Antithrombotics and Endoscopy: Advice for Endoscopy Nurses from

Cardiogastroenterology Clinic

Neena S. Abraham MD, MSc (EPID), FACG, FASGE, AGAFProfessor of Medicine, Mayo Clinic College of Medicine

Arizona Site 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

US Population: Age 65+ & Cardiac disease

Administration on Aging- 2012; Heidenreich et al. Circulation 2011.

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By 2030, >40% of US adults will have ≥ 1 form of cardiovascular disease.

*Expected aggressive increase in antiplatelet and anticoagulant use for primary and secondary prevention.

Learning Objectives

1. Understand the GI bleeding risk of patients on antithrombotic regimens Antiplatelets

Anticoagulants

2. Review best-practice recommendations for peri-endoscopic antithrombotic management

ASA + Plavix (DAPT)

Coumadin- when/how/why to hold

Novel Oral Anticoagulants (Pradaxa, Xarelto, Eliquis, Lixiana) and procedure implications

Disclaimers--

THERE ARE NO RECIPES… ONE SIZE DOES NOT FIT ALL…

General Principles to follow for your education

Use Your Resources: a)ANTICOAGULATION Clinic….b)Referring physician/PCP/cardiologist

Low- vs. High-Risk Thromboembolic Conditions

Low-Risk High-RiskUncomplicated or

paroxysmal nonvalvular

atrial fibrillation

Bioprosthetic valve

Mechanical valve in the

aortic position

Deep-vein thrombosis

Atrial fibrillation associated with:Valvular heart diseaseProsthetic valvesActive CHFLVEF <35% History of thromboembolic event

Mechanical valve in any position and

previous thromboembolic event

Non-stented PCI after MI

Anderson et al. Gastrointest Endosc 2009.

Recently (~1 yr) placed coronary stent

Acute coronary syndrome

Prior stent occlusion

HypertensionDiabetes mellitusAge >75 yrs

Endoscopic Bleeding RisksBleeding risk varies with procedure type and presence/absence of

therapeutic interventions.

Becker et al. Am J Gastroenterol 2009; Kwok et al. Am J Gastroenterol 2009; Anderson et al. GIE 2009.

Low Risk (<2% @ 48 hours) High Risk (>2% @ 48 hours)

• Diagnostic + biopsy EGD Double balloon

enteroscopy Colonoscopy

• Biliary/pancreatic stent without sphincterotomy

• ERCP without sphincterotomy• EUS without FNA• Flexible sphincterotomy +

biopsy• Endosonography without FNA• Wireless capsule endoscopy

• Polypectomy: Gastric (7.2%) Duodenal/ampullary

1-3 cm (4.5%) >3 cm (10.3%)

• Endoscopic mucosal resection (22%)• Biliary sphincterotomy (2.0-3.2%)• PEG placement (0.2-2.5%)• Endosonography-guided FNA (0.5-2.9%)• Laser ablation and coagulation (1.1%)• Treatment of varices (2.4-25.4%)

Antiplatelets

Decrease platelet aggregation and inhibit thrombus formation

Aspirin (ASA)

P2Y12 Receptor-Antagonist

Clopidogrel (Plavix)

Prasugrel (Effient)

Ticagrelor (Brilinta)

Mechanism of Action

Irreversible inhibition of COX-1

and COX-2

Irreversible inhibition of

P2Y12 receptor

Irreversible inhibition of

P2Y12

receptor

Reversible inhibition of

P2Y12 receptor

Required time to recover adequate platelet function

7 days 5-7 days 7-9 days 3-5 days

Management of ASA Monotherapy

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

StudyAntiplatelet

AgentProcedure Case Control

Bleeding Risk

Yousfi et al. 2004

ASA use within 3

days prior

Colonoscopy + polypectomy

40% 33%OR 1.41

(0.68-3.04)

Hussain et al. 2007

ASA or clopidogrel

within 10 days prior

Sphincterotomy 16% 17%OR 0.41

(0.13-1.31)

Becker et al. Am J Gastroenterol 2009.

2012-2013 Indications: Dual Antiplatelet Therapy

Jneid et al. J Am Coll Cardiol 2012; O’Gara et al. Circulation 2013.

ASA indefinitely and clopidogrel or ticagrelor for: Up to 12 months after

bare metal stent (BMS) placement

At least 12 months after drug-eluting stent (DES) placement

Post-StentPost-ACS Up to 12 months following

unstable angina or NSTEMI managed without PCI

At least 14 days (12 months in some) following STEMI

Updated to include ticagrelor and prasugrel.

Risk of Clinical Events After Clopidogrel Cessation Among Patients with ACS

Ho et al. JAMA 2008.

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PCI-Treated PatientsMedically Treated Patients

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0-90d 91-180d 181-270dDays Post-Clopidogrel Cessation

Significantly higher risk of adverse events (~2-fold increase) during first 0-90 days post-ACS with clopidogrel discontinuation

Stent Thrombosis Post-DES: Risk with Antiplatelet Cessation

Eisenberg M et al. Circulation 2009.

ASA and thienopyridine discontinued simultaneously (n=33)

ASA discontinued after thienopyridine previously discontinued (n=15)

Only thienopyridine discontinued; ASA continued (n=94)

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Short-term discontinuation of thienopyridine is safe in patients with DES if ASA therapy maintained

P<0.0001P<0.0001

Patients with Thrombotic Event

ASA After Endoscopic Control of Peptic Ulcer Bleeding

RCT

Hospital-based cohort

Discontinuation of ASA CV patients is associated with increased mortality.

Sung et al. Ann Intern Med 2010. Derogar M et al. Clin Gastroenterol Hepatol 2013.

• Low-dose ASA (n=78) vs. placebo (n=78)

• 30-day recurrent bleeding: 10.3% vs. 5.4% ARR: 4.9%; NNT=20

• 30-day mortality: 1.3% vs. 9.0% ARI: 7.7%; NNH= 13

• N=118 • Discontinued ASA therapy: Mortality and CV event HR 6.3 (1.3-31.3)

Post-Polypectomy Bleeding With and Without Antithrombotic Therapy

Manocha D et al. Am J Med 2012. Singh M et al. Gastrointest Endosc 2010.

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Overall Immediate(at endoscopy)

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Post-Polypectomy Bleeding Type

Delayed(< 4 weeks)

ASA/NSAID (n=502)

No ASA/NSAID (n=672)

Clopidogrel (n=142)

No Clopidogrel (n=1243)

Overall Immediate(at endoscopy)

Delayed(< 4 weeks)

P=NS P=NS

P=NS P=NS

P=NS

P=0.02

100% on ASA

Cessation of ASA/NSAID before

colonoscopy/polypectomy is unnecessary.

Second Generation Thienopyridine Drugs: Rates of Bleeding Events

2nd generation thienopyridine agents

Higher levels of platelet inhibition than clopidogrel higher bleeding risk Most common bleeding location= GI Absolute increase greatest in elderly patients*

Ticagrelor and Prasugrel unaffected by variants of CYP2C19 genotype

Prasugrel unaffected by variants of ABCB1 genotype

Wiviott et al. NEJM 2007

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2.4%1.8%

2.8%2.2%

Prasugrel Clopidogrel ClopidogrelTicagrelor

HR 1.32 (1.03-1.68) HR 1.19 (1.02-1.38)

TRITON-TIMI 38 Trial PLATO Trial

Bliden KP et al. Am Heart J 2011; Husted S et al. Circ Cardiovasc Qual Outcomes 2012; Cayla G QJM 2012; O’Gara et al. Circulation 2013.

Wallentin et al. N Engl J Med 2009.

Vorapaxar: New PAR-1 Inhibitor

Vorapaxar (Zontivity©)–protease-activated receptor 1 (PAR-1) inhibitor; First-in-class antiplatelet medication

Approved January 2014 and prescribed with DAPT

TRA 20 TIMI-50 trial (N=26,499)

13% reduction of MI, stroke, CV death and revascularization in patients with a previous MI or peripheral artery disease (v. placebo)

Increased moderate or severe bleeding in 4.2% (v. 2.5% placebo); 66% increased risk of bleeding overall

Black Box Warning: contraindicated with history of stroke, TIA and intracranial hemorrhage due to high-risk of bleeding

Bhatt D L et al. Circulation Research. 2014;114:1929-1943

Summary:Peri-Endoscopic Antiplatelet Management

Becker et al. Am J Gastroenterol 2009; Anderson et al. Gastrointest Endosc 2009; Boustiere C et al. Endoscopy 2011; Jneid et al. Circulation 2012; O’Gara Circulation 2013.

1. Avoid stopping all antiplatelets simultaneously.

2. When thienopyridine drugs are discontinued, you must maintain patient on ASA monotherapy.

3. Avoid cessation of thienopyridine drugs (even when ASA is continued) within the first 30 days of PCI and DES or BMS placement.

4. Avoid stopping DAPT in the first 90 days post-ACS.

5. Defer elective endoscopic procedures until patients finishes appropriate course of thienopyridine drug therapy, possibly up to 12 months following PCI and DES placement.

6. Perform elective high-risk endoscopic procedures 5-7 days after clopidogrel cessation, 7-9 days after prasugrel cessation, and 3-5 days after ticagrelor cessation.

7. Resume DAPT once hemostasis is achieved.

8. Continue antiplatelet therapy during elective low-risk endoscopy.

Oral Anticoagulants

Warfarin

Direct Oral Anticoagulants

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)*

Mechanism of Action

Inhibition of Vitamin K-dependent γ-carboxylation

Direct thrombin inhibitor

Direct factor Xa 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 h

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

FDA Approves Edoxaban • Approved by FDA January 2015

Oral, reversible Factor Xa inhibitor

62% bioavailable & [T Max]:1-2 Hrs

50% renal excretion

• AFIB Stroke Prevention, DVT/PE

• ENGAGE AF-TIMI 48 Trial warfarin vs. edoxaban (N=21,105)

EDX High Dose: 60 mg/day

EDX Low Dose: 30 mg/day

Both doses non-inferior to warfarin

23% increased GIB risk (High)

33% fewer bleeds overall (Low) Dose reduce with modest renal

impairment, <60 kg, P-glycoprotein inhibitor use

Giugliano et al. NEJM 2013; 369:22

Coumadin– Facts

Discontinue 5 days before procedure

Resume with hemostasis (immediately in most)

Peak onset within 72-96 hours; half-life 20-60 hours; 100% bioavailability

Reversal agents: FFP (fast), Vit K (slow)

High-risk thromboembolic patients

Bridge vs. no bridge?

Bridge Therapy –Who? Thromboembolic Risk Category

Atrial Fibrillation Mechanical Heart Valve

VenousThromboembolism(VTE)

Annual Risk >10% CHADS2* - 5 or 6CVA/TIA w/in 3 mosRheumatic valvular Disease

*CHF, HTN, Age >75, DM, Stroke

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

VTE within 3 mosHigh-risk thrombophlebitis

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

VTE 3-12 mos ago

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

Bileaflet Aortic Valve in low risk patient

VTE > 12 mos ago

Bridge Therapy organized thru Anticoagulation Clinic

New Data Regarding Bridge Therapy

BRIDGE investigators RCT (2015)

1884 non-valvular atrial fibrillation patients

May not apply to valvular afib, mechanical valves, LVADs, recently diagnosed thromboembolism (<3 months), Afib patients with CHF, post ACS setting etc.

Elective endoscopic and surgical procedures

Randomized to bridging vs. no bridging

Bridging Group (when compared to no bridging)

More major bleeding (3.2% vs. 1.3%)

No difference in thromboembolism risk (0.3% vs, 0.4%)

Douketis et al. NEJM 2015;373:823-833.

Supratherapeutic Warfarin Bleed

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

INR at time of endoscopy is not

predictive of rebleeding

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

procedure heparin and PPI use, hypotension, ulcer as bleeding 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)• Important stigmata identified in 83% of cases

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

Resuming Warfarin After GI Bleeding (GIB)

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 the first week following hemorrhage.

90-Day Thrombosis 90-Day Recurrent GI Bleeding

P=0.002

Warfarin Resumption within 4-7 days

HR: 0.05 (0.01-0.58)

P=0.10

Warfarin Resumption

Within 4-7 days HR: 1.32 (0.50-3.57)

Time in Days Time in Days

Trends in DOAC PrescriptionBarnes et al. Am J Med 2015

Temporary interruption of NOAC prior to endoscopic procedure

Drug (Creatinine Clearance)Last dose prior to low–risk endoscopic procedure *

Last dose prior to high–risk endoscopic procedure **

Dabigatran (>50 mL/min) 1 day 2 days

Dabigatran (31- 50 mL/min) 2 days 4 days

Dabigatran (<30 mL/min) 4 days 6 days

Rivaroxaban/Apixaban/Edoxaban (>50 mL/min)

1 days 2 days

Rivaroxaban/Apixaban/Edoxaban (31 to 50 mL/min)

1-2 days 3-4 days

Rivaroxaban/Apixaban/Edoxaban (< 30 mL/min)

2 days 4 days

* A low-risk procedure has a 48 hour risk of major bleeding of 0% to 2%; a high-risk procedure ** has a 48 hour risk of major bleeding of 2% to 4%

Management of DOAC Bleeding

van Ryan et al. Thromb Heamost 2010.

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

Mild Bleeding

Moderate-Severe Bleeding

Life-Threatening Bleeding

Correct hemodynamics to perfuse kidneysBlood-product transfusionEndoscopic evaluation +/- hemodialysis with renal failure Oral charcoal (if ingestion <2h)*; PPI probably helpful if recent ingestion (decreases absorption)

Consider rFVIIa or **PCC Charcoal filtration

Delay next dose Anticoagulant effect dissipates 24 h (with no renal failure)T1/2= 12-17 h

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

NOAC reversal agents: 2015 or 2016

• Idarucizumab (Praxbind®)•Humanized monoclonal antibody with high affinity for dabigatran; binds free and thrombin-bound dabigatran

• Clinical outcomes (Pollock CV et al. NEJM 2015):

•N=90 bleeding patients on Dabi or with need for surgery.

•2.5 gram bolus IV X 2 normalized dilute thrombin time in 93-98% of patients.

•Cessation of bleeding in 11.4 hours; normal surgical hemostasis in 92%

•Approved 10/16/15 by FDA for “life threatening hemorrhage/need for emergency surgery or procedures”; REVERSE-AD trial ongoing (N=450)

• Andexanet alpha• Phase II study in healthy volunteers

• Decreased anti-Xa activity and plasma concentration of free apixaban

• Future studies required in the setting of major hemorrhage

• Aripazine (PER977)• Synthetic molecule binds to heparin, LMWH and NOACs

in animals

• Whole blood clotting time (in vitro) show reduction of edoxaban effect within 10 minutes of IV infusion (restoration to 10% over baseline)

• Needs human studies and clinical trials

DOAC reversal agents: In Development

My Top 10 Cardiogastroenterology Tips

1. It is safe to perform endoscopy on ASA monotherapy.

2. Avoid stopping thienopyridine in first 90 days post-ACS.

3. Continue ASA therapy when stopping thienopyridine.

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

Leads to faster cardiac catheterization in 43%

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

My Top 10 Cardiogastroenterology Tips

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

7. New oral anticoagulants have GIB risk.

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

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

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

o High-risk endoscopy Hold 2-3 days prior to caseo Low-risk endoscopy Hold 1-2 days prior to case

With impaired CrCL:o High-risk endoscopy Hold 4-6 days prior to caseo Low-risk endoscopy Hold 2-3 days prior to case