-No updates on Apixaban or rivaroxaban at this time
A cow farmer approached Professor Karl Paul Link’s Lab at the U of W school of agriculture Cows dying – blood not coagulating Suspected is was Sweet Clover Hay In 1941, the compound was isolated and found to be a potent anti coagulant Put to use as a rat poison in 1948 In 1955, Warfarin was given to President Dwight Eisenhower following a myocardial infarction As Duxbury and Poller point out; ‘What was good for a war hero and the President of the United States must be good for all, despite being a rat poison!
DabigatranDr Ihab Suliman2013
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
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
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 BWann LS, et al. 2011 ACCF/AHA/HRS Focused Update on the Management ofPatients with Atrial Fibrillation (Update on Dabigatran). Jour Amer CollegCardio. 2011. 57(11):1331-38.
2011 ACCF/AHA/HRS Focused Update on the Management ofPatients With Atrial Fibrillation (Update on Dabigatran )
Dabigatran: FDA Approved Dosing 150 mg BID for SPAF 150 mg for CrCl >30 mL / min 75 mg for CrCl 15-30 mL / min
Stroke from Atrial FibrillationAF 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% ↓
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
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?
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.
Development of the syndrome is associated with the use of large loading doses at the start of treatment
In warfarins 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.[
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.
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.[
1933 Deer Park, WisconsinBr J Haematol. 2008 Jun;141(6):757-63
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 Links student Harold A. Campbell to recover 6 mg of crystalline anticoagulant. Next, Links 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 Campbells 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.
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.
An early recipient of warfarin was US president Dwight Eisenhower , who was prescribed the drug after having a heart attack in 1955.