new oral anticoagulants in peri-operative medicine teresa l. carman, md director, vascular medicine...

New Oral Anticoagulants in Peri-operative Medicine

Teresa L. Carman, MDDirector, Vascular Medicine

University Hospitals Case Medical CenterAssociate Professor of Medicine

Case Western Reserve University School of Medicine

• Review the new anticoagulants and clinical indications

• Discuss the pharmacology of the drugs

• Review available surgical and trauma guidelines for reversing and monitoring the new anticoagulants

Objectives

Historical Perspective

1916

Heparin

1950s 1990s 2002

Warfarin LMWHsIndirect

Factor Xa Inhibitors

DTIs

Lepirudin ArgatrobanBivalirudinDesirudin

Fondaparinux

EnoxaparinDalteparinTinzaparin

2010

DabigatranRivaroxaban

Apixaban

2012

EndoxabanBetrixaban

Ideal Anticoagulant

• Oral administration • Rapid and predictable anticoagulant effect• Broad therapeutic window• Efficacious with a low bleeding risk• No food-drug and drug-drug interactions• No need for laboratory monitoring• Easily reversible• Affordable (acceptable cost-benefit ratio)

Mechanisms of Anticoagulation

XIIa

IIa

Xa

Intrinsic system(surface contact)

XII

XI XIa

Tissue factor

IX IXa VIIa VII

VIII VIIIa

Extrinsic system(tissue damage)

X Xa

V Va

II

Fibrinogen Fibrin

(Thrombin)IIaFactor Xa inhibitors

Direct thrombin inhibitors

Vitamin K antagonists

Heparins

New Terminology

• DOAs – Direct oral anticoagulants

• NOAs – New oral anticoagulants

• TSOAs – Target specific oral anticoagulants

Emerging Therapies• Pentasacchaide anti-Xa

– Idrabioptraparinux**

• Oral DTIs– Ximelagatran**– Dabigatran– AZD0837– SB-424323– TGN-167

• Oral direct Anti-Xa– Rivaroxaban– Apixaban– Edoxaban– Betrixaban– Otamixaban

• FVIIa inhibitors– rNAP-c2

– TFPI

TSOAs

Dabigatran Rivaroxaban Apixaban

VTE prevention

RE-MODELRE-NOVATERE-MOBILIZERE-SOLVE

RECORD 1RECORD 2RECORD 3RECORD 4MAGELLAN

ADVANCE IADVANCE 2ADVANCE 3ADOPT

VTE treatmentRE-COVERRE-MEDYRE-SONATE

EINSTEIN-DVTEINSTEIN-PEEINSTEIN-EXT

AMPLIFYAMPLIFY-EXT

Stroke prevention in AF RE-LY ROCKET-AFARISTOTLEAVERROES

Prevention of secondary events in ACS

— ATLAS 2 APPRAISE 2

TSOA• Phase III trials of new/emerging

anticoagulants demonstrate promise– Ease of dosing– Bioeffective– Safe compared to conventional therapies– Monitoring and dose adjustments are typically

not required• Apply caution in renal insufficiency

Dabigatran• Oral direct thrombin inhibitor (DTI)

• Rapidly converted from dabigatran etexilate to dabigatran

• Binds clot-bound and free thrombin with high affinity and specificity

• Predictable anticoagulant effect

• Low plasma protein binding

• No liver toxicity based on available clinical data

Dabigatran

• Onset is immediate with peak activity at 2-3 hrs• Plasma t ½ 12-17 hours• Excreted renally (80%); eliminated in bile• No significant food-drug • Few drug-drug interactions (amiodarone,

quinidine, verapamil – dose once daily)• Bottled product has a 4-month shelf life once

opened• Needs acidic environment for best absorption

Dabigatran• Approved for NONVALVULAR AFIB

– Fixed dose CrCl>30 ml/min - 150 mg BID• Once daily dosing with verapamil, quinidine, and amiodarone• Dose adjustment or avoidance with other strong P-gp agents

– Caution with CrCl < 30 ml/min – CrCl 15-30 ml/min - 75 mg BID

• FDA recommended based on pharmacology (no trial data)

• No monitoring is required• NOT for use in patients with valves• Approved in Europe and Canada for orthopedic

prophylaxis

Rivaroxaban

• Direct factor-Xa inhibitor• Inhibits free factor-Xa as well as prothrombinase-bound

and clot bound factor-Xa• Circulates primarily bound to albumin• 80-100% oral bioavailability• Peak activity at 2-4 hours• T ½ - 7 to 11 hours• Hepatic metabolism with renal and fecal excretion• Avoid with CrCl <15 ml/min; caution when CrCl 15-

30ml/min • No food and few drug interactions

Riveroxaban• VTE prophylaxis in THA/TKA

– 10 mg daily (w/ or w/o food)• Nonvalvular Afib

– 20 mg daily w/ evening meal– 15 mg daily with CrCl 15-50 mg/ml w/ evening meal

• VTE dosing– 15 mg BID x 21 days then 20 mg daily with food

• VTE extended prophylaxis– 20 mg daily with food

• Approved in European Union for VTE prophylaxis after TKA/THA, nonvalvular afib, and VTE

• Approved in Canada for VTE prophylaxis after TKA/THA

Apixaban• Direct factor-Xa inhibitor• Inhibits free factor Xa as well as clot bound

Xa and activated prothrombinase bound Xa• Peak activity at 3 hours• T ½ - 8 to 11 hours• Non-renal metabolism with renal (25-30%)

and fecal (65%) excretion• Reduce dosing with ketoconazole,

itraconazole, ritonair, clarithromycin

Apixaban Dosing

• Nonvalvular Afib– 5 mg BID

– With 2 or more risk factors – dose 2.5 mg BID• age >80 • Cr > 1.5 • wt < 60 kg

TSOAs

J Thromb Thrombolysis 2013;36:133-140.

New Anticoagulants

• Benefits– Efficacy similar in to present therapy in many clinical settings– Large trials support relative safety compared to VKA– Wide therapeutic window

• Problems– Inability to accurately monitor the agents– NO antidotes– Short t ½ may leave patients unprotected with missed doses– No clear indication of patients that may benefit most from the

new therapies– $$$

Special Clinical Situations

• Peri-procedural management– Determining the need for bridging

• Acute reversal for surgery or bleeding

Pre-procedural Interruption


Pre-procedural Interruption

Cleve Clin J Med 2013;80:443-451.

Bridging algorithm for vitamin K antagonists and new oral anticoagulants.

Gallego P et al. Circulation 2012;126:1573-1576

Copyright © American Heart Association

Pre-op Management• If surgery cannot be delayed, there is an increased risk

of bleeding in patients receiving anticoagulants. • Risk of bleeding should be weighed against the urgency

of intervention.• Discontinue drugs minimum 1 to 2 days (CrCl ≥ 50

mL/min) • Patients with the highest risk of bleeding hold for 2-4

days– major surgery, spinal puncture, or placement of a spinal or

epidural catheter or port, in whom complete hemostasis may be required

• CrCl< 50 mL/min hold 2 to 5 days before elective invasive or surgical procedures

van Ryn et al. Thromb Haemost 2010;103:1116-1127.

Need for Bridging

Estimated that >250,000 patients interrupt AC annually for procedures

>10% risk

5-10% risk

< 5% risk

Bridging Therapy• Bridging -- transitioning warfarin to a short-acting

anticoagulant for a temporary interruption of anticoagulation, especially for surgery or a potential invasive procedure (colonic polyp removal).

• Pro– avoid thromboembolism– avoid prolonged hospitalization

• Con– May increase bleeding complications– Creates miscommunications, logistical nightmares– Prolongs the hospital stay in some cases– Lack of evidence (no RCTs)– Published reports are cohort studies, without tight protocols

Periprocedural Heparin Bridging in Patients ReceivingVitamin K Antagonists

Systematic Review and Meta-Analysis of Bleeding andThromboembolic Rates

Circulation 2012; 126:1630

Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall (OR 5.4) and major bleeding (OR 3.6)

and at similar risk of thromboembolic events compared to nonbridged patients (0.9% vs. 0.6%).

Bridging Decisions• Does AC need interrupted?• Is bridging required (risk assessment)?• “Bridge in”– Preop strategy• “Bridge out”– Postop strategy• Anticoagulation Intensity

– (risk/bleeding assessment)

“full” or “therapeutic” (e.g., Enoxaparin 1 mg/kg BID or UFH gtt)

“prophylactic” (e.g., Enoxaparin 40 mg/day or SQ UFH)

Bridging Protocol

Arch Cardiovasc Dis 2011;104:669-676.

Basic Recommendations1. “Bridging” is becoming more selective

because of the high bleeding risks, logistical problems, and communication mishaps.

2. The higher the risk the tighter the management.

3. Don’t forget about the option of “bridging-in” with LMWH (OP) or IV UFH in-hospital when necessary.

4. “Bridging-out” may be unnecessary in many patients.

Regional Anesthesia

Anesthesiology 2013;118:1466-1474.

Why Monitor?

Monitoring

• Requires understanding of the available coagulation tests

• Should not be done “routinely” but limited to clinical situations a specific goal in mind– Urgent pre-op assessment– Active bleeding assessment

• Presently – do not quantitatively assess the degree of anticoagulation but can make a qualitative assessment

Cautions - Monitoring

• Do not have reliable laboratory monitoring– 150 mg BID dose

• Peak - 184 ng/ml

• Trough - 90 ng/ml

– PT is insensitive to dabigatran

• INR rarely exceeds 1.2

– aPTT is more sensitive with less variability

– Very high dabigatran levels are underestimated by aPTT values



Thromb Haemost 2010;105 (epub)

PT/INR and aPTT are variable based on the coagulometer and the reagent


• For DTIs - ECT is the best lab monitor – not widely available/not FDA approved

• Chromogenic anti-factor II – FDA approved but not for monitoring DTIs

• Thrombin time is too sensitive



Limited data a best are available for rivaroxaban and apixaban for monitoring or reversal

• Rivaroxaban and Apixaban influences prothrombin time (PT) > aPTT

Rivaroxaban and apixaban should be able to be monitored by chromogenic Anti-Xa assays

• Standards have not been set/reported

Monitoring Guidelines


Dabigatran


Riveroxaban


Managing Bleeding

• Hold the drug

• Local hemostatic measures

• Supportive PRBC/PLT transfusions

• FFP unlikely to be useful

• Initiate a hematology consult early

• Institutional protocols are recommended*

Managing Bleeding• Specific reversal agents (“antidotes”) not yet available • Protamine sulfate and vitamin K should not be expected to affect the

anticoagulant activity

• With overdose – when given within 1-2 hours of ingestion activated charcoal can adsorb dabigatran (in vitro data)

• Maintain adequate diuresis given renal elimination• Dabigatran can be dialyzed with removal of about 60% of drug over

2-3 hrs.• Rivaroxaban is not expected to be dialyzable (high plasma protein

binding).• Consider transfusion of fresh frozen plasma, platelets or red blood

cells for supportive management

Erenberg ES et al. Circ 2011:124:1573-9

Effect of PCC infusion (vs placebo) on the Protime after administration of

Rivaroxaban 20 mg BID x 2.5 days

Effect of PCC infusion (vs placebo) on the Ecarin Clotting Time after administration

of Dabigatran 150 mg BID x 2.5 days

Note: PCC infusion also reversed the effect of rivaroxaban on new thrombin generation as measured by the endogenous thrombin potential

Note: PCC infusion did NOT reverse the anticoagulant effect of dabigatran on aPTT or Thrombin Time

Reversal Agents

Managing Bleeding

• Some evidence supports use of activated prothrombin complex concentrates (FEIBA) for rivaroxaban, recombinant factor VIIa (Novoseven) for dabigatran or concentrates of coagulation factors II, IX, or X (PCC) but data are limited.

• 4-factor PCC recently approved in the US.– Best data available for the DTIs

• Always concerns about the “potentially” prothrombotic state created with bypassing agents.

• Xa recombinant reversing agent is under investigation. Phase II data was encouraging– Phase III in development

Conclusions

• Available anticoagulants successfully inhibit thrombin formation and the interactions of thrombin within the coagulation cascade

• There is no antidote yet available. • Mechanisms to bypass the anticoagulant effect

are available. • In the appropriate patient the half-life is typically

short. Withholding therapy may be sufficient

Conclusions

• Reversibility still need to be addressed

• Monitoring is problematic– Common/familiar coagulation assays are

helpful but not the most accurate

• Be wary in high risk clinical settings

• Advise the use of Med-alert devices for patients using the drugs

Ongoing Clinical Challenges• No validated tests to measure anticoagulation

effect• No established therapeutic range• No true antidote for most agents• Assessment of compliance more difficult than

with vitamin K antagonists• Potential for unknown long-term adverse events• Balancing cost against efficacy• Lack of head-to-head studies comparing new

agents

Questions

new oral anticoagulants in peri-operative medicine teresa l. carman, md director, vascular medicine...

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