Antiplatelet Agents andAntiplatelet Agents and …gi.org/wp-content/uploads/2012/08/12ACG_Midwest_Abraham...Lancet 2009; Casado-Arroyo et al. Best Pract Res Clin Gastroenterol 2012;

ACG Regional Course – Indianapolis Copyright 2012 ACG

August 2012 1

Antiplatelet Agents andAntiplatelet Agents and Endoscopy

Neena S. Abraham, MD, MSCE, FACG

Michael E DeBakey Veterans Affairs Medical CenterMichael E. DeBakey Veterans Affairs Medical CenterSections of Gastroenterology & Health Services Research

Associate Professor of MedicineBaylor College of Medicine, Houston, TX, USA

Learning Objectives

1. To clarify the CV risk of modifying antiplatelet y y gtherapy

2. To define strategies to reduce the risk for patients on antiplatelet therapy who are undergoing endoscopyundergoing endoscopy

3. To review best-practice recommendations


August 2012 2

Antiplatelets Definition: Pharmacotherapy that

decreases platelet aggregation and inhibits thrombus formation

Includes: Aspirin (ASA)

Thienopyridine (P2Y12 receptor antagonist):

Clopidogrel (Plavix®)

Prasugrel (Effient®)

Ticagrelor (Brilinta®)

Clinical Indications for Antiplatelet Therapy Use

Acute coronary syndrome (ACS)ST segment elevation MI (STEMI)

Acute peripheral occlusion ST-segment elevation MI (STEMI)

Non-ST-segment elevation MI (NSTEMI)

Coronary revascularization Percutaneous coronary

intervention (PCI)

Coronary artery bypass graft

occlusion

Secondary prevention Coronary artery

disease (CAD)/ACS

CVA/TIA

Peripheral arterial disease (PAD)y y yp g

(CABG)

Acute cerebrovascular accident (CVA)

( )

Heart failure

Atrial fibrillation

Mechanical valve


August 2012 3

Antiplatelet Therapy Use in the United States: REACH Registry

Aspirin (ASA) Thienopyridine (P2Y12 receptor antagonist): Clopidogrel (Plavix®)

Antiplatelet Therapy

Thienopyridine + anticoagulant (1%)

Anticoagulant only (8%)

Thienopyridine only (8%)

ASA + anticoagulants (4%)

ASA + thienopyridine + anticoagulants (1%)

Clopidogrel (Plavix )

Prasugrel (Effient®)

Ticagrelor (Brilinta®)

Cannon et al. Am Heart J 2010.

ASA only (69%)

ASA + thienopyridine

(13%)

anticoagulants (4%)

ASA Monotherapy

Arachidonic Acid

COX-1(constitutive)

COX-2(inducible)

Thromboxane A2 Prostacyclin

ASA

2

(TXA2)Prostacyclin

(PGI2)

Required Time to Recover Adequate Platelet Function: 7 days

Platelet Aggregation


August 2012 4

AHA Recommendations for Primary and Secondary Prevention in CV Disease

Indications for Primary Prevention:

10-year CV risk >10%

Diabetes and no previous history of vascular disease with 10-year CV risk >10% AND no increased risk for bleeding

Women >65 years if benefit outweighs the risk of GI bleeding and hemorrhagic stroke.bleeding and hemorrhagic stroke.

Indications for Secondary Prevention:

After coronary or cerebrovascular event

Pignone et al. Circulation 2010; Mosca et al. Circulation 2011; Pearson et al. Circulation 2002; Goldstein et al. Stroke 2011; Furie et al. Stroke 2011; Wright et al. JACC 2011.

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

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

Event Primary Prevention Secondary Prevention

Vascular events: 0 88 (0 82-0 94) 0 81 (0 75-0 87)

MI, stroke or vascular death

0.88 (0.82-0.94)ARR= 0.06%; NNT= 1667

0.81 (0.75-0.87)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 1 54 (1 30-1 82) 2 69 (1 25-5 76)Major GI Bleeding

1.54 (1.30-1.82)ARI= 0.03%; NNH= 3333

2.69 (1.25-5.76)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 ASA primary prevention (NNT= 1667 vs. NNH= 3333)

2 vascular events prevented, ~1 GI bleeding would occur


August 2012 5

Endoscopic Bleeding Risks in Patients on Monotherapy: Case-Control Studies

StudyAntiplatelet

AgentProcedure Case Control

BleedingRiskAgent Risk

Yousfiet al. 2004

ASA use within 3 days

prior

Colonoscopy + polypectomy

40% 33%OR 1.41

(0.68-3.04)

Hussainet al.

ASA or clopidogrel

within 10Sphincterotomy 16% 17%

OR 0.41 (0 13 1 31)

Recommendation: In the absence of a pre-existing bleeding disorder, it is reasonable to perform all elective procedures in patients taking

ASA. Becker et al. Am J Gastroenterol 2009.

2007within 10

days prior

p y(0.13-1.31)

Endoscopy-Related GI Bleeding RisksBleeding risk varies with procedure type and presence/absence of

therapeutic interventions.

Low Risk (<1%) High Risk (>1%)

Diagnostic + biopsy Polypectomyg p y

EGD (1.0%-0.1%)

Double balloon enteroscopy(0.1%)

Colonoscopy (0-0.02%)

Biliary/pancreatic stent without sphincterotomy (0.3%)

ERCP without sphincterotomy*

yp y

Gastric (7.2%)

Duodenal/ampullary

1-3 cm (4.5%)

>3 cm (10.3%)

Colonic (0.7-3.3%)

Endoscopic mucosal resection (22%)

Biliary sphincterotomy (2.0-3.2%)

Endoscopic mucosal resection (22%)

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

*Limited data, presumed negligible

EUS without FNA

Flexible sphincterotomy + biopsy*

Endosonography without FNA

Wireless capsule endoscopy*

y p y ( %)

Pneumatic or bougie dilation (1.7%)

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%)Treatment of varices (2.4-25.4%)


August 2012 6

Recommendation for Management in Primary Prevention

ASA Monotherapy

Primary Prevention (Low Thromboembolic Risk)

Low Endoscopic High Endoscopic

Becker et al. Am J Gastroenterol 2009; *Anderson et al. Gastrointest Endosc 2009.

Bleeding Risk Bleeding Risk

Continue ASAContinue ASA; *May elect to

discontinue 7 days prior

Dual Antiplatelet Therapy

Arachidonic Acid

ASA THIENOPYRIDINES

ADP

Clopidogrel PrasugrelTicagrelor

COX-1(constitutive)

COX-2(inducible)

Thromboxane A2

(TXA2)Prostacyclin

(PGI2)

ASA

Ticagrelor

P2Y12 Receptor

GP IIb/IIIa

TXA2


Required Time to Recover Adequate Platelet Function: ASA: 7 days

Clopidogrel: 5-7 days

Prasugrel: 7-9 days

Ticagrelor: 3 days



August 2012 7

Case 65-year-old man with a family history of

colorectal cancer

STEMI with PCI and drug-eluting stent (DES) g g ( )13 months ago with history of stent occlusion

Dual antiplatelet therapy: ASA + clopidogrel

Asthma—Rx: Inhalers

No other comorbidities/medications

Normal labs Normal labs

PLAN: Elective screening colonoscopy

How should you manage his antiplatelet therapy?

Endoscopic Endoscopic Bleeding RiskBleeding Risk

Thromboembolic Thromboembolic RiskRisk


August 2012 8

Indication for antiplatelet therapy

Thromboembolic RiskProbability of event depends on 3 factors

Douketis JD. Thromb Res 2002.

Presence of additional thromboembolic risk

factors

Consequence of thromboembolic

event

Low- vs. High-Risk Thromboembolic Conditions

Low-Risk High-RiskUncomplicated or

paroxysmal nonvalvular

Atrial fibrillation associated with:

Valvular heart disease

atrial fibrillation

Bioprosthetic valve

Mechanical valve in the

aortic position

Deep-vein thrombosis

Prosthetic valves

Active CHF

LVEF <35%

History of thromboembolic event

Hypertension

Diabetes mellitus

Age >75 yrs

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


August 2012 9

The Cardiac Patient: Indications for ASA+Clopidogrel

Acute Coronary Syndrome (ACS)

Up to 12 months following Up to 12 months following unstable angina or NSTEMI managed without intervention

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

Becker et al. Am J Gastroenterol 2009.

Up to 12 months after bare metal stent (BMS) placement

At least 12 months after DES placement

Risk of Clinical Events After Clopidogrel Cessation Among Patients with ACS

75.0%

PCI-Treated PatientsMedically Treated Patients

Significantly higher risk of

30.0%

45.0%

60.0%

nce

of

Dea

th o

r M

I adverse events (~2-fold increase) during first 0-90 days post-ACS with clopidogrel discontinuation

Ho et al. JAMA 2008.

0.0%

15.0%

Inci

den

0-90d 91-180d 181-270d

Days Post-Clopidogrel Cessation


August 2012 10

The Cardiac Patient: Indications for ASA+Clopidogrel

Up to 12 months following unstable angina or NSTEMIunstable angina or NSTEMI managed without intervention

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

Post-Stent Up to 12 months after bare


pmetal stent (BMS) placement

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

30

Stent Thrombosis: Risk of Cardiac DeathN=431 STEMI Patients, Post-PCI on Antiplatelet Therapy

23 6%25.3%

27.9%

Rat

e

1 in 5 patients who experience a first definite stent thrombosis experience

a second stent thrombosis.

20 18.0%

23.6%

Cu

mu

lati

ve D

eath

R

10

van Werkum JW et al. Circulation 2009; Daemen J et al. Lancet 2007.

C

30 days 1 year 2 years 3 years

More common among patients with DES (vs. BMS): 3-year rate = 2.9% Steady incidence over 3 years rate of 0.6% per year


August 2012 11

Duration of Dual Antiplatelet Therapy (DAPT) Post-PCI

EXCELLENT P=NS

P=NSP=NS

Primary Endpoint Safety Endpoint

EXCELLENT Trial:

6 vs. 12 mo post-DES

P=NS

PRODIGYP=NS

No difference in cardiac risk (p=0.60)

No difference in major bleeding (p=0.64)

24-mo: 7.4%

Gwon et al. Circulation 2012.

PRODIGY Trial:

6 vs. 24 mo post-DES or

BMS

No difference in cardiac risk (p=0.91)

GI bleeding at 2 years.24 vs. 6-mo: HR 2.2 (1.4-3.2)

24 mo: 7.4%12-mo: 3.5%P=0.002

Valgimigli M et al. Circulation 2012.

Summary: Duration of DAPT DAPT for 6 mo post-stent likely sufficient for most

Benefit of reducing late-stent thrombosis may not outweigh risk of bleeding with longer-term DAPT

Higher-risk patients need prolonged DAPT Unstable disease presentation

Extensive/complex CAD

Diabetes Diabetes is a prothrombotic condition

Diabetics are more frequently resistant to aspirin

L i l h ti DAPT f i i f 12 Logical approach continue DAPT for a minimum of 12 mo post-DES and 6 mo post-BMS Longer durations reserved for patients with complex presentations,

difficult stent procedures or diabetes

Earlier termination should be assessed on a case-by-case basis with input from the cardiologist

Gwon et al. Circulation 2012; Valgimigli M et al. Circulation 2012; Klein NS. Circulation 2012.


August 2012 12

Risk Factors for Early Stent Thrombosis (0-30 days) (Prevalence ≈ 1%)

Clinical Prior stent thrombosis

Presentation with ACS or STEMI

Procedural Diffuse CAD

Smaller post-PCI diameter

Multivessel PCI

Diabetes

Renal failure

BMS implantation within last 30 days or DES implantation within last 12 months

Noncardiac surgery early after

Multiple stents

Residual dissection

Bifurcation stenting

Large thrombus burden

First-generation DES

Genotypes associated with Noncardiac surgery early after PCI

Genetic factors: ABCB1 3435 TT genotype

CYP2C19 metabolic status

Becker et al. Am J Gastroenterol 2009; Sherwood et al. Curr Treatment Options Cardio Med 2011; Cayla G et al. JAMA 2011.

Genotypes associated with impaired clopidogrel metabolism and platelet function Independent risk factors for early stent thrombosis

Prevalence of Genotypes and 1-Year Risk of Death, Stroke or MI: FAST-MI Trial (N=2208 French Patients)

ABCB1 Alleles CYP2C19 Loss-of-Function Alleles (*2 *3 *4 and *5)

2 variant alleles1 variant allele No variant alleles

( 2, 3, 4, and 5)

25.8%

26.2% 2.6%

71.2%

26.1%

74.2%

28.7%

Simon T et al. N Engl J Med 2009.

48.0%

ABCB1 Alleles

1 variant allele= 51% risk

2 variant alleles= 72% risk

CYP2C19 Loss-of-Function Alleles

2 variant alleles= 98% risk

Post-PCI: HR 3.6 (1.7-7.5)


August 2012 13

Prevalence of 1 CYP2C19*2 Allele: U.S. Data

33%24%

African Americans Caucasians Mexican Americans Asians

18%

51%

Shuldiner et al. JAMA 2009; Luo et al. Clin Pharmacol Ther 2006; Xiao et al. J Pharmacol Exp Ther 2006; Takakubo et al. Pharmacogen 1996.

Reduction in clopidogrel efficacy associated with CYP2C19*2: 1 copy of allele= 47% reduction 2 copies= 65% reduction

3rd-Generation Thienopyridine Includes prasugrel and ticagrelor

Achieves significantly higher levels of platelet inhibition than clopidogrel

Prasugrel and ticagrelor unaffected by variants in the CYP2C19 genotypeg yp

Prasugrel unaffected by variants in the ABCB1genotype

Wiviott SD et al. Circulation 2007; Bliden KP et al. Am Heart J 2011; Cayla G QJM 2012.


August 2012 14

Rates of Bleeding Events in Antiplatelet Drug Trials for ACS

3.5 2 8%

TRITON-TIMI 38 Trial PLATO Trial

1

1.5

2

2.5

3

3.5

Maj

or

Ble

edin

g(n

on

-CA

BG

) (%

)

2.4%

1.8%

2.8%

2.2%

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

Wiviott et al. NEJM 2007; Wallentin et al. N Engl J Med 2009.

0

0.5

M (

Prasugrel Clopidogrel ClopidogrelTicagrelor

Most common bleeding location = Gastrointestinal

Thromboembolic Thromboembolic RiskRisk

Endoscopic Endoscopic Bleeding RiskBleeding Risk


August 2012 15

Endoscopy-Related GI Bleeding RisksBleeding risk varies with procedure type and presence/absence of

therapeutic interventions.

Risk 2-12x:

Age

Polypectomy with cautery

Removal of >1 polyp

Pre-procedural wafarin

Colonic (0.7-3.3%)

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

wafarin

*Limited data, presumed negligible

Ko et al. Clin GastroenterolHepatol 2010.

Post-Polypectomy Bleeding With and Without Clopidogrel Therapy

Clopidogrel (n=142) No Clopidogrel (n=1243)

Single-site (VAMC), retrospective case-control

4

6

erce

nt

(%)

5.6%

3.0%2.1% 2.1%

3.5%

1 0%

P=0.02

p g ( ) p g ( )

100% on ASA

Singh M et al. Gastrointest Endosc 2010.

0

2Pe

Immediate(at endoscopy)

Delayed(< 4 weeks)

Post-Polypectomy Bleeding Type

1.0%P=0.1 P=1.0

Overall


August 2012 16

Continuation of ASA After Endoscopic Control of Peptic Ulcer Bleeding

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

10.3%

10.0%

15.0%

20.0%

ent

Rat

e (%

)

(3.4-17.2%)

5.4% (0.3-10.5%)

1.3%

9.0% (2.7-15.3%)

ARR 4 9%

ARI 7.7%(NNH= 13)

Sung et al. Ann Intern Med 2010.

0.0%

5.0%

Eve

30-day Recurrent Bleeding

30-day All-Cause Mortality

(0-3.8%)ARR 4.9%(NNT= 20)


August 2012 17

Current Best-Practice Recommendations for Secondary Prevention

1.Avoid cessation of all antiplatelet therapies after PCI with stent placement, when possible.

2. Avoid cessation of clopidogrel (even when ASA is continued) within the first 30 days of PCI and either DES or BMS placement, when possible.

3.Defer elective endoscopic procedures, possibly up to 12 months, if clinically acceptable, from the time of PCI and DES placement.

4.Perform endoscopic procedures, particularly those associated with high bleeding risk, 5-7 days after thienopyridine drug cessation. In patients on dual therapy, ASA should be continued.

Resume thienopyridine and ASA drug therapy after the procedure5.

Resume thienopyridine and ASA drug therapy after the procedure once hemostasis is achieved.

6.Continue platelet-directed therapy in patients undergoing elective endoscopic procedures associated with low risk for bleeding.


EXCELLENT and PRODIGY Trial data suggest up to 6 months DAPT in most patients is sufficient.

Guidance on Stopping or Continuing Antiplatelet Therapy: Questions to Ask

Why is the patient taking the drug? Why is the patient taking the drug? Primary or secondary prevention?

Is the patient at-high risk? DES vs. BMS

Diabetes

Multivessel PCI

Are there other known high-risk factors? Genetic polymorphisms

Prior stent occlusion


August 2012 18

Antiplatelet Pearls: Urgent Setting

Patients who present with GIB leading to ACS h ld b dshould be scoped. There is a high likelihood of finding an important

lesion (HR 3.9; 95% CI: 1.8-8.5).

Patients who present with hematemesis or hemodynamic instability should be scoped.

Leads to faster cardiac catheterization in 43% Leads to faster cardiac catheterization in 43%

Peri-procedural risks are high in the first 24 hours of an ACS event but decline to 1-2% by 30 days.

Lin S. Dig Dis Sci 2006; Spier BJ et al. J Clin Gastroenterol 2007; Cappell MS. Am J Med 1999.

Clinical Summary To minimize risk: One size does not fit all.

Primary vs. secondary cardioprotective regimen

Acute vs. elective Acute vs. elective

Balance real risk of thrombosis with short-term cessation vs. endoscopic bleeding risk.

Consult with cardiologist Regarding early cessation of thienopyridine after 6 months of

DAPT

Always continue ASA monotherapy with thienopyridine cessation Always continue ASA monotherapy with thienopyridine cessation

Unknown “real-life” magnitude of GI bleeding risk associated with 3rd-generation thienopyridines. Guidelines have yet to address this class of drugs

Discuss recommendations with your patient.

Documents

Antiplatelet Agents andAntiplatelet Agents and …gi.org/wp-content/uploads/2012/08/12ACG_Midwest_Abraham...Lancet 2009; Casado-Arroyo et al. Best Pract Res Clin Gastroenterol 2012;