New Kids on the Block: A case based review of the NOACs

Marc Zumberg Associate Professor

Division of Hematology/Oncology May 2013

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Disclosures – None

–  http://coi.med.ufl.edu/

Comparison of warfarin vs. New Oral Anticoagulants

Weitz. Hematology 2012. 536-540

Case 1 •  Pt is a 48 yo female with valvular atrial

fibrillation placed on warfarin 6 years ago – AVR 10 years prior –  INR has been in range 66% of the time – No bleeding problems – No renal insufficiency – Wants to know about the NOACs

Case 1

•  You recommend: – A. Continue warfarin – B. Apixiban – C. Rivaroxaban – D. Dabigatran – E. ECASA

Case 1

•  You recommend: – A. Continue warfarin – B. Apixiban – C. Rivaroxaban – D. Dabigatran – E. ECASA

– What if pt was poorly compliant with warfarin? •  Would your choice change?

Case 1 •  Note all studies of the NOACs only included nonvalvular

atrial fibrillation

•  No studies included patients with mechanical valves –  Long effective half-life of warfarin may be of benefit

•  It is generally recommended if patients are stable and doing well on warfarin and monitoring is not prohibitive then they should remain on this agent

•  Pt poorly compliant on warfarin also likely to be poorly compliant with NOACs –  Can monitor compliance easier on warfarin –  Less effect with single missed dose

NOACs: Atrial fibrillation

Adam. Ann Intern Med 2012;157:796-807

Case 2

•  Pt is a 48 yo male with a newly diagnosed unprovoked iliofemoral DVT

– Normal creatinine – No bleeding risks – No other medications – Travels a lot

– He asks you about short and long term treatment options for his DVT

Case 2

•  You recommend which of the following for short and long anticoagulation: – A. Lovenox/Warfarin – B. Apixiban – C. Rivaroxaban – D. Dabigatran – E. Lovenox/Warfarin/ECASA – F. Stop anticoagulation after 3 months

Case 2

•  You recommend for short and long term – A. Lovenox/Warfarin – B. Apixiban – C. Rivaroxaban – D. Dabigatran – E. Lovenox/Warfarin/ECASA – F. Stop anticoagulation after 3 months

Prandoni, P. et al. Haematologica 2007;92:199-205 Goldhaber. Circulation. 2011;123:664-7. Boutitie F et al. BMJ 2011;342:bmj.d3036

Incidence of recurrent thromboembolism in patients with idiopathic (unprovoked) and secondary VTE

Eichinger, S. et al. Circulation 2010;121:1630-1636 Beyth. Am J Med. 1998 Aug;105(2):91-9.

Nomograms to compute risk scores and estimate cumulative rates of recurrent VTE and bleeding

Hazard Ratios for Venous Thromboembolism, Major Vascular Events, and Clinically Relevant Bleeding

with ECASA use compared to placebo

Brighton TA et al. N Engl J Med 2012;367:1979-1987.

VTE Conclusions •  Idiopathic VTE is a chronic condition

– Risk of recurrence remains after discontinuation of anticoagulation

– Treat for 3 months at a minimum – Consider indefinite anticoagulation based on:

•  VTE recurrence risk •  Bleeding risk •  Patient preference

•  Rivaroxaban is the only NOAC currently FDA approved for treatment of VTE

•  Extended ECASA therapy may be an option

Apixaban for extended VTE

Agnelli G et al. N Engl J Med 2012. DOI: 0.1056/NEJMoa1207541

Case 3: Pre-op A 78 year-old male is on apixiban for non-valvular atrial fibrillation (CHADS2 score 3)

– Needs semi-elective resection of a complex thigh mass

– CrCl 45 ml/min – No other medications – Surgery thought to be of high bleeding risk due to

vascular involvement

Case 3

•  In terms of apixiban you recommend: – A. Hold 12 hours pre-op – B. Continue throughout the procedure – C. Hold 24 hours pre-op – D. Hold 48 hours pre-op – E. Hold 72 hours pre-op – F. Hold 96 hours pre-op – G. Transition to LMWH

Case 2

•  In terms of apixiban you recommend: – A. Hold 12 hours pre-op – B. Continue throughout the procedure – C. Hold 24 hours pre-op – D. Hold 48 hours pre-op – E. Hold 72 hours pre-op – F. Hold 96 hours pre-op – G. Transition to LMWH

Pre-operative

Connolly. J Thromb Thrombolysis. On-line March 27, 2013

How about restarting?

Connolly. J Thromb Thrombolysis. On-line March 27, 2013

Case 4: Major Bleed •  54 year-old male on dabigatran for atrial

fibrillation is brought to the ER after MVA – Patient is unconscious –  Internal bleeding and splenic laceration on CT – Uncertain last administration or dose – No history of renal insufficiency – Family providing all information

•  Pt also on amiodarone, lisinopril, simvastatin, and ketoconazole

Case 4: Trauma

•  In addition to supportive care and holding further dabigatran what therapy might you reconsider: No labs yet available – A. FFP – B. Protamine – C. Activated charcoal – D. Dialysis – E. Prothrombin complex concentrates – F. DDAVP – G. Recombinant VIIa

Case: Trauma

•  What labs would be affected by dabigatran? (ie how could you monitor if the drug is present?) – A.PT – B.PTT – C.Platelet function assay (PFA) – D.Thrombin time (TT) – E. Fibrinogen – F. None

Labs Dabigatran Rivaroxaban Apixiban

PT

Not useful May be useful Not useful

PTT Useful Not useful Not userful Thrombin time Useful, but very

sensitive Not useful Not useful

Anti-Xa assay Not useful Useful Useful

Note labs may be useful for qualitative assessment, but not for quantitative use

ie. not for monitoring levels

Garcia. J of Thromb and Haem. 2012; 11: 245-252

Treatment •  No true reversal agents for new oral anticoagulants

– Activated charcoal if dabigatran ingested within hours – Dialysis helpful with dabigatran if renal failure

•  FFP, cryoprecipitate, platelet, protamine not generally useful

•  Prothrombin complex concentrates and/or recombinant VIIa may be useful – Doesn’t reverse/Not an antidote – May help generate thrombin

Dabigatran: Guidelines for management of bleeding

Van Ryn Thromb Haemostasis 2010

Interactions

Lindsley. Cardiology Today. May 2012 Horn. Pharmacy Times. Online Dec 13, 2010

Case 5: Cost containment

•  A physician requests Rivaroxaban be added to the Shands formulary for VTE prophylaxis after total hip replacement (THR)

•  The VA is considering adding rivaroxaban to the formulary for atrial fibrillation

•  Your hospital administrators ask you whether this is cost effective

Shands/UF acquisition costs DRUG COST

Warfarin 5mg $0.04 Enoxaparin 30mg $4.44 Enoxaparin 40mg $5.92 Rivaroxaban 10mg $5.25 Rivaroxaban 20mg $5.33 Dabigatran 75mg $3.11 Dabigatran 150mg $3.11 Apixaban 2.5mg $3.38 Apixiban 5mg $3.38

THR Prophylaxis: Rivaroxaban Efficacy

Eriksson BI et al. N Engl J Med 2008;358:2765-2775

Erikkson Annu Rev Med 2011

Choices and Summary

Weitz. Hematology. 2012. 536-540

New or old ?

Weitz. Hematology. 2012. 536-540