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 = 1000-4000 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: 4000-5000

• 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

• FondaparinuxIdraparinux

• RivaroxabanApixaban

• LY517717• YM150• DU-176b• Betrixaban• TAK 442

• Dabigatran

New AnticoagulantsNew Anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bBetrixabanTAK 442

Dabigatran

ORAL PARENTERAL

DX-9065a

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

TTP889

VIIa

Xa

IXa

XIa

XIIa

Direct Thrombin inhibitionDirect Thrombin inhibitionTissue factor

Factor IIa(thrombin)

Dabigatran

II

×

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionDirect Factor Xa inhibitionTissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixaban

YM150DU-176b LY517717

BetrixabanTAK 442

×

ApixabanApixaban

Oral, direct, selective factor Xa inhibitorOral, direct, selective factor Xa inhibitor Produces concentration-dependent Produces concentration-dependent

anticoagulationanticoagulation No formation of reactive intermediatesNo formation of reactive intermediates No organ toxicity or LFT abnormalities in No organ toxicity or LFT abnormalities in

chronic toxicology studies chronic toxicology studies Low likelihood of drug interactions or Low likelihood of drug interactions or

QTc prolongationQTc prolongation Good oral bioavailability Good oral bioavailability No food effect No food effect Balanced elimination (~25% renal) Balanced elimination (~25% renal) Half-life ~12 hrs Half-life ~12 hrs

He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

Rivaroxaban: oral direct Factor Xa Rivaroxaban: oral direct Factor Xa inhibitorinhibitor

Predictable Predictable pharmacologypharmacology

High bioavailability High bioavailability Low risk of drug–drug Low risk of drug–drug

interactionsinteractions Fixed doseFixed dose No requirement for No requirement for

monitoringmonitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

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;110:453-60.

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= 44 563, mean age 70 to 73 y, 60% to 65% men, median follow-up 657 to 730 d)ARISTOTLE (n= 18 201) assessed apixabanRE-LY (n= 18 113) assessed dabigatranROCKET-AF (n= 14 264) assessed rivaroxaban.

Results

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 !!