How to Manage Antiplatelet Therapy in the Peri-Endoscopic Period Neena S. Abraham MD, MSCE, FACG Michael E. DeBakey Veterans Affairs Medical Center Sections of Gastroenterology & Health Services Research Associate Professor of Medicine Baylor College of Medicine, Houston, TX, USA Learning Objectives 1. To accurately assess the risk of endoscopic procedures in non-bleeding patients on antiplatelet therapy 2. To clarify the CV risk of modifying antiplatelet therapy in the peri-endoscopic setting 3. To understand best-practice recommendations for management in the non-urgent and urgent setting 1
Clinical Indications for Antiplatelet Therapy Use Acute coronary syndrome (ACS) ST-segment elevation MI (STEMI) Non-ST-segment elevation MI (NSTEMI) Coronary revascularization Percutaneous coronary intervention (PCI) Coronary artery bypass graft (CABG) Acute cerebrovascular accident (CVA)/Transient ischemic attack (TIA) Acute peripheral occlusion Secondary prevention Coronary artery disease (CAD)/ACS CVA/TIA Peripheral arterial disease (PAD) Heart failure Atrial fibrillation Mechanical valve Antiplatelet Therapy Use in the United States: REACH Registry Antiplatelet agents only (8%) ASA plus antiplatelets and anticoagulants (1%) ASA and anticoagulants (4%) Anticoagulant only (8%) Antiplatelet agents and anticoagulant (1%) ASA and antiplatelet agents (13%) ASA only (69%) Cannon et al. Am Heart J 2010. 2
Case 1 65-year-old 1. Stop ASA man + clopidogrel with a family 7-10 history days prior of to colorectal colonoscopy cancer STEMI with PCI and drug-eluting g stent (DES) 13 2. months Stop ASA ago only 7-10 days prior to Dual colonoscopy antiplatelet therapy: ASA + clopidogrel (Plavix) Asthma Rx: 3. Stop clopidogrel Inhalers only 7-10 days prior to No colonoscopy other comorbidities/medications Normal labs PLAN: 4. Proceed Elective with screening colonoscopy exam on dual How antiplatelet should you manage therapyhis antiplatelet therapy? Thromboembolic Risk Endoscopic Bleeding Risk 3
Indication for antiplatelet therapy Thromboembolic Risk Probability of event depends on 3 factors Presence of additional thromboembolic risk factors Consequence of thromboembolic event Douketis JD. Thromb Res 2002. Low- vs. High-Risk Thromboembolic Conditions Low-Risk Uncomplicated or paroxysmal nonvalvular atrial fibrillation Bioprosthetic valve Mechanical valve in the aortic position Deep-vein thrombosis High-Risk Atrial fibrillation associated with: Valvular heart disease 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 Recently (<1 yr) placed coronary stent Acute coronary syndrome Non-stented PCI after MI Anderson et al. Gastrointest Endosc 2009. 4
The Cardiac Patient: Indications for ASA+Clopidogrel Up to 12 months following unstable angina or NSTEMI managed without intervention Greatest risk for thrombotic event with cessation of antiplatelet therapy At least 14 days (12 months in some) following STEMI Up to 12 months after bare metal stent (BMS) placement (i.e., PCI) At least 12 months after DES placement (i.e., PCI) Becker et al. Am J Gastroenterol 2009. Stent Thrombosis: Risk of Cardiac Death N=431 STEMI Patients, Post-PCI on Antithrombotic Therapy Prevalence of early stent thrombosis (0-30 days post-pci) 1% lative Death Rate 30 1 in 5 patients who experience a first definite stent thrombosis experience a second stent thrombosis. 27.9% Varies depending on clinical, procedural, 25.3% treatment and genetic risk factors Late stent 18.0% thrombosis (31-360 days post-pci) Cumu 20 23.6% more common among patients with DES (vs. BMS) 3-year rate = 2.9%* Steady incidence over 3 years rate of 0.6% per 10 year* 30 days 1 year 2 years 3 years *Daemen J et al. Lancet 2007. van Werkum JW et al. Circulation 2009. 5
Risk Factors for Stent Thrombosis Clinical Prior stent thrombosis Presentation with ACS or STEMI Multivessel PCI Diabetes Renal failure BMS implantation within last 30 days or DES implantation within last 12 months Noncardiac surgery early after PCI Procedural Diffuse CAD Smaller post-pci diameter Multiple stents Residual dissection Bifurcation stenting Large thrombus burden First-generation DES Becker et al. Am J Gastroenterol 2009; Sherwood et al. Curr Treatment Options Cardio Med 2010. Risk of Clinical Events After Clopidogrel Cessation Among Patients with ACS Medically Treated Patients PCI-Treated Patients Inciden nce of Death or MI 75.0% 60.0% 45.0% 30.0% 15.0% 0.0% Significantly higher risk of adverse events (~2-fold increase) during first 0-90 days after stopping clopidogrel 0-90d 91-180d 181-270d Days Post-Clopidogrel Cessation Ho et al. JAMA 2008. 6
Tim me from Drug Discon ntinuation to Thrombotic Ev vent Stent Thrombosis Post-DES: Risk with Antithrombotic Cessation Short-term discontinuation of a thienopyridine is safe in patients with DES if ASA therapy is maintained. 120 60 0 P<0.00010001 7 days 7 days Eisenberg M et al. Circulation 2009. P<0.0001 Patients with a Thrombotic Event 122 days ASA and thienopyridine discontinued simultaneously (n=33) ASA discontinued after thienopyridine previously discontinued (n=15) Only thienopyridine discontinued; ASA continued (n=94) Thromboembolic Risk Endoscopic Bleeding Risk 7
Endoscopy-Related GI Bleeding Risks Bleeding risk varies with procedure type and presence/absence of therapeutic interventions. Low Risk (<1%) High Risk (>1%) Diagnostic + biopsy EGD (1.0%-0.1%) 01%) Double balloon enteroscopy (0.1%) Colonoscopy (0-0.02%) Biliary/pancreatic stent without sphincterotomy (0.3%) ERCP without sphincterotomy* EUS without FNA Flexible sphincterotomy + biopsy* Endosonography without FNA Wireless capsule endoscopy* *Limited data, presumed negligible Polypectomy Gastric G t i (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%) 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%) Becker et al. Am J Gastroenterol 2009; Kwok et al. Am J Gastroenterol 2009; Anderson et al. GIE 2009. Colonoscopy: Risk of GI Bleed N=21,375 (CORI Database) Complications Variables directly related to colonoscopy* OR (95% CI) 60-69 years 1.2 (0.5-2.7) 70-79 years 2.1 (0.9-4.6) >80 years 2.4 (0.8-7.2) Polypectomy with cautery 6.7 (2.8-16.1) >1 polypectomy with cautery 12.1 (5.1-28.7) Pre-procedure warfarin use Pre-procedure clopidogrel use 2.9 (1.2-7.0) Not statistically significant Ko et al. Clin Gastroenterol Hepatol 2010. GI bleeding was the most common complication requiring hospitalization: Incidence 1.6/1000 exams (1.1-2.2) Transfusion required in 0.8/1000 exams (0.5-1.3) Risk of polypectomy bleed 2-12x: Age Any polypectomy with cautery Removal of >1 polyp Pre-procedural warfarin *Includes perforation, GI bleeding, post-polypectomy syndrome, diverticulitis 8
Post-Polypectomy Bleeding With and Without Clopidogrel Therapy Single-site (VAMC), retrospective case-control Clopidogrel (n=142) No Clopidogrel (n=1243) Percent (%) 6 4 2 5.6% 3.0% 2.1% 2.1% P=0.1 P=1.0 100% on ASA 3.5% P=0.02 1.0% 0 Overall Immediate (at endoscopy) Post-Polypectomy Bleeding Type Delayed (< 4 weeks) Singh M et al. Gastrointest Endosc 2010. Continuation of ASA After Endoscopic Control of Peptic Ulcer Bleeding Ev vent Rate (%) 20.0% 15.0% 10.0% 50% 5.0% Low-dose ASA (n=78) Placebo (n=78) 10.3% (3.4-17.2%) 90% 9.0% (2.7-15.3%) 5.4% (0.3-10.5%) ARR 4.9% (NNT= 20) 1.3% (0-3.8%) ARI 7.7% (NNH= 13) 0.0% 30-day Recurrent Bleeding 30-day All-Cause Mortality Sung et al. Ann Intern Med 2010. 9
Summary: Management of Antiplatelets 1. 2. 3. 4. 5. 6. Avoid cessation of all antiplatelet therapies after PCI with stent placement when possible. Avoid cessation of clopidogrel (even when ASA is continued) within the first 30 days of PCI and either DES or BMS placement when possible. Defer elective endoscopic procedures, possibly up to 12 months, if clinically acceptable from the time of PCI and DES placement. Perform endoscopic procedures, particularly those associated with high bleeding risk, 5-7 days after thienopyridine drug cessation. ASA should be continued when possible. Resume thienopyridine and ASA drug therapy after the procedure once hemostasis is achieved. Continue platelet-directed therapy in patients undergoing elective endoscopic procedures associated with low risk for bleeding. Becker et al. Am J Gastroenterol 2009. 10
Management of Antiplatelet Therapy Becker et al. Am J Gastroenterol 2009; Anderson et al. Gastrointest Endosc 2009; Veitch et al. Gut 2008 Case 2 78-year-old female with history of: Stroke Hyperlipidemia Congestive heart failure (EF<40%) Atrial fibrillation PLAN: Pneumatic dilation of known achalasia How should you manage her anticoagulation? 11
Low- vs. High-Risk Thromboembolic Conditions Low-Risk Uncomplicated or paroxysmal nonvalvular atrial fibrillation Bioprosthetic valve Mechanical valve in the aortic position Deep-vein thrombosis High-Risk Atrial fibrillation associated with: Valvular heart disease 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 Recently (<1 yr) placed coronary stent Acute coronary syndrome Non-stented PCI after MI Anderson et al. Gastrointest Endosc 2009. Endoscopy-Related GI Bleeding Risks Bleeding risk varies with procedure type and presence/absence of therapeutic interventions. Low Risk (<1%) High Risk (>1%) Diagnostic + biopsy EGD (1.0%-0.1%) 01%) Double balloon enteroscopy (0.1%) Colonoscopy (0-0.02%) Biliary/pancreatic stent without sphincterotomy (0.3%) ERCP without sphincterotomy* EUS without FNA Flexible sphincterotomy + biopsy* Endosonography without FNA Wireless capsule endoscopy* *Limited data, presumed negligible Polypectomy Gastric G t i (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%) 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%) Becker et al. Am J Gastroenterol 2009; Kwok et al. Am J Gastroenterol 2009; Anderson et al. GIE 2009. 12
Thromboembolic Risk: Atrial Fibrillation mboembolic Rat te (%) Thro 3.0% 2.2% (0.8-6.3%) Thromboembolic risk Absolute still Risk 3.0% among high- risk patients: t 1-2 per 1000 patients 2.0% Age >80 years History of stroke Hyperlipidemia 0.4% 1.0% Hypertension (0.2-1.0%) 4-7 days Family history of vascular disease 0.0% Blacker et al. Neurology 2003. <5 days >7 days Anticoagulation (INR <1.3) Interruption Interval (days) Garcia et al. Arch Intern Med 2008; Eisen et al. Gastrointest Endosc 2002. Management of Anticoagulants Efficacy and Safety of Bridge Therapy: In patients requiring temporary interruption of warfarin therapy, bridge therapy is associated with low risk of thromboembolic and major bleeding complications. Evidence for bridge therapy with LMWH or UFH for endoscopic procedures is limited. Douketis et al. Arch Intern Med 2004. Anderson et al. Gastrointest Endosc 2009; Veitch et al. Gut 2008. 13
Endoscopic Procedures in Acutely Bleeding Patients Patient presenting with GI bleeding (GIB) in the setting of a supratherapeutic INR Patient who presents with ACS and GIB Patient who bleeds following anticoagulation for stent placement, ACS or neurological event Acute GIB in Anticoagulated Patients: Case- Control Study N=23 cases (severe GIB while taking warfarin); N=50 Endoscopic therapy is effective even with matched controls* elevated INRs INR range 1.5-6.0; Corrected to 1.5-2.5 with FFP Warfarin (n=23) No Warfarin (n=50) Technical success 22 (95.6%) 47 (94.0%) Injection:heater probe 18:4 36:11 Continued bleeding/rebleeding 4 (17.4%) 9 (18.0%) Emergency surgery 2 (8.7%) 4 (8.0%) Mean PRBCs transfused 6.0 (0.79) 4.48 (0.50) Median duration of admission (d) 10 (4-57) 7 (3-84) 30-day mortality 0 2 (4.0%) *Controls matched for age, gender, presence of shock on admission, and endoscopic findings Choudari & Palmer. Gut 1994. 14
Impact of Anticoagulation on Rebleeding Following Endoscopic Therapy N=233 patients with nonvariceal bleeding INR at time of Adjusted OR*: 0.50 (0.21-1.16) *Controlling for age, comorbidity, antiplatelet endoscopy is use, post-procedure heparin and PPI use, not predictive hypotension, ulcer as bleeding source, and active bleeding at endoscopy of rebleeding Normalizing INR does not reduce rebleeding but does delay endoscopy N=103 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) Wolf A. Am J Gastroenterol 2007. Endoscopic Procedures in Acutely Bleeding Patients Patient presenting with GI bleeding (GIB) in the setting of a supratherapeutic INR Patient who presents with ACS and GIB Patient who bleeds following anticoagulation for stent placement, ACS or neurological event 15
EGD OR (95% CI) 8 6 4 Utility of Endoscopy in Patient with Concomitant GIB and ACS Urgent EGD should be performed in patients with GIB as the inciting event or those Retrospective, with ACS who Durham VAMC medical Performing record EGD review in ACS (1/1996-12/2002) patients experience N=183 patients hematemesis EGD within or days may of still initial alter ACS whether (n=105) cardiac or GIB (n=78) hemodynamic instability catheterization is performed during High probability bilit of finding the hospitalization ti treatable lesion Influenced timing of cardiac 10 catheterization in 43% 2 0 3.9 (1.8-8.5) Inciting event: GIB (vs. ACS) Lin S. Dig Dis Sci 2006. 3.1 (1.3-7.6) 3.1 (1.4-6.9) Hematemesis (vs. none) Hemodynamic instability (vs. none) Endoscopic Procedures in Acutely Bleeding Patients Patient presenting with GI bleeding (GIB) in the setting of a supratherapeutic INR Patient who presents with ACS and GIB Patient who bleeds following anticoagulation for stent placement, ACS or neurological event 16
Urgent Endoscopy in the Patient with ACS or Recently Placed Stent 1-3% develop GIB with ACS Mortality risk: 4-7 times more than non-bleeders* High procedure-related mortality on the day of the ACS event 12%** Mortality risk drops 1-2% within 30 days of ACS and diagnostic yield is high (85%) *Al-mallah AM et al. J Thromb Thrombolysis 2007; Abbas AE et al. Am J Cardiol 2005. **Spier BJ et al. J Clin Gastroenterol 2007. Cappell MS. Am J Med 1999. Anticoagulant Summary: Urgent Setting Endoscopy therapy is very effective even in patients with elevated INR Rebleeding rates is unaffected by preprocedural INR Correcting INR delays time to procedure Patients who present with GIB leading to ACS should be scoped High likelihood of finding an important lesion Peri-procedural risks are high in the first 24 hours of an ACS event, but decline to 1-2% by 30 days 17
Antiplatelet Summary To minimize risk: One size does not fit all. Balance indication and real risk of thrombosis with short-term cessation, vs. indication and endoscopic bleeding risk Consult with cardiologist/hematologist Discuss recommendations with your patient 18