THROMBIN
Canine Model of Blood CoagulationOral Anti-Xa
Factor IXa Factor Xa THROMBIN
Canine Model of Blood CoagulationOral Anti-thrombin
Factor IXa Factor Xa THROMBIN𝐝𝐚𝐛𝐢𝐠𝐚𝐭𝐫𝐚𝐧rivaroxaban
apixaban
There is no free lunch
The effectiveness of an anticoagulant must be weighed against the risk of bleeding
Bleeding
Thrombosis
Apixaban, Dabigatran and Rivaroxaban
• Oral• Short half-lives• Renal clearance• No INRs• No food interactions• Few drug interactions
Prevention of Stroke-Apixaban
Granger et al. NEJM 3654: 981-92, 2011Number needed to treat/1.8 years: 167
Atrial Fibrillation- Dabigatran
Connolly et al. NEJM 361, 2009
35% RRR
!
Number needed to treat/ 2 years: 88
Atrial Fibrillation- Rivaroxaban
CPatel et al. NEJM 365: 883-91, 2011Number needed to treat/1.6 years: 135
Atrial Fibrillation- Dabigatran
Modified from Connolly et al. NEJM 361, 2009
STRO
KENo Treatment Warfarin
Dabigatran
Number needed to treat NT 88 v. warfarin
No Tre
atm
ent
CHADS2 Scores
0-1 33%2 35%3-6 33%
ESTIMATE 5% risk/yearIn a non-treated group
Percentage of AF patients with stroke per year
No treatment 5.0%Warfarin 1.6%Dabigatran 1.0%
~
Modified from Connolly et al. NEJM 361, 2009
3.4%
0.6%68% of strokes gone; 32 occur
80% of strokes gone; 20 occur
100 strokes occur
STROKE = Ischemic Stroke and Hemorrhagic Stroke*
*Subdural hematomas, epidural hematomas, subarachnoid hematomas and intracerebral hemorrhage
Stroke rates (percent/year)
All Stroke Hemorrhagic Stroke
Time INR in 2-3 range
Dabigatran/ Warfarin
1.44/1.57 0.10/0.38 64
Rivaroxaban/Warfarin(as treated)
2.61/3.12 0.5/0.7 55
Apixaban/ Warfarin
1.19/1.51 0.24/0.47 62
Bleeding and death rates (percent/year)Major Bleeding
Death
Dabigatran/ Warfarin
3.11/3.36 3.64 /4.13
Rivaroxaban/Warfarin(as treated)
3.60/3.40 1.90/2.20
Apixaban/ Warfarin
2.13/3.09 3.52/3.94
Bleeding Event Rate (%/year)Intracranial Gastrointestinal
Apixaban 0.33 0.76Warfarin 0.80 0.86
Dabigatran 0.30 1.51Warfarin 0.74 1.02
Rivaroxaban 0.77 3.15Warfarin 1.18 2.16
N Engl J Med 2011;365:981-92N Engl J Med 2009;361:1139-51.N Engl J Med 2011;365:883-91.
NNT with dabigatran for 1 year to prevent one adverse event compared to warfarin
NNT
Stroke or systemic embolus
172
Intracranial bleeding 227
Major bleeding 154
Life-threatening bleeding
286
Nature Reviews Cardiology 7, 10-11 (January 2010)
Can atrial fibrillation studies be directly compared?
Mean Age and CHADS2 Score
Apixaban 70y 2.1 ± 1.1
Rivaroxaban 73y 3.5 ± 0.94
Dabigatran 72y 2.1 ± 1.1
Direct comparison of strokes and bleeding between studies is difficult.
CHF 1Hypertension 1Age > 75 1Diabetes 1Prior stroke 2
New oral agents in atrial fibrillation
Apixaban superior to warfarinRivaroxaban not inferior to warfarinDabigatran superior to warfarin
Davis, N Engl J Med 2012;366:1914-22.
No food interactions
Compare to WARFARIN AND FOOD
Dietitians
CHLOROPHOBIA (fear of the color green)
Green Tea
Green Tea333 liters of green tea contain 1 mg vitamin K
Iceberg Lettuce
New anticoagulants have short half- lives (9-17 hours)
Compliance
Forgetfulness 30%Other priorities 16%Decision to omit doses 11%Lack of information 9% Osterberg l et al. NEJM 353: 487-97 2005
1,800,000 patients prescribed a statin:
Patients filled prescriptions for a mean of 11.4 medications/3 month
10% of patients filled prescriptions for 23 or more medications.
10% had prescriptions written by 4 or more prescribers.
Choudhry NK The Implications of Therapeutic Complexity on Adherence to Cardiovascular Medications. Archives of Internal Medicine 171:814-822, 2011
Retrospective Study of Medication Prescription in Oklahoma City, n=3
• 64 year old man: 14 medications daily; 31 pills• 61 year old woman: 15 medications; 39 pills• 90 year old man: 15 medications; 27 pills
Drugs don’t work in patients who don’t take them C. Everett Koop, M.D.
1916-2013
Typical Clinical Trial Patient
Who is the ideal patient?
• Does not like INRs• Reliable• Well insured
Who will have a bleed?
• Frail (<60 kg)• Reduced creatinine clearance• Over 80 years of age
Harper. Bleeding Risk with Dabigatran in the Frail ElderlyN Engl J Med 2012; 366:864-866
Proper prescriber behavior
• At each visit – Are your taking drug X?• At every visit – Why are you taking drug X?• At each visit – Are you taking X every day?
KIDNEY FUNCTION IS IMPORTANT!CHECK THE CREATININE CLEARANCE
What is the effect of no more INRs?
No more anticoagulation clinics and fewer office visits.Will that reduce compliance?
BOUNCING BEN in a BAD candidate!
00.5
11.5
22.5
33.5
44.5
INR
Who to switch from warfarin
• Not a cure for the bouncing INR• Stroke risk: Least benefit to well controlled
warfarin patients• Fewer potential drug interactions in
polypharmacy patients?
Warfarin > new anticoagulant
Patients angst: Miss INRsMiss food restrictions
If bleeding occurs
Little data availablea. Factor VIIab. Factor VIII Inhibitor Bypassing Activity (FEIBA)c. Hydration
Fresh frozen plasma and Vitamin K are not the way to go!
Everyone is developing an antidote
Oral anticoagulant inhibits factor Xa
Xa
Inhibitor
Everyone is developing an antidote
A recombinant antidote (DU-176b)
Xa
Surgery while on medication
Dabigatran (100% renal)Rivaroxaban (65% renal clearance)Apixaban (25% renal clearance)
When to stop the medication preoperatively depends on the medication and renal function.
Look it up!
What is the cost per day*
Dabigatran = $9.50Rivaroxaban= $9.46Apixaban = $9.40
*Sam's Club, Northwest Highway, OKC 10/10/13
Advising patients
• Explain they are taking lots of medications – stroke preventers critical • Avoid friendly little black dogs and
get someone else to clean the gutters!
Summary of New Anticoagulants
• Marginally better than warfarin for atrial fibrillation
• No food interactions; few drug interactions• No need for INRs• Short-half life – take regularly• Check creatinine clearance yearly