Journal Club – September 2012

Coagulation – Brief Review

Brief Review: Warfarin Blocks vitamin K- dependent glutamate carboxylation of precursor factors II, VII, IX, X Vit K = cofactor Warfarin blocks the reduction of Vit K Oral administration

Review: Heparin Indirect thrombin inhibitor: IV only Called UFH (unfractionated heparin) Complexes with AT (heparin co-factor I) AT by itself inactivates SLOWLY! –Thrombin –Factor Xa –XIIa, XIa, IXa (lesser extent) AT + Heparin: conformational change in AT = fold acceleration in inactivation At high concentrations: Also binds to platelets and heparin co-factor II—which inhibits thrombin

Limitations of Warfarin and Heparin: Both have narrow therapeutic windows Highly variable dose responses: requires laboratory monitoring (PT, APTT) –Heparin can bind to other plasma proteins making bioavailability variable –Warfarin has numerous food, drug interactions Limited ability to stop a clot from propagating: –Heparin does not inactivate thrombin bound to fibrin or Xa bound to platelets very well

LMWHs Molecular wt: Heparin: 15,000 vs LMWH: LMWHs inactivate Xa but have less effect on thrombin (some molecules not long enough) –ratio of anti-Xa to anti-thrombin activity of 3:1 –Do not prolong PTT unless dose high Advantages over heparin: –Easier to administer: sq, BID dosing –Dosage and anticoagulant effect easier to predict; dose based on body weight –Lab monitoring not necessary in all patients –Less chance of inducing immune- mediated thrombocytopenia

New Anticoagulants Fondaparinux Idraparinux Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 442 Dabigatran

New Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 442 Dabigatran ORALPARENTERAL DX-9065a Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) TTP889

VIIa Xa IXa XIa XIIa Direct Thrombin inhibition Tissue factor Factor IIa (thrombin) Dabigatran II ×

VIIa Xa IXa XIa XIIa Direct Factor Xa inhibition Tissue factor Fibrinogen Fibrin clot Factor II (prothrombin) Rivaroxaban Apixaban YM150 DU-176b LY Betrixaban TAK 442 ×

Apixaban  Oral, direct, selective factor Xa inhibitor  Produces concentration-dependent anticoagulation  No formation of reactive intermediates  No organ toxicity or LFT abnormalities in chronic toxicology studies  Low likelihood of drug interactions or QTc prolongation  Good oral bioavailability  No food effect  Balanced elimination (~25% renal)  Half-life ~12 hrs He et al., ASH, 2006, Lassen, et al ASH, 2006

Rivaroxaban: oral direct Factor Xa inhibitor  Predictable pharmacology  High bioavailability  Low risk of drug–drug interactions  Fixed dose  No requirement for monitoring Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005 Rivaroxaban ® – rivaroxaban

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110: In patients with atrial fibrillation (AF), are new oral anticoagulants effective and safe for preventing stroke and systemic embolism compared with warfarin?

Scope of Review  Included studies compared a new, non–vitamin K antagonist oral anticoagulant with warfarin in patients with AF, had >1 year follow-up, and were published in peer-reviewed journals.  Primary efficacy outcome was a composite of stroke (including hemorrhagic stroke) and systemic embolism.  Secondary efficacy outcomes were ischemic and unidentified stroke, hemorrhagic stroke, all-cause mortality, vascular mortality, and myocardial infarction.  Primary safety outcome was major bleeding; secondary safety outcomes were gastrointestinal bleeding and intracranial bleeding.

Review Method  MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, Science Citation Index Expanded, and ProQuest’s Dissertations and Theses database (all to Jul 2011) clinical trials databases; reviews; and reference lists were searched for randomized controlled trials (RCTs).  3 noninferiority RCTs met the selection criteria: (n= , mean age 70 to 73 y, 60% to 65% men, median follow-up 657 to 730 d) ARISTOTLE (n= ) assessed apixaban RE-LY (n= ) assessed dabigatran ROCKET-AF (n= ) assessed rivaroxaban.

Results

Results - Summary

Conclusions  The new oral anticoagulants reduced the risk for a composite end point of stroke and systemic embolism compared to warfarin.  New oral anticoagulants were also found to be associated with a lower risk for key secondary efficacy outcomes, including ischemic and unidentified stroke, hem-orrhagic stroke, all-cause mortality, and vascular mortality, compared to warfarin  The review was inconclusive with respect to major bleeding and gastrointestinal bleeding but found a substantial decrease in the risk for intracranial bleeding.  Overall, the results support the use of the new oral anticoagulants as alternatives to warfarin for long- term anticoagulation therapy in patients with AF.

Comments (1)  The highest benefit for prevention of stroke and emboli in patients at moderate risk was with dabigatran (150 mg)  Rivaroxaban seemed best suited for patients at highest risk.  The safest bleeding profile was achieved with apixaban or dabigatran (110 mg - a dose that is unavailable in the US)  The only drug that showed a significant decrease in major bleeding was apixaban.

Comments (2)  Dabigatran is contraindicated in patients with renal dysfunction.  Apixaban is safe for patients with moderate renal disease.  Patients with creatinine clearance <30 mL/min should use warfarin.  Once-daily rivaroxaban is more convenient than twice-daily dabigatran or apixaban.  Patients on warfarin with good control of international normalized ratio (>70% of time in thera-peutic range) or those with valvular AF should continue to use warfarin.

Comments (3)  There are no specific treatments to reverse the new anticoagulants during bleeding events, although dabigatran may be dialyzable and prothrombin complex concentrates to reverse apixaban and rivaroxaban are being evaluated.  Individualized drug selection is important and can be achieved by using risk stratification schemes for thrombosis (CHA2DS 2 -VASc) and bleeding (HASBLED).

Thank you !!