Perioperative Management of Anticoagulation...1/18/2016 1 Perioperative Management of...

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Perioperative Management of Anticoagulation

Rapid Fire Session

Hospital Medicine 2016

San Diego

8 March 2016

Scott Kaatz, DO, MSc, FACP, FHM

Hurley Medical Center

Flint, MI

Associate Professor of Medicine

Michigan State University

• Grant support to institution– Boehringer-Ingelheim– Bristol Myer Squibb– Bayer/Jansen/Johnson and Johnson– Eisai– Iverson Genetics Diagnostics/Medicare – National Institute of Health– Canadian Institute of Health Research– Blue Cross/Blue Shield of Michigan

• Speaker honorarium– Janssen– Boehringer-Ingelheim– Bristol Myer Squibb/Pfizer– CSL Behring– Daiichi Sankyo

• Consultant– Boehringer Ingelheim– Bristol Myer Squibb/Pfizer– Janssen– Daiichi Sankyo– Portola

• Board membership (non-profit)– Thrombosis and Hemostasis Societies of North America– AC Forum– National Certification Board of Anticoagulation Providers– National Blood Clot Alliance Medical and Scientific Advisory Board

Full Disclosure

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PERIOPERATIVE MANAGEMENT OF ANTICOAGULATION

• Bridging anticoagulation

– Mechanical valves

– Atrial fibrillation

– Venous thromboembolism

• Anticoagulation reversal

– Warfarin

– Dabigatran

– Rivaroxaban, Apixaban, Edoxaban

• Anticoagulation measurement

4Case

• 76 yo woman with a mechanical mitral valve, chronic atrial fibrillation, and a previous stroke 2 years ago

• To undergo (open) subtotal colectomy for resection of adenocarcinoma of the colon

• What would you do?

A. Don’t interrupt warfarin, perform procedure at therapeutic INR

B. No bridging, hold and restart warfarin only

C. Therapeutic dose UFH or LMWH bridging

D. Prophylactic dose UFH or LMWH bridging

E. Another strategy

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5 ACCP Guidelines

Douketis JD. Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266

• 2.4. In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest• bridging anticoagulation instead of no bridging during interruption

of VKA therapy (Grade 2C)

• In patients with a mechanical heart valve, atrial fibrillation, or VTE at low risk for thromboembolism, we suggest • no bridging instead of bridging anticoagulation during interruption

of VKA therapy (Grade 2C)

• In patients with a mechanical heart valve, atrial fibrillation, or VTE at moderate risk for thromboembolism, • the bridging or no-bridging approach chosen is, as in the higher-

and lower risk patients, based on an assessment of individual patient- and surgery-related factors

6 Risk Stratification for Perioperative Thromboembolism


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7 Mechanical Heart Valves

a) Starr Edwards – Ball in Cage

b) Medtronic Hall –Single tilting disc

c) St. Jude – Bileaflet tilting disc

d) Carpentier Edwards – Bioprosthetic

e) Hancock -Bioprosthetic







– Warfarin

– Dabigatran



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Case

• 78 yo female with AF, HTN, DM on warfarin

• Scheduled for open cholecystectomy

• CHA2DS2-VASc score = 5, CHADS2 = 3

• Would you bridge with therapeutic LMWH?

A. Yes

B. No

10 Risk Stratification for Perioperative Thromboembolism


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BRIDGE Trial• Question: is a strategy of NOT using LMWH

bridging as effective and safer during peri-procedural warfarin interruption in AF?

• Design: RCT• Patients: atrial fibrillation patients undergoing

warfarin interruption for a an invasive procedure or surgery?

• Intervention: dalteparin 100 u/kg q 12 hours bridging

• Control: placebo• Outcome: thromboembolic events and “major”

bleeding• Timeframe: 30 days post procedure

Douketis JD. N Engl J Med. 2015 Aug 27;373(9):823-33. PMID: 26095867

12BRIDGE Trial


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13BRIDGE Trial


14BRIDGE Trial


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15BRIDGE Trial


Resume LMWH/placebo 24 hours post procedure

Resume LMWH/placebo 48 - 72 hours post procedure

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Question

• If the CHA2DS2-VASc score = 9, CHADS2 = 6

• Would you bridge with therapeutic LMWH?

A. Yes

B. No

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– Warfarin

– Dabigatran



18Case

• 69 yo with recurrent idiopathic PE, last PE 2 years ago

• Elective hip replacementA. Don’t interrupt warfarin, perform procedure at therapeutic INR

B. No bridging, hold and restart warfarin only

C. Therapeutic dose UFH or LMWH bridging

D. Prophylactic dose UFH or LMWH bridging

E. Another strategy

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19 AF Risk Stratification


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VTE (DVT and PE) Bridging

• Design: cohort study

• Patients: 775 with DVT or PE with standard bridging protocol from 1997-2007

• Intervention: 1 of 3 LMWHs

• Comparison: no bridging

• Outcome: thromboembolic and major bleeding events

McBane RD. Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):442-8. PMID: 20139361

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Proportion Bridged

47/53 = 89%92/111 = 83%360/591 = 61%

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• Active cancer was the only independent risk for• Recurrent throboembolism

• Major bleeding

• Death


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– Warfarin

– Dabigatran



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Case

• 62 yo female with AF, HTN, DM and peripheral vascular disease

• Admitted with severe cellulitis and wet gangrene

• Needs urgent below-knee amputation for infection control

• On warfarin, INR = 4.1, weight 120 kg


A. Give vitamin K and go to surgery

B. Administer 2 units FFP + vitamin K and go to surgery

C. Administer 3 units FFP + vitamin K and go to surgery

D. Administer 4 units FFP + vitamin K and go to surgery

E. Give 4-factor PCC + Vitamin K and go to surgery

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25 Reversal of VKA• Design: RCT, open label

• Patients: Need rapid VKA reversal for surgery/procedure

• Intervention: 4 factor PCC (Kcentra)

• Comparison: FFP

• Outcome: effective haemostasis and rapid INR reduction

Goldstein JN. Lancet. 2015 May 23;385(9982):2077-87. PMID: 25728933

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274 Factor PCC vs. FFP for

Urgent Surgery


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4 Factor PCC and FFP Dosing

Sarode R. Circulation. 2013 Sep 10;128(11): 1234-43. PMID: 2393511

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– Warfarin

– Dabigatran



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Case

• 78 yo female with AF, HTN, and peripheral vascular disease

• Admitted with moderate cellulitis and dry gangrene

• Will need BKA in next few days

• On dabigatran (Pradaxa), CrCl = 40 ml/min


A. Hold dabigatran for 2 days prior to surgery

B. Hold dabigatran for 4 days prior to surgery

C. Hold dabigatran for 4 days prior to surgery and bridge with LMWH

D. Give idarucizumab (Praxbind) and go to surgery now

E. Measure aPTT daily and go to surgery when normal

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Spyropoulos AC, Douketis JD. Blood. 2012 Oct 11;120(15):2954-62. PMID: 22932800

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Post hoc Analysis of RELY Trial

• Randomized open label comparison of dabigatran vs. warfarin in AF

• Bridging defined as LMWH or heparin

• Prophylactic doses

• Intermediate doses

• Therapeutic doses

• Proportion of patients bridged

• Warfarin 27.5%

• Dabigatran 15.4%

Douketis JD. Thromb Haemost. 2015 Mar;113(3):625-32. PMID: 25472710

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Post hoc Analysis of RELY Trial

Douketis JD. Thromb Haemost. 2015 Mar;113(3):625-32. PMID: 25472710

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Perioperative Management of Dabigatran

• Cohort study of 541 cases (97% AF) using standard protocol

• Approximately 80% adherence to protocol

• Major bleed (ISTH surgical): 1.8% [95% CI (0.7 – 3.0)]

• 1 TIA

Schulman S. Circulation. 2015 Jul 21;132(3):167-73. PMID: 25966905

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35 Residual Anticoagulation Effect of Pre-op Dabigatran

Douketis JD. J Thromb Haemost. 2015 Oct 29. PMID: 26512880

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RE-VERSE AD Study

• 39 patients in procedure group

• 36 underwent a procedure

• 33 with normal hemostasis

• 2 mild abnormal hemostasis

• 1 moderate abnormal hemostasis

• Primary outcome: reversal at 4 hours

• 93% with dilute thrombin time

• 88% with ecarin clotting time

Pollack CV Jr. N Engl J Med. 2015 Aug 6;373(6):511-20. PMID: 26095746

88% - 93% reversal at 4 hours

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RE-VERSE AD Study

• Thrombotic complications of all 90 patients post idarucizumab

• No patient was receiving anticoagulation

Pollack CV Jr. N Engl J Med. 2015 Aug 6;373(6):511-20. PMID: 26095746

Thrombotic event Time after idarucizumab

DVT and PE 2 days

DVT 7 days

DVT, PE and left atrial thrombus 9 days

NSTMI 13 days

Ischemic stroke 26 days

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Protocol to Reverse Dabigatran with Idarucizumab

Eikelboom JW. Circulation. 2015 Dec 22;132(25):2412-22. PMID: 26700008

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– Warfarin

– Dabigatran



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Systematic Review of Factor VIIa RCTs

Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223

42 Systematic Review of Non-Activated PCC Cohort Studies

Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002

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43

Andexanet Alpha

• Short duration of action

• Will require bolus + infusion

• Dose different for apixaban and rivaroxaban

• ANNEXA 4 study

• only bleeding, not urgent surgery

Siegal DM. N Engl J Med. 2015 Dec 17;373(25):2413-24. PMID: 26559317







– Warfarin

– Dabigatran



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Lab Testing of DOACs

Blann AD. J Am Coll Cardiol. 2014 Sep 16;64(11):1140-2. PubMed PMID: 25212649







– Warfarin

– Dabigatran



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