Managing AnticoagulantsManaging Anticoagulants During...

Neena S. Abraham, MD, MSCE, FACG

Managing AnticoagulantsManaging Anticoagulants During Procedures

Neena S. Abraham MD, MSc (EPID), FACGProfessor of Medicine, Mayo Clinic College of Medicine

A i di l i Cli i b d i i K C fAssociate Medical Director, Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery

Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZDivision of Health Care Policy & Research, Department of Health Sciences

Research, Mayo Clinic, Rochester, MN

Learning Objectives

1. Understand GI bleeding risk of anticoagulant regimens Anticoagulants (warfarin, novel oral anticoagulant g ( g

[NOAC])

Combination anticoagulant and antiplatelet therapy (complex antithrombotic therapy [CAT])

2. Strategies for common endoscopic situations Stopping and restarting drugs in the elective setting

Antithrombotic management in the acute setting

©2013 MFME

R |

Bridge therapy- what is the evidence?

3. Cardiogastroenterology tips Pragmatic and actionable tips for your practice

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Complex Antithrombotic Therapy (CAT) in Elderly Patients: Bleeding Outcomes

Dual Therapy Triple Therapy

One-Year Number Needed to Harm (NNH)

1-Year NNH for CAT-relatedEvents

Anticoagulant and

Antiplatelet Agent

Aspirin and Anticoagulant

Aspirin and Antiplatelet

Agent

Aspirin,Antiplatelet and Anticoagulant

Agents

Upper GI Bleeding NNH (95% CI)

65 (24-379) 56 (22-231) 93 (34-544) 52 (20-210)

Lower GI Bleeding NNH 19 (11-37) 15 (9-30) 18 (10-37) 23 (13-49)Bleeding NNH (95% CI)

19 (11 37) 15 (9 30) 18 (10 37) 23 (13 49)

Transfusion NNH (95% CI)

43 (21-128) 16 (9-31) 51 (24-182) 25 (14-50)

Hospitalization* NNH (95% CI)

39 (18-121) 34 (16-89) 67 (30-214) 45 (21-126)

Abraham NS et al. Circulation 2013.

Oral AnticoagulantsWarfarin

New Generation Oral Anticoagulants

Dabigatran Rivaroxaban Apixaban

Mechanism of Action

Inhibition of Vitamin K-dependent γ-carboxylation

Direct thrombin inhibitor

Direct factorXa inhibitor

Direct factor Xa inhibitor

Metabolism Liver Renal Renal Renal/Liver

Time to maximum effect

90 d for circulating drug; ~5-7 d for a therapeutic INR

1.25-3 h 2-4 h 1-3 hp

Half-life36-42 h for circulating

drug; ~5 d to normalize INR

12-14 h 9-13 h 8-15 h

Excretion 92% renal 80% renal 66% renal ~25% renal

Other agents: Edoxaban (Factor Xa inhibitor) not yet approved for use in the U.S. (2014)


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CARDIOGASTROENTEROLOGY TIPClassic Supratherapeutic Warfarin Bleed

INR at time of endoscopy is not

predictive of

Adjusted OR*: 0.50 (0.21-1.16) *Controlling for age, comorbidity, antiplatelet use, post-

procedure heparin and PPI use, hypotension, ulcer as bleeding prebleeding source, and active bleeding at endoscopy

Normalizing INR does not reduce rebleeding but

delays endoscopy

• N=102 INR >1.3; Mean INR 1.8 (1.3-2.7)• Rebleeding rate similar with and without reversal agent: 24.7% vs. 30.0% (p=0.54)• Significant delay in endoscopy with normalization of INR: 20.9 h vs. 73.6 h (p<0.0001)

Choudari & Palmer. Gut 1994; Wolf A. Am J Gastroenterol 2007.

• Important stigmata identified in 83% of cases

Endoscopic therapy is very effective – even in patients with moderately elevated INR.

CARDIOGASTROENTEROLOGY TIP Resuming Warfarin After GI Bleeding (GIB)

90-Day Thrombosis 90-Day Recurrent GI Bleeding

P=0.002

Warfarin Resumption HR: 0.05 (0.01-0.58)

P=0.10

Warfarin Resumption HR: 1.32 (0.50-3.57)

Witt DM et al. Arch Intern Med 2012.

Patients with warfarin-associated GIB and indications for continued long-term antithrombotic therapy should resume anticoagulation

within 4-7 days following hemorrhage.

Analysis Time in Days Analysis Time in Days


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Warfarin + ASA+ Clopidogrel: Time to Bleeding in Atrial Fibrillation Patients Post-MI/PCI

3

4

e R

atio

s )* 1.15

(0 6 2 04)

0

1

2

Inci

den

ce R

ate

(95%

CI

0-29 days 30-89 days 90-179 days

(0.65-2.04)

2.65 (1.37-4.03)

2.12(1.29-3.47)

Triple Therapy Treatment Interval

GI bleeding = 33.8% non-fatal and 45.3% fatal

Risk highest after initiation and continually elevated in comparison to other regimens (i.e., dual antiplatelet or monotherapy therapy)

Lamberts M et al. Circulation 2012.

*Compared to 180-360d treatment interval

p py

Novel Oral Anticoagulants High GI Bleeding Risk: Meta-Analysis

GI Bleeding Risk by Indication GI Bleeding Risk by NOAC

Holster L et al. Gastroenterology 2013.


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New Generation Oral Anticoagulants + Antiplatelet Therapy: GI Bleeding in Post-ACS PopulationCV EVENTS

ESTEEM (2003)ATLAS ACS-TIMI 46 (2009)

APPRAISE (2009)APPRAISE 2 (2011)

0.76 (0.59-0.98)0.78 (0.58-1.05)0.76 (0.50-1.16)1 05 (0 56 1 90)

Meta-Analysis

MAJOR BLEEDS

APPRAISE-2 (2011)RUBY-1 (2011)

RE-DEEM (2011)ATLAS ACS 2-TIMI 51 (2012)

POOLED OR (95% CI)

1.05 (0.56-1.90)0.95 (0.81-1.12)1.30 (0.71-2.38)0.84 (0.74-0.96)

0.86 (0.79-0.94); NNT= 77

Favors Anticoagulant Favors Placebo

1.00.5 5.0

ESTEEM (2003) 1 98 (0 80-4 89)

Komosci A et al. Arch Intern Med 2012.

3.03 (2.20-4.16); NNH= 111

ATLAS ACS-TIMI 46 (2009)APPRAISE (2009)

APPRAISE-2 (2011)RUBY-1 (2011)

RE-DEEM (2011)ATLAS ACS 2-TIMI 51 (2012)

POOLED OR (95% CI)

1.98 (0.80-4.89)1.43 (0.24-8.58)

15.68 (2.14-114.97)2.55 (1.48-4.41)

2.05 (0.25-17.05)1.75 (0.21-14.24)3.92 (2.43-6.33)

Favors Anticoagulant Favors Placebo1.00.5 5.0

CARDIOGASTROENTEROLOGY TIP Management of NOAC Bleeding

Initial Assessment and Risk Stratification: The ABC’sA= Airway; B= Breathing; C= Circulation

Mild Bleeding

Moderate-Severe Bleeding

Life-Threatening Bleeding

Correct hemodynamics to perfuse kidneysBlood-product transfusionEndoscopic evaluation / h di l i ith l

Consider rFVIIa or **PCC

Charcoal filtration

Delay next dose Anticoagulant

van Ryan et al. Thromb Heamost 2010.

*Recommendations based on limited nonclinical data ** PCC= prothrombin concentrate complex

+/- hemodialysis with renal failure Oral charcoal (if ingestion <2h)*; PPI probably helpful if recent ingestion (decreases absorption)

geffect dissipates 24 h (with no renal failure)T1/2= 12-17 h


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CARDIOGASTROENTEROLOGY TIPPeri-Procedural Management of NOACPre-Procedure - Determine last NOAC dose and creatinine clearance

Creatinine Timing of Discontinuation Before ProcedureCreatinine Clearance(mL/min)

Half-life (h)

Timing of Discontinuation Before Procedure

Moderate procedural bleeding risk (2-3 half-lives)

High procedural bleeding risk (4-5 half-lives)

>80 13 (11-22) 1-1.5 days 2-3 days

>50 to <80 15 (12-34) 1-2 days 2-3 days

>30 to <50 18 (13-23) 1.5-2 days 3-4 days

<30 27 (22-35) 2-3 days 4-6 days

Post-Procedure

Patients at high risk of bleeding: Perform aPTT day before procedure. Normal result= no clinically significant dabigatran effect.

Weitz et al. Circulation 2012.

- Consider rapid onset of action (1.5 h) when restarting.- Consider prophylaxis (i.e., enoxaparin bridge) until hemostasis established so full dose can be resumed.

Practical Endoscopic Concerns …Synthesis of Current State of Evidence

Should I stop cardiac ASA?

What is the GI bleeding risk of hemostatic What is the GI bleeding risk of hemostaticmaneuvers?

What about prophylactic clip placement?

Should I bridge the patient if planning to stop the anticoagulant?g

When do I restart the drugs?


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ASA for Primary and Secondary Prevention: Meta-Analysis of RCTs

Rate Ratio (95% CI) (ASA monotherapy vs. control)

Event Primary Prevention Secondary Prevention

Vascular 0.88 (0.82-0.94) 0.81 (0.75-0.87)events* ARR= 0.06%; NNT= 1667 ARR= 1.5%; NNT= 67

Non-fatal MI0.77 (0.69-0.86)

ARR= 0.05%; NNT= 20000.69 (0.60-0.80)

ARR= 0.66%; NNT=152

CV mortality0.95 (0.85-1.06)

ARR= 0.01; NNT= 10,0000.87 (0.78-0.98)

ARR= 0.33%; NNT=303

Major GI Bleeding

1.54 (1.30-1.82)ARI= 0 03%; NNH= 3333

2.69 (1.25-5.76)ARI= 0 19%; NNH=526Bleeding ARI= 0.03%; NNH= 3333 ARI= 0.19%; NNH=526

Antithrombotic Trialists’ Collaboration. Lancet 2009; Casado-Arroyo et al. Best Pract Res Clin Gastroenterol 2012; De Beradis et al. JAMA 2012; Siller-Matula. JAMA 2012.

Narrow threshold between efficacy and safety with primary prevention (NNT=1667 vs. NNH=3333)

2 vascular events prevented, ~1 GI bleed would occur

*MI, stroke or vascular death

CARDIOGASTROENTEROLOGY TIP Management of ASA Monotherapy

StudyAntiplatelet

AgentProcedure Case Control

BleedingRisk

Yousfi ASA useYousfiet al. 2004

ASA use within 3

days prior

Colonoscopy + polypectomy

40% 33%OR 1.41

(0.68-3.04)

Hussainet al. 2007

ASA or clopidogrel

within 10 days prior

Sphincterotomy 16% 17%OR 0.41

(0.13-1.31)

It is reasonable to perform endoscopic procedures in patients taking ASA.

Becker et al. Am J Gastroenterol 2009.


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ASA After Endoscopic Control of Peptic Ulcer Bleeding

Placebo (n=78)Low-dose ASA (n=78)

20 0% 10.3%9 0%

5.0%

10.0%

15.0%

20.0%

ven

t R

ate

(%)

10.3% (3.4-17.2%)

5.4% (0.3-10.5%)

1.3% (0-3.8%)

9.0% (2.7-15.3%)

ARR 4.9%(NNT= 20) ARI 7.7%

(NNH= 13))

Sung et al. Ann Intern Med 2010.

30-day Recurrent Bleeding

30-day All-Cause Mortality

0.0%

5.0%

Ev

Endoscopic Risk of BleedingEndoscopic Procedure Low-Risk Bleeding (<1.5%) High-Risk Bleeding (>1.5%)

Diagnostic EGD or

colonoscopy (with or

without biopsy)

X

Non thermal removal of

small polyps

X

Coagulation or ablation of

tumors or vascular lesions

(includes APC, bi-polar

)

X

cautery and laser ablation)

Large (>1 cm) polypectomy X

Variceal band ligation X

Hemostatic clip placement X (unknown real life risk)

Injection therapy X (unknown real life risk)


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CARDIOGASTROENTEROLOGY TIP Avoiding the Post-Polypectomy Bleed Cold snare technique for small lesions (< 5mm) *

Saline/epi lifts to prevent excessive bleeding during hot snare procedures of sessile/flat lesions**

Combined loop +clip can be considered for ped nc lated Combined loop +clip can be considered for pedunculated lesions >2.0 cm ^^

Prophylactic clip placement following removal of large polyps (>1.0 cm) to close mucosal defects

Reduces post-polypectomy bleeds (1.8% vs. 9.7%; p=0.001)^

Cost-effective in patients on antiplatelets and/or anticoagulants**

RCTs needed to confirm this finding

Avoid cautery alone for immediate post-polypectomy bleeding, due to risk of delayed bleeding with eschar sloughing*

**Parikh et al. Clin Gastroenterol Hepatol 2013; ^ Liaquat et al. GIE 2013; * Repici et al. Endoscopy 2012; ^^ Kouklakis et al. Surg Endosc 2009; * anecdotal

Bridge Therapy – Who? Thromboembolic Risk Category

Atrial Fibrillation MechanicalHeart Valve

VenousThromboembolism(VTE)

Annual Risk >10% CHADS2 - 5 or 6CVA/TIA w/in 3 mos

Mechanical Mitral Valve

VTE within 3 mosHigh riskCVA/TIA w/in 3 mos

Rheumatic valvulardisease

Mitral ValveCaged-ball or tilting disk aortic valveCVA/TIA w/in 3 mos

High-risk thrombophlebitis

Annual risk 5-10% CHADS2 - 3 or 4 Bileaflet Aortic Valve in high risk

VTE 3-12 mos agoValve in high-risk patient

Annual Risk <5% CHADS2 - ≤ 2 No prior CVA/TIA

Bileaflet Aortic Valve in low risk patient

VTE > 12 mos ago


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Bridge Tx– Evidence?Mechanical Heart ValveStudies

Clot (%) Bleed (%)

Douketis 2004 (n=215)Pengo 2009 (n=190)Kovacs 2004 (n=112)H ti l 2007 ( 116)

1.2 % 2.7%Hammerstingl 2007 (n=116)Daniels 2009 (n=556)TOTAL (n=1189)

AFIB/VTE/Vascular Bypass GraftStudies

Clot (%) Bleed (%)

Douketis 2004 (n=346)Pengo 2009 (n=663)K 2004 ( 112) 0 9 % 2 0%Kovacs 2004 (n=112)Dunn 2007 (n=76)Wysokinski 2008 (n=345)TOTAL (n=1532)

0.9 % 2.0%

Wysokinski et al. Mayo Clin Proc 2008; Wysokinski & McBane R Circulation 2012

No thrombotic protection but increased bleeding risk

What’s the verdict on Bridging? American College of Chest Physicians: Favor no bridging therapy in low to moderate risk

patients and possible bridging therapy for moderate topatients and possible bridging therapy for moderate to high risk patients *

In evolution in the era of NOAC Absence of data

BRIDGE trial^– helpful for warfarin; excludes patients on NOAC p

Most common agents– enoxaparin and dalteparin have similar pharmacokinetics to NOAC– can NOAC be used in the place of standard bridging therapy?

*Guyatt GH, Akl EA, Crowther M, Schunemann HJ, Gutterman DD, Zelman Lewis S. Introduction to the ninth edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):48S-52S; ^Investigators TBS. Bridging Anticoagulation: Is it Needed When WarfarinIs Interrupted Around the Time of a Surgery or Procedure? Circulation 2012;125(12):e496-e498.


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NOAC temporary interruptions•Dabigatran: similar to warfarin with comparable risk of bleeding (HR 0.83; 95% CI, 0.59 to 1.17).

•Rivaroxaban: similar risk of embolism (HR 0.71; 95% CI 0.34-1.49) and bleeding as warfarin (HR 1.17, 95% CI 0.68-) g ( ,2.03)

•Apixaban: for low risk procedures, interruption of apixaban is unnecessary No data showing a rebound hypercoagulability effect exists with

cessation of NOACs.

FDA issued black box warnings for all three NOAC regarding g g gincreased risk of thrombotic events following discontinuation of use; thus, need to switch to another agent if CHADS2 >5

Restart the drug as soon as hemostasis is assured

Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012;126:343-348; Sherwood MW, Hellkamp A, Patel M, et al.Outcomes of temporary interruptions of rivaroxaban or warfarin in patients with atrial fibrillation in the ROCKET-AF trial. J Am Coll Cardiol 2013;61(10, Supplement):E316.; Lopes RD, Garcia DA, Wojdyla D, et al. Use of Apixaban and Warfarin in Patients Undergoing Invasive Procedures: Insights From Aristotle. Can J Cardiol 2013;29(10, Supplement):S232-S233.;

Take-Home Points for Practice1. It is safe to perform endoscopy on ASA monotherapy.

Never stop cardiac aspirin; can dose minimize

2. GIB leading to ACS should be scoped 48-72 h post-ACS. chance of finding high-risk endoscopic stigmata that are

treatable by endoscopy.

Leads to faster cardiac catheterization in 43%

3. Endoscopic therapy is effective in patients with moderately elevated INR (< 2.7). No need to normalize INR.

4. Warfarin should be resumed within 4-7 days post-GIB

5. Hemostatic manoeuvers are associated with >1.5% risk of GIB in this population.


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6. Some new oral anticoagulants have 3X GIB risk

7. DAPT + new oral anticoagulants (triple antithrombotic therapy) is associated with 3-fold risk of GIB.

8. Consider mechanical hemostasis post-polypectomy to close large mucosal defects (C/E with 1 clip)

9. NOAC-related bleeding Support hemodynamics to promote renal excretion of drug.

10.Elective peri-procedural NOAC management depends on patient’s CrCl:

With l C Cl• With normal CrCl: o High-risk endoscopy Hold 2-3 days prior to case

o Low-risk endoscopy Hold 1-2 days prior to case

• With impaired CrCL:o High-risk endoscopy Hold 4-6 days prior to case

o Low-risk endoscopy Hold 2-3 days prior to case


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