Complicated issues in GI bleeding for internists? Nonthalee Pausawasdi, M.D. Faculty of Medicine Siriraj Hospital

Complicated issues in GI bleeding for internists? Nonthalee Pausawasdi, M.D. Faculty of Medicine Siriraj Hospital

Complicated issues in GI bleeding; Survey results from internists Optimal resuscitation The proper use of PPI (dosage and duration) Management of refractory bleeding GI bleeding in elderly with multiple medical problems Management of antiplatelet/anticoagulants in CAD/CVD patients with bleeding

Management of acute upper GI bleeding in patient with acute coronary syndrome;

Case CC: Hematemesis after CAG with PCI HPI: 67 y/o man with CAD, HTN, DM, DLP, RA. Presented with unstable angina and underwent cardiac cath with placement of RCA stent (DES). He was given IIb IIIa inhibitor, heparin iv drips, ASA, plavix.

Clinical Course Patient developed hematemesis within 12 hours after RCA stent placement BP 100/60 mmhg, HR 110/min NG lavage showed red blood Resuscitation began High dose IV omeprazole was started (80 mg iv bolus followed by 8 mg/h)

Questions How would you manage antiplatelet agents in this situation? ( IIbIIIa, heparin, ASA, plavix) A. Stop everything B. Continue everything C. Continue single agent D. Continue dual agents (ASA, plavix) E. Continue heparin drips and hold ASA, plavix

Questions How would you manage antiplatelet agents in this situation? ( IIbIIIa, heparin, ASA, plavix) A. Stop everything B. Continue everything C. Continue single agent D. Continue dual agents (ASA, plavix) E. Continue heparin drips and hold ASA, plavix

EGD

Clinical Course Heparin and IIb IIIa inhibitor were stopped after completion of their courses ASA and plavix were continued Endoscopic hemostasis was obtained IV omeprazole was continued for 72 hours followed by oral omeprazole 20 once daily No recurrent bleeding

Anti-platelet (ASA/Plavix) management for peptic ulcer bleeding in CAD s/p DES Should ASA/Plavix be held? For how long?

Serious Upper GI Bleeding from Antithrombotic Agents (Population Based Case-Control Study) No. Cases 1063 Controls 50498 Adjusted OR (95% CI) NNTH Low dose ASA 196 4123 1.8 (1.5-2.1) 1040 Clopidogrel 12 203 1.1 (0.6-2.1) 8800 Dipyridamole 36 738 1.8(1.3-2.4) 873 VKA 56 1227 1.9(1.3-2.8) 985 ASA + Clopidogrel 13 49 7.4 (3.5-15) 124 ASA + dipyridamole 44 737 2.3(1.7-3.3) 595 ASA + VKA 16 114 5.3(2.9-9.5) 184 VKA=Vitamin K antagonist Hallas J, et al. BMJ 2006;333(7571):726.

Time to thrombotic event after discontinuation of antiplatelet MI; 8 days (1 week) Stroke; 14 days (2 weeks) Ischemic peripheral complications; 25 days (4 weeks) Pipilis A, et al. Hellinic J Cardiol 2014;55:499-509.

ASA+ Clopidogrel 4 wk for BMS UGIB - clopidogrel/ +ASA Stop both 12 mo for DES 122 days 7 days

Period of time when thromboembolic risk are the highest in patients with coronary stent First 3 months following acute coronary syndrome First month (30-45 days) following PCI and bare metal stent (BMS) First 3-6 months following PCI and drugeluting stent (DES) Abraham NS. Gastrointest Endosc Clin N Am 2015;25:449-462.

Mortality in 8 weeks Recurrent UGIB in 30 days 1.3% in ASA 12.9% in placebo 10.3% in ASA 5.3% in placebo 1.3% in ASA 10.3% in placebo Discontinuation of ASA in CV patients is associated with increased mortality Sung JJ et al. Ann Intern Med 2010

If the patient develops significant upper GI bleed while on ASA alone Endoscopic hemostatic treatment Intravenous infusion of high-dose PPI for 3 days followed by oral PPI May withhold ASA for 3 days Highest risk of rebleeding during first 72h Resume ASA Resume as soon as possible* CONTINUE ASA** Avoid prolonged discontinuation of ASA *Becker RC, et al. ACG/JACC White Paper. Am J Gastro 2009;667:2903 **Sung JJ et al. Ann Intern Med 2010;152:1-9

If the patient develops significant upper GI bleeding while on dual anti-platelet Withhold clopidogrel for up to 5-7 days Continue aspirin, especially if: < 30 days of any stent placement < 6 months of DES If stopping both anti-platelet drugs is deemed necessary, withhold them for 3 days High risk of stent thrombosis Lower rebleeding risk after 3 days Discontinues clopidogrel but remains on ASA, the median time to event was 122 D Stent thrombosis occurs as early as Day 7 (median time) after stopping both ASA and clopidogrel Sianos G et al. J Am Coll Cardiol 2005

Primary prevention Assessment for indication of antiplatelet therapy Secondary prevention Discontinue antiplatelet High risk stigmata for rebleeding (spurting, NBBV, adherent clot) No Yes Resume antiplatelet immediately after endoscopy Coronary stent : < 4-6 wk after BMS : < 6 mo after DES No Resume antiplatelet 3 days for ASA 5-7 days for clopidogrel Yes - Maintain ASA if hemostasis achieved - Resume DAPT ASAP Laine L et al. Am J Gastroenterol 2012 Hsu PI. J Gastroenterol Hepatol 2012

Clinical Course Patient is ready to be discharged on ASA, Plavix, and PPI Patient complaint of joint pain from RA and rheumatologist recommended NSAID

ASA, Plavix + NSAID? (after recent GI bleeding in CAD s/p DES)

What would you do? A. Use non-nsaid pain killer i.e. opioids, paracetamol B. Start NSAID C. Start COX-2

Drugs Relative risk Celecoxib 1.5 Ibuprofen 1.8 Sulindac 2.9 Diclofenac 3.3 Meloxicam 3.5 Nimesulide 3.8 Naproxen 4.1 Indomethacin 4.1 Piroxicam 7.4 Ketorolac 11.5

Myocardial infarction Cardiovascular death All drugs except naproxen showed some evidence for an increased risk of cardiovascular death Trelle S, et al. BMJ 2011

Canadian Consensus on managing NSAID patients: balancing GI & CV risks 28 Rostom A, et al. APT 2009

Clinical Course Patient is discharged on ASA, Plavix, ACEI, beta-blocker, statin, and omeprazole, naproxen prn

What about oral anticoagulant?

Oral Anticoagulant Warfarin New Generation Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Mechanism of Action Inhibition of Vit K-dependent γ- carboxylation Direct thrombin inhibitor Direct factor Xa inhibitor Metabolism Excretion Liver 92% renal Renal 80% renal Renal 66% renal Renal/Liver ~25% renal Time to maximum effect Half-life ~5-7 d for a therapeutic INR ~5 d to normalize INR 1.25-3 h 2-4 h 1-3 h 12-14 h 9-13 h 8-15 h Reversal agents Protamine Idarucizumab No reversal agent now Management of severe bleeding FFP HD PCC, apcc PCC, apcc PCC=Prothrombin concentration complex

Efficacy of noac vs Warfarin in patients with AF meta-analysis All-cause stroke and systemic embolism Ischemic stroke Hemorrhagic stroke Favors noac Favors warfarin

Efficacy of noac vs Warfarin in Patients With AF Meta-Analysis Major bleeding Intracranial bleeding GI bleeding Favors noac Favors warfarin

Resuming warfarin after GI bleeding 90-Day Thrombosis 90-Day Recurrent GIB P = 0.002 P = 0.1 Warfarin resumption HR : 0.05 (0.01-0.6) Warfarin resumption HR : 1.3 (0.50-3.6) Warfarin should be resumed within the first week following hemorrhage Witt DM et al. Arch Intern Med 2012

Summary; ASA, NSAIDs, Plavix Management International guidelines NSAIDs+PPI and Cox-2 inh alone associated re-bleeding risk Cox-2 inh + PPI recommended ( if patients need NSAIDs and low cardiac risk) Resume ASA/plavix as soon as possible in high cardiac-risk patients Plavix alone is no better than ASA+PPI in patients with increased risk of ulcer bleeding PPI is recommended in patients on ASA+plavix