The Cardiogastroenterologist: Managing Antiplatelet and Antithrombotic Drugs. Do the following clinical scenarios make you tachycardic?

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1 The Cardiogastroenterologist: Managing Antiplatelet and Antithrombotic Drugs Neena S. Abraham MD, MSc (EPID), FACG Professor 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, AZ Division of Health Care Policy & Research, Department of Health Sciences Research, Mayo Clinic, Rochester, MN Do the following clinical scenarios make you tachycardic? The patient with ischemic heart disease, on dual or triple antithrombotic therapy, who just won t stop bleeding! You are on what new cardiac drug? It s another left ventricular device (LVAD) bleeding patient! Now what? Copyright 2015 American College of Gastroenterology 1

2 U.S. Population: Age 65+ & Cardiac disease By 2030, >40% of US adults will have 1 form of cardiovascular disease. 100 *Expected aggressive increase in antiplatelet and anticoagulant use for primary and secondary prevention. Millions Administration on Aging- 2012; Heidenreich et al. Circulation Antithrombotic Bleeding: Quantifying Risk Hemorrhagic complications: 10% following ACS and PCI (USA) National Surveillance System (USA) Emergency hospitalization in patients 65 years Warfarin #1 & Antiplatelets #3 drug related GIB Emergency Room visits (France) N=98,377 ( )--913 antithrombotic-related GIB; 1.2 patients/day Antiplatelet-related GIB 42% Anticoagulant-related GIB 33% Doyle et al. J Am Coll Cardiol 2009 ;Budnitz et al. NEJM 2011; 365: 2002; Bouget et al. Thrombosis Res 2014; 135:84 Copyright 2015 American College of Gastroenterology 2

3 Complex Antithrombotic Therapy (CAT) in Elderly Patients: GI Bleeding Outcomes One-Year Number Needed to Harm (NNH); N=78,133 1-Year NNH for CAT-related Events Upper GI Bleeding NNH (95% CI) Lower GI Bleeding NNH (95% CI) Transfusion NNH (95% CI) Hospitalization* NNH (95% CI) Anticoagulant and Antiplatelet Agent Dual Therapy Aspirin and Anticoagulant Aspirin and Antiplatelet Agent Triple Therapy Aspirin, Antiplatelet and Anticoagulant Agents 65 (24-379) 56 (22-231) 93 (34-544) 52 (20-210) 19 (11-37) 15 (9-30) 18 (10-37) 23 (13-49) 43 (21-128) 16 (9-31) 51 (24-182) 25 (14-50) 39 (18-121) 34 (16-89) 67 (30-214) 45 (21-126) Abraham NS et al. Circulation Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban and warfarin (N= 92,816) Unadjusted and adjusted propensity-matched rates similar for all anticoagulants Heterogeneity of treatment effect models reveal important age-related differences in bleeding rates GIB risk increased after age 65 such that by 76 GIB risk exceeded that of warfarin AFIB: dabigatran vs. warfarin (HR 2.49; CI 1.61 to 3.83) AFIB and non-afib: rivaroxaban vs. warfarin (HR 2.91; CI 1.65 to 4.81 and HR 4.58; CI: 2.40 to 8.72). Abraham et al. BMJ 2015; 350:1857 Copyright 2015 American College of Gastroenterology 3

4 Direct Oral Anticoagulants + Antiplatelet Therapy: GI Bleeding in Post-ACS Population Meta Analysis CV EVENTS ESTEEM (2003) 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) MAJOR BLEEDS 0.76 ( ) 0.78 ( ) 0.76 ( ) 1.05 ( ) 0.95 ( ) 1.30 ( ) 0.84 ( ) 0.86 ( ); NNT= Favors Anticoagulant Favors Placebo ESTEEM (2003) 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) Favors Anticoagulant Favors Placebo Komosci A et al. Arch Intern Med ( ) 1.43 ( ) ( ) 2.55 ( ) 2.05 ( ) 1.75 ( ) 3.92 ( ) 3.03 ( ); NNH= 111 Why Cardiogastroenterology? New drugs, complex patients, new clinical needs Intersectional innovation Multidisciplinary approach Collaboration between disciplines Change the way you think Diversity in scientific and clinical thinking Overcomes knowledge gaps Copyright 2015 American College of Gastroenterology 4

5 Clinical Case: Mr. HK 87 year old gentleman, pastor, grandfather Atrial fibrillation status post ablation, CRF, DM, CAD status post 3V CABG, PTCA, multiple stents, diffuse coronary artery disease Antithrombotic Burden: ASA + clopidogrel (DAPT) From March 2012 March hospitalizations for GI bleeding >15 units PRBCs transfused Multiple endoscopies: gastric ulcers, diverticulosis, AVMs, MWT, gastritis Mr. HK Patient enrolled in CardioGI clinic in April 2013 Patterns emerged and treatment was individualized: Patient exquisitely sensitive to ASA Consistent pattern prior to GI bleeding (dyspepsia followed by vomiting, MWT and endoscopic stigmata of gastric ulceration, proximal small intestinal AVMs) Minimizing ASA/NSAID exposure became critical Plavix monotherapy, then M/W/F reduced bleeding Continuous shared decision making and preference elicitation led to decision to discontinue all antithrombotics Unstable angina PTCA with stent (bare metal not drug eluting); six weeks of DAPT then clopidogrel monotherapy NO GI Bleeding in 12 months = Clinical Equipoise Copyright 2015 American College of Gastroenterology 5

6 Use Partnership Building Language to Engage Patients in Shared Decision Making Partnership Building Language Ask patient s opinions/preferences Request questions Involve patients in decisionmaking process Examples What do you think about that? Is that something you would to consider? Tell me more about that. Do you have any questions? The choice is yours. Acknowledge/accommodate patient s preferences and requests Sure, I can tell you more about that (in response to patient s request). Abraham NS. Clin Gastro Hep 2012 Managing the CardioGI patient: Essential GI clinical questions. Can I stop cardiac ASA? How do I safely hold antiplatelet agents? Is it safe to perform endoscopy post-acs? What are the important new drugs? What do I need to know about DOACs? When do I restart the drugs? LVAD bleeding now what? What are simple risk-minimization strategies? Copyright 2015 American College of Gastroenterology 6

7 CARDIOGASTROENTEROLOGY TIP Management of ASA Monotherapy Study Yousfi et al Hussain et al Antiplatelet Agent ASA use within 3 days prior ASA or clopidogrel within 10 days prior Procedure Case Control Colonoscopy + polypectomy 40% 33% Sphincterotomy 16% 17% Bleeding Risk OR 1.41 ( ) OR 0.41 ( ) It is reasonable to perform endoscopic procedures in patients taking ASA. Becker et al. Am J Gastroenterol CARDIOGASTROENTEROLOGY TIP Quantifying the Risk of Cardiac ASA Discontinuation Low-dose ASA (n=78) vs. placebo (n=78) RCT 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 Hospitalbased cohort N=118 Discontinued ASA therapy: Mortality and CV event HR 6.3 ( ) Discontinuation of ASA in CV patients is associated with increased mortality. Sung et al. Ann Intern Med Derogar M et al. Clin Gastroenterol Hepatol Copyright 2015 American College of Gastroenterology 7

8 Indications: Dual Antiplatelet Therapy Current AHA and ACC guidelines include clopidogrel, ticagrelor and prasugrel. Post-ACS Up to 12 months following unstable angina or NSTEMI managed without PCI At least 14 days (12 months in some) following STEMI Post-Stent 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 Jneid et al. J Am Coll Cardiol 2012; O Gara et al. Circulation CARDIOGASTROENTEROLOGY TIP Stent Thrombosis Post-DES: Antiplatelet Cessation Short-term discontinuation of thienopyridine is safe in patients with DES if ASA therapy maintained 122 days Time from Drug Discontinuation to Thrombotic Event P< days 7 days P< Patients with Thrombotic Event ASA and thienopyridine discontinued simultaneously (n=33) ASA discontinued after thienopyridine previously discontinued (n=15) Only thienopyridine discontinued; ASA continued (n=94) Eisenberg M et al. Circulation Copyright 2015 American College of Gastroenterology 8

9 Temporary Interruption of Thienopyridine Among Patients with ACS Medically Treated Patients PCI-Treated Patients Incidence of Death or MI Significantly higher risk of adverse events (~2-fold increase) during first 0-90 days post-acs with clopidogrel discontinuation 0-90d d d Days Post-Clopidogrel Cessation Ho et al. JAMA CARDIOGASTROENTEROLOGY TIP Antiplatelet Pearls: Urgent Setting GIB in post-acs patients associated with increased inhospital mortality (OR 13.2 [ ]) and 30-day mortality (OR 8.9 [ ]) GIB leading to ACS should be scoped High likelihood of finding important lesions: HR 3.9 ( ) Hematemesis or hemodynamic instability should be scoped Faster cardiac catheterization in 43% Peri-procedural risks high (12%) in the first 24 hours after ACS but decline to 1-2% by 30 days Time your urgent procedure accordingly Within hours if still oozing Shalev A et al. Int J Cardiol 2012; Lin S. Dig Dis Sci 2006 ; Cappell MS. Am J Med 1999; Spier BJ et al. J Clin Gastroenterol Copyright 2015 American College of Gastroenterology 9

10 Vorapaxar: New PAR-1 Inhibitor Vorapaxar protease-activated receptor 1 (PAR-1) inhibitor; First-in-class antiplatelet medication Approved May 2014 and prescribed with DAPT TRA 2 0 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: 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 Copyright 2015 American College of Gastroenterology 10

11 * 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% CARDIOGASTROENTEROLOGY TIP Management of DOAC Bleeding Initial Assessment and Risk Stratification: The ABC s A= Airway; B= Breathing; C= Circulation Mild Bleeding Moderate-Severe Bleeding Life-Threatening Bleeding Delay next dose Anticoagulant effect dissipates 24 h (with no renal failure) T1/2= h Correct hemodynamics to perfuse kidneys Blood-product transfusion Endoscopic evaluation +/- hemodialysis with renal failure Oral charcoal (if ingestion <2h)*; PPI probably helpful if recent ingestion (decreases absorption) *Recommendations based on limited nonclinical data ** PCC= prothrombin concentrate complex Consider rfviia or **PCC Charcoal filtration van Ryan et al. Thromb Heamost Copyright 2015 American College of Gastroenterology 11

12 DOAC reversal agents: 2015 or 2016 Idarucizumab Accelerated approval by FDA 10/16/15 for life threatening uncontrolled hemorrhage Humanized monoclonal antibody - high affinity for dabigatran RE-VERSE-AD trial (interim analysis)* N=123 patients with uncontrolled bleeding or requiring major surgery Reversal of anticoagulant effect in 89% within 4 hours of receiving idaricizumab IV? Thromboembolism must restart dabigatran *Carroll et al. NEJM 2015 DOAC reversal agents: In Development 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 Perosphere 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 Copyright 2015 American College of Gastroenterology 12

13 Left ventricular assist device (LVAD) CHF affects 5 million Americans 1.2 M end-stage- high hospitalization, death $39.2 billion RE-MATCH trial LVADs- destination therapy for end-stage CHF 58% survival at 2 years 2X greater than medication alone Alternative for those ineligible for cardiac transplant Aggarwal et al. Annals of Thoracic Surgery. 2012;93: ; Kushnir et al. GI endoscopy. 2012;75:5: ; Crow et al. Cardiopulmonary Support and Physiology 2009; 137: LVADs and GI Bleeding (GIB) Two types: pulsatile v. non pulsatile flow Pulsatile most similar to cardiac physiology poor durability and bulky Non pulsatile used now: GIB in 18 50% Narrow pulse pressure (~to aortic stenosis) increases intraluminal pressure and dilates mucosal veins, leading to AVMs. Hypoperfusion superficial tissue hypoxia and inflammation Acquired von Willebrand factor deficiency HEYDE S Syndrome Low levels of large multimer vwf necessary for plateletmediated hemostasis in high shear areas AVMs are tortuous and demonstrate high shear stress blood flow Antithrombotic ulcers and erosions 4X increased risk in 1 st 18 months Prevalence: 18% to 50% Etiology: 54% gastric erosions/ulcers; 15 30% AVMs (~SI, cecal and rectal); 30 40% Dieulafoy s ; Repeat bleeding 40% to 60% Aggarwal et al. Annals of Thoracic Surgery. 2012;93: ; Kushnir et al. GI endoscopy. 2012;75:5: ; Crow et al. Cardiopulmonary Support and Physiology 2009; 137:208 15; Letsou et al. J Heart Lung Trans 2006; 24:105 Copyright 2015 American College of Gastroenterology 13

14 Endoscopic Yield: LVAD Bleeding % Positive Findings Diagnostic Yield of Modality Kushnir V, Sharma S, Ewald G, et al. Evaluation of GI bleeding after implantation of left ventricular assist device. GI endoscopy. 2012;75:5: Treatment for recurrent LVAD bleeds Angioectasias (acquired vascular abberancy) or arteriovenous malformations (fetal development) Thin-walled, dilated, ectatic blood vessels RCTs to inform choice lacking Options Supportive (transfusion, iron replacement; endoscopic hemostasis prn) Estrogen therapy (unhelpful) Octreotide (IM monthly at mg/month); trial in LVAD therapy; can cause mesenteric ischemia (IHD patients) Thalidomide (antiangiogenic, PROTHROMBOTIC properties limit use) Bevacizumab (antiangiogenic [anti-vegf]; associated with bowel perforation and bleeding reported with CTX use) Copyright 2015 American College of Gastroenterology 14

15 Minimization of Risk Factors Know GI bleeding Risk Factors Document in your history Risk Factors are synergistic Especially in 60 year olds Modify Risk Factors whenever possible Avoidance of OTC NSAIDs Lowest possible dose of ASA Check and eradicate H. pylori Be aware of polypharmacy Advanced age History of GI bleeding Use of antiplatelets Use of anticoagulants Use of NSAIDs Use of chronic ASA Use of steroids H. pylori infection Non GI co morbidity Cardiac & Renal *Abraham et al. Am J Gastroenterol 2010; Circulation 2010; J Am Coll Cardiol ^ Crooks CJ et al. Gastroenterology My Top Cardiogastroenterology Tips It is safe to perform endoscopy on ASA monotherapy. Avoid stopping thienopyridine in first 90 days post-acs and the first 30 days following stent insertion; defer elective exams. Do low-risk endoscopic procedures on antithrombotics. Continue ASA therapy when stopping thienopyridine or PAR-1. Perform elective procedures 5-7 days after clopidogrel, 7-9 days after prasugrel, and 3-5 days after ticagrelor cessation Resume antithrombotic drugs with hemostasis GIB leading to ACS should be scoped h post-acs; leads to faster cardiac catheterization in 43%. Copyright 2015 American College of Gastroenterology 15

16 Direct oral anticoagulants have 3X GIB risk; highest risk in the elderly >75 years DAPT + new oral anticoagulants (triple antithrombotic therapy) is associated with 3-fold risk of GIB. Unknown GIB risk of PAR-1 inhibitor Vorapaxar DOAC-related bleeding Support hemodynamics to promote renal excretion. Reversal agents coming. No need to normalize INR to perform endoscopy; resume warfarin within 4-7 days of GI bleed Elective peri-procedural DOAC management depends on patient s CrCl LVAD patients have unique bleeding conditions. RCTs needed to better inform management strategies. Aggressively manage modifiable risk factors. Conclusions Cardiac patients are a special GI bleeding population A collaborative, multi-specialty approach to care is best for these complicated patients. New drugs and increasing patient complexity require clinical paradigm shifts Cardiogastroenterology Individualizing strategies to maximize cardiac benefit while minimizing GI bleeding risk Aggressive use of risk minimization strategies Iterative shared-decision making important Copyright 2015 American College of Gastroenterology 16