AF, Warfarin skin necrosis, dabigatran PPT

1. Dabigatran
Dr Ihab Suliman
2013

2. The New Oral Anticoagulants:
Similar Yet Different
 Thrombin Inhibitors:
1. Dabigatran: pro-drug, renal clearance - twice daily
 FXa Inhibitors:
1. Rivaroxaban: renal clearance - once daily
2. Apixaban: hepatic clearance - twice daily
3. Edoxaban: hepatic clearance - once daily
Circulation 2010;121:1523-1532

4. Dabigatran: FDA Status
 Pradaxa® trade name
 For the prevention of DVT/PE after orthopedic
surgery:
 Pradaxa approved in EU and Canada
 For the prevention of stroke in patients with
non-valvular atrial fibrillation (SPAF):
 Pradaxa 150 mg BID FDA approved (Oct. 2010)
 Pradaxa approved in EU, Canada and Japan

5. 2011 ACCF/AHA/HRS Focused Update
1-B
 Dabigatran (150mg BID) can be an alternative to
warfarin in patients with paroxysmal to
permanent Afib
 LOE B
Wann LS, et al. 2011 ACCF/AHA/HRS Focused Update on the Management of
Patients with Atrial Fibrillation (Update on Dabigatran). Jour Amer Colleg
Cardio. 2011. 57(11):1331-38.

6. 2011 ACCF/AHA/HRS Focused Update on the Management of
Patients With Atrial Fibrillation (Update on Dabigatran )

9. Dabigatran: FDA Approved Dosing
 150 mg BID for SPAF
 150 mg for CrCl >30 mL / min
 75 mg for CrCl 15-30 mL / min

10. Stroke from Atrial Fibrillation
AF is the most preventable cause of stroke:
12-16 million will be on warfarin treatment by
2050 in the US
Clinical trials have shown stroke can be
reduced:
Placebo vs ASA = 19% ↓
ASA vs warfarin = 30% ↓
Placebo vs warfarin = 62% ↓
Dabigatran vs warfarin = 34% ↓

12. Dabigatran: Not Without Issues
1. No anticoagulant effect if missed dose
• 2% discontinuation rate due to GI distress
• Cost of drug ($240/mo vs $4/mo for warfarin)
1. No test to assess anticoagulation
2. Difficult to modulate dose
3. Bleeding in the elderly and renal impaired patients (5
dabigatran related deaths in Japan)
4. ‘Real world’ untested populations
5. Drug interactions
6. Limited data on bridging between anticoagulants
7. No specific antidote
8. 0.2% increase in myocardial infarction
9. Off-label use

13. Dabigatran: Laboratory Testing
 Monitoring vs anticoagulant assessment
 PT and aPTT
 Differing reagent sensitivities
 Not a linear association between assay values and drug level
 Not validated for association to bleeding
 aPTT may be applicable for qualitative assessment
 INR: not sensitive; not validated
 TT: Super-sensitive; can identify if any drug onboard
 Ecarin clotting time: results can vary depending on plasma factors;
research use only (RUO)
 PiCT: RUO
 Chromogenic anti-FIIa
 Hemoclot: quantitative using dabigatran calibrators; FDA approved
yet?

33. Management of bleeding

36.  Warfarin necrosis is a rare but severe complication of treatment with
warfarin or related anticoagulants. The typical patient appears to be an
obese, middle aged woman (median age 54 years, male to female ratio
1:3).
 This drug eruption usually occurs between the third and tenth days of
therapy with warfarin derivatives. The first symptoms are pain and
redness in the affected area. As they progress, lesions develop a sharp
border and become petechial, then hard and purpuric.
 They may then resolve or progress to form large, irregular,
bloody bullae with eventual necrosis and slow-healing eschar formation.
Favored sites are breasts, thighs, buttocks and penis, all areas with
subcutaneous fat.[In rare cases, the fascia and muscle are involved.

37. Development of the
syndrome is associated with
the use of large loading doses
at the start of treatment

38.  In warfarin's initial stages of action, inhibition of protein
C and Factor V11 is stronger than inhibition of the other
vitamin K-dependent Coagulation factor 11, 1X1 and . This
results from the fact that these proteins have different HALF
LIVES: 1.5 to six hours for factor VII and eight hours for
protein C, versus one day for factor IX, two days for factor X
and two to five days for factor II. The larger the initial dose
of vitamin K-antagonist, the more pronounced these
differences are. This coagulation factor imbalance leads to
paradoxical activation of coagulation, resulting in
a HYPERCCOGULABLE and Thrombosis.The blood clots
interrupt the blood supply to the skin, causing necrosis.
Protein C is an innate anticoagulant, and as warfarin further
decreases protein C levels, it can lead to massive thrombosis
with necrosis and gangrene of limbs.
 Notably, the Prothrombin time (or INR, INR) used to test the
effect of coumarins is highly dependent on factor VII, which
explains why patients can have a therapeutic INR (indicating
good anticoagulant effect) but still be in a hypercoagulable
state.[

39.  The first element of treatment is usually to
discontinue the offending drug, although there
have been reports describing how the eruption
evolved little after it had established in spite of
continuing the medication.[
 Vitamin K can be used to reverse the effects of
coumarins, and Heparin or (LMWH) can be used
in an attempt to prevent further clotting. None of
these suggested therapies have been studied
in clinical trials.

40.  Many conditions mimic or may be
mistaken for warfarin necrosis,
including Pyoderma
gangrenosum or necrotizing fasciitis.
 Warfarin necrosis is also different from
another drug eruption associated with
warfarin, purple toe syndrome which
usually occurs three to eight weeks after
the start of anticoagulation therapy. No
report has described this disorder in the
immediate postpartum period in patients
with protein S deficiency.[

41. 1933 Deer Park, Wisconsin
Br J Haematol. 2008 Jun;141(6):757-63

42.  The identity of the anticoagulant substance in spoiled sweet clover
remained a mystery until 1940. In 1933 Karl Paul Link and his lab
of chemists working at the University of wisconsinset out to isolate
and characterize the hemorrhagic agent from the spoiled hay. It
took five years for Link's student Harold A. Campbell to recover
6 mg of crystalline anticoagulant. Next, Link's student Mark A.
Stahmann took over the project and initiated a large-scale
extraction, isolating 1.8 g of recrystallized anticoagulant in about 4
months. This was enough material for Stahmann and Charles F.
Huebner to check their results against Campbell's and to
thoroughly characterize the compound. Through degradation
experiments they established that the anticoagulant was 3,3'-
methylenebis-(4-hydroxycoumarin), which they later
named Dicoumarol . They confirmed their results by synthesizing
dicoumarol and proving in 1940 that it was identical to the
naturally occurring agent.

43.  The first drug in the class to be widely
commercialized was dicoumarl itself, patented in
1941 and later used as a pharmaceutical. Karl Link
continued working on developing more potent
coumarin-based anticoagulants for use as rodent
poison, resulting in warfarin in 1948. The name
"warfarin" stems from the acronym WARF,
for Wisconsin Alumni Reseach Foundation + the
ending -arin indicating its link with coumarin.
Warfarin was first registered for use as a
rodenticide in the US in 1948, and was
immediately popular. Although warfarin was
developed by Link, the Wisconsin Alumni
Research Foundation financially supported the
research and was assigned the patent.

44. An early recipient of warfarin
was US president Dwight
Eisenhower , who was prescribed
the drug after having a heart
attack in 1955.