Anti-Thrombotic Therapy: Management in the Upper Gastrointestinal Bleeding Patient

New anti-Thrombotic Therapy and Management in the Upper Gastrointestinal Bleeding Patient

November 9th 2018

Col.Krit Opuchar, MD Department of Medicine, Phramongkutklao hospital Major disease Attributable to Disability-Adjusted Life Years Lost of Thai People by Sex US Population: Age 65+ & Cardiac disease

Heidenreich et al. Circulation 2011 Changing Face of Antithrombotics

Warfarin Prasugrel Rivaroxaban Apixaban 1954 2009 2011 2012

ASA Clopidogrel Dabigatran Ticagrelor Vorapaxar 1899 1998 2010 2011 2014 Major Causes of Death in Thailand, 1967-2009 Mortality per 100.000 population

Year

Thailand Healh Profile 2008-2010 Learning Objectives 1. Review the basics of bleed risk • Anticoagulants (warfarin, novel oral anticoagulant [NOAC]) • Antiplatelets (aspirin, thienopyridines and PAR-1 inhibitors) • Combination therapy (complex antithrombotic therapy [CAT]) 2. Highlight what is new 3. Discuss tricky situations • Stopping and restarting drugs in non-variceal upper gastrointestinal bleeding • Bridge therapy- what is the evidence? Antiplatelet: Site of Action Antiplatelets Decrease platelet aggregation and inhibit thrombus formation Vorapaxar : FDA Approves new PAR-1 inhibitor

• Vorapaxar (Zontivity)–protease-activated receptor 1 (PAR-1) inhibitor • First-in-class antiplatelet medication • Approved January 2014 and now widely prescribed (concomitant with DAPT) • TRA 20 TIMI-50 trial (N=26,499) • 13% reduction of MI, stroke, CV death and need for revascularization procedures in patients with a previous MI or peripheral artery disease (v. placebo) • Increased risk of moderate or severe bleeding in 4.2% vs. 2.5% in placebo; 66% increased risk of bleeding overall • Black Box Warning: high risk of bleeding and contraindicated in patients with history of stroke, TIA and intracranial hemorrhage Gastric acid plays a central role in NSAID-associated gastroduodenal damage Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial: Life-threatening or major bleeding

% of patients By aspirin dose, n=6293 4 3.5 3 2.5 2 1.5 1 0.5 0 <100 mg 100-150 mg 151-300 mg >300 mg

Eur Heart J 2004;4:Suppl, 510 CURE: Aspirin Plus Clopidogrel All Bleeding Episodes

% of patients

6 Aspirin Aspirin+Clopidogrel 5

4 P<0.01

0 <100 mg 110-162 mg >200 mg

Eur Heart J 2004;4:Suppl, 510 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 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. Evolution of Antiplatelet Therapy

20 25% 15 20% 19/16% CVD, MI or stroke Event(%) 10 Major bleeding

5 60% 38% 32/19%

1.3 2.4 0 0.8 1.8 None ASA ASA + Clopidogrel ASA + Clopidogrel or BMJ. 1994;308:81-106. Ticagrelor BMJ. 2002;324:71-86. N Engl J med. 2007;357:2001-15. N Engl J med. 2009;361:1045-57. Complex Antithrombotic Therapy (CAT) in Elderly Patients: GI Bleeding Outcomes One-Year Number Needed to Harm (NNH); N=78,133

Abraham NS et al. Circulation 2013. Steps for Minimizing Gastrointestinal Bleeding

PPI

Writing Committee Members et al. Circulation. 2008;118:1894-1909 Circulation. 2008;118(18):1894-1909. Copyright © American Heart Association, Inc. All rights reserved. Indications: Dual Antiplatelet Therapy

•CurrentCirculation AHA 2013.and ACC Circulation guidelines 2013. include clopidogrel, ticagrelor and prasugrel

Post-ACS Post-Stent • ASA indefinitely and clopidogrel or • Up to 12 months following unstable ticagrelor for: angina or NSTEMI managed without • Up to 12 months after Bare metal PCI stent (BMS) Placement • At least 14 days (12 months in some) • At least 12 months after drug- following STEMI eluting stent (DES) placement Circulation 2013. Risk of Clinical Events After Clopidogrel Cessation Among Patients with ACS

Ho et al. JAMA 2008. Peptic Ulcer Bleeding: HRS Forrest Classification System

Ia: Spurting Bleed Ib: Oozing Bleed

IIb: Adherent IIa: NBVV Clot CARDIOGASTROENTEROLOGY TIP Stent Thrombosis Post-DES: Risk with Antiplatelet Cessation Short-term discontinuation of thienopyridine is safe in patients with DES if ASA therapy maintained

Eisenberg M et al. Circulation 2009. CARDIOGASTROENTEROLOGY TIP ASA After Endoscopic Control of Peptic Ulcer Bleeding

• Low-dose ASA (n=78) vs. placebo (n=78) • 30-day recurrent bleeding: 10.3% vs. 5.4% RCT • ARR: 4.9%; NNT=20 • 30-day mortality: 1.3% vs. 9.0% • ARI: 7.7%; NNH= 13

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

Discontinuation of ASA in CV patients is associated with increased mortality.

Sung et al. Ann Intern Med 2010. Derogar M et al. Clin Gastroenterol Hepatol 2013 Non-variceal upper GI bleeding: Platelet transfusion for life-threatening bleeding

APAGE-APSDE: not recommended

ASGE: an option for patients on antiplatelet agents

BSG-ESGE: an option for patients on DOACs Non-variceal upper GI bleeding: Patient on DAPT

APAGE-APSDE: continue aspirin, withhold second antiplatelet agent for up to 5 days after endoscopic haemostasis

ASGE: discuss with cardiologist

ESGE: continue aspirin, consult cardiologist for resumption of second antiplatelet agent

CARDIOGASTROENTEROLOGY TIP Peri-Endoscopic Antiplatelet Management

1. Avoid stopping all antiplatelets simultaneously after PCI with stent insertion. 2. You must maintain patient on ASA monotherapy when stopping thienopyridine agents. 3. Avoid cessation of thienopyridine agents (even when ASA is continued) within the first 30 days of 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 agents, possibly up to 12 months following DES placement. Anticoagulants: Site of Action

• Circulation Research. 2014;114:1929-1943

Circulation Research. 2014;114:1929-1943 Oral Anticoagulants Bleeding complications in Warfarin users •Major haemorrhage in Warfarin users (intracranial, GI, GU and respiratory sites): 1–3% / person-year •The GI tract is the most common bleeding site (age-standardized incidence rate of 5.8 /1000 person-year). •Endoscopic findings are similar between VKA users and patients taking no anticoagulants with peptic ulcer being the main cause of bleeding . •VKAs-related GI bleeding events are associated with long hospitalization, relevant resource utilization, and a 30-day mortality of up to 15%.

F. Radaelliet al. / Digestive and Liver Disease 47 (2015) 621–627 New oral anticoagulants (direct oral anticoagulants ,DOACs)

•In general, DOACs reduce the risk of hemorrhagic stroke and have a comparable risk of major bleeding into all organs compared with warfarin. •DOACs are associated with a modestly increased risk of gastrointestinal (GI) bleeding compared with warfarin. •Warfarin increases the risk of major GI bleeding approximately 3-foldover placebo in the AF population, and 3 DOACs have been shown to further increase this risk 1.5- foldcompared with warfarin.

Gastroenterology & Hepatology Volume 10, Issue 2 February 2014 The Rate of Major GIB in Non-valvular AF Population From The Three Pivotal trials

Dabigatran 150 mg bid Rivaroxaban 20 mg OD Apixaban 5 mg BID

HR for major GIB 1.49[CI 1.21-1.84] 1.61[CI 1.3-1.99] 0.89[CI 0.73-1.15] (VS. warfarin)

Jay Desai; Jennifer M. Kolb; Jeffrey I. Weitz; James Aisenberg Gastrointestinal bleeding with the new oral anticoagulants – defining the issues and the management strategies . Thrombosis and Haemostasis 110.2/2013 Non-variceal upper GI bleeding: VKA

1. Assess the severity of bleeding ,Start hemodynamic resuscitation. 2. Discontinue the Anticoagulant if bleeding is more than minor. 3. Actively reverse the coagulation if bleeding is more than minor . 4. Assess for proper timing for endoscopy. 5. Determine the necessity and proper timing for re-instituationof Anticoagulant therapy. Pre-endoscopic management: VKA

• Patients on VKAs • Timing of endoscopy* • After obtaining INR levels of 1.5–2.5 • Treatment options for VKA reversal • Vitamin K: II, VII, IX and X: IV infusion of 5–10 mg, infusion over a of 30 minutes • FFP: IV infusion of 15 mL/kg • PCCs: 3F-PCC, 4F-PCC, aPCC: 25–50 IU of factor IX/Kg • Recombinant factor VIIa (rFVIIa)

*Gut1994;35:464–6. Annals of Internal Medicine 2010;152:101–13 Treatment options for VKA reversal

VitK : •In bleeding patients, IV route is preferred over the oral one. •Vitamin K1 (phytomenadione), 10 mg (one ampoule) in 100 ml of 0.9% normal saline or 5% glucose solution: 10 ml over 10 minutes (1 mg/10 min) and the remaining over 30 minutes. •IV vitamin K is associated with an estimated 3/100 000 risk of anaphylaxis; thus,aslow infusion over a minimum of 30 minutes is advised to minimize this risk. •Following IV infusion of 5–10 mg vitamin K, the INR begins to decrease within 2–4 h and usually reaches a normal range within 24 h .

Digestive and Liver Disease 47 (2015) 621–627 Treatment options for VKA reversal

FFP: •The recommended dose : IV infusion of 15(10-30) mL/kg corresponding to about 3–4 units of plasma (one unit = 250 mL) in the average adult weighing 70 kg. •Half the dose can be repeated at 6 hours, as the half-life of the factors is 5 to 8 hours. •Cons : •large infusion volume, risk of fluid overload. •prolonged time needed to match blood group and to thaw and transport the units. •transfusion-related acute lung injury and a minimal risk of infection transmission •Time to effect of FFP is 10 min, but it takes a few hours for partial reversal of INR and at least 9 h for complete reversal (i.e.,INR< 1.5) F. Radaelliet al. / Digestive and Liver Disease 47 (2015) 621–627 Alberca-de-las-ParrasF. Clinical practice guidelines for managing coagulation in patients undergoing endoscopic procedures. Rev Esp Enferm Dig 2010; 102: 124-138. Treatment options for VKA reversal PCCs: •Lyophilized inactivated concentrates of factors II, IX, and X, with variable amounts of factor VII, derived from the cryoprecipitate supernatant of large plasma pools after at least one viral inactivation step . •Main advantages of PCCs over FFP: •Prompt reconstitution into a small volume (20 mL for about 500 IU) , blood group independent, rapid IV infusion over 20–30 min with faster INR correction. •The PCCs are standardized according to their factor IX content and administered IV, usually at the dose of 25–50 IU of factor IX/Kg, depending on baseline INR. •Prothrombin complex concentrate combined with factor IX (ProthromplexImmunoTIM 4600 I.U®),Dosage: (required-obtained prothrombin time) x weight in kg x 0.6. Activated recombinant factor VII: 80 μg/kg per slow i.v.bolus (2 ml amp = 1.2 mg). •Effect takes place within 10 to 30 minutes after administration and lasts up to 12 hours. •It should not be combined with prothrombin complexes. •It adjusts prothrombin time and corrects platelet function defects. Supratherapeutic Warfarin Bleeding Acute GI bleeding

Urgent clinical assessment and resuscitation, including blood type &cross-match for active and significant bleeding Complete blood count / Clotting screen (INR,aPTT, fibrinogen)

Active bleeding / Shock Significant bleeding without haemodynamic compromise Minor rectal bleeding

1. Stop VKA 1. Stop VKA Potential outpatient management 2. Actively reverse anti coagulation: - Vitamin K (5-10 mg IV infusion over 30 minutes) 2. Actively reverse anticoagulation: - PCC 25-50 IU/kg according to baseline INR value -Vitamin K (5-10 mg IV infusion over 30 min) INR < 5 5 ≤ I NR <9 INR ≥ 9 3. Check INR 20-30 minutes after PCC infusion: 1. Omit one 1. Stop VKA 1. Stop VKA VKA dose 2. Oral vit.K 2. Vit. K 2. Close (1-2.5 mg) (2.5-5 mg oral Inadequate correction: Adeqate correction (INR <1.5): Therapeutic INR Supratherapeutic INR monitoring or 1 mg IV) - Seek haematologist advice - Rechec k in 6 hours - Consider PCC re-in fusion No further action Consider PCC infusion if - Recheck clotting screen at 24 hours, or sooner if Consider urgent endoscopy is scheduled clinical deterioration Consider emergent endoscopy preferably when INR <2.5 endoscopy Within 6-12hours - Consider endoscopy evaluation as appropriate

Digestive and Liver Disease 47 (2015) 621–627 Resuming Warfarin After GI Bleeding 90 Day Thrombosis 90 Day Recurrent GI Bleeding

Resumed Not resumed P=0.002 Patients with warfarin-associated GIB and indications for continued long- term antithromboticNot resumed therapy should resume anticoagulation within P=0.1the resumed Warfarin Resumptionfirst within week following hemorrhageWarfarin Resumption 4-7 days Within 4-7 days % % Thrombosis without

HR: 0.05(0.01-0.58) GIB Recurrent % without HR: 1.32(0.50-3.57)

Time in Days Time in Days Witt DM, et al. Arch Intern Med. 2012. When to resume Warfarin?

• Lower Mortality when warfarin started < 30 days vs. >30 days following GI bleeding (p < 0.05 for all comparisons). • resumed warfarin within 7 days had an approximately two-fold higher risk of rebleeding and a non-significant decrease in thromboembolism as compared resumed anticoagulation after 30 days. • suggesting that the second week following GI bleeding could be appropriate to resume VKAs in a majority of patients.

Qureshi W, et al. American Journal ofCardiology.2014;113:662–8. Resuming Warfarin After GI Bleeding

Indications of heparin bridging for temporary discontinuation of warfarin ESGE ► Non-valvular atrial fibrillation with a CHA2DS2-VASc score >5*APAGE -APSDE - Resume► warfarinMetallic betweenmitral valve 7 and 15 - Resume warfarin by day 3 once days ►followingProsthetic the bleeding valve with event atrial fibrillation adequate haemostasis is achieved - No mention► <3 aboutmonths bridging after VTE - Consider bridging with unfractionated ► Severe thrombophilia (protein C or protein S deficiency, heparin antiphospholipid if high thrombotic syndrome) risk Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline.Endoscopy 2015; 47: a1–a46 Chan FKL, et al. Gut 2018;0:1–13

*CHA2DS2-VASc, congestive heart failure (1 point), hypertension (1 point), age ≥75 years (2 points), diabetes mellitus (1 point), stroke, TIA or thromboembolism (2 points), vascular disease (1 point), age 65–74 years (1 point), female sex (1 point).92 93 VTE, venous thromboembolism.

Lancet 2009;373:1849–60. Am J Med 2000;109:45–51. Non-variceal upper GI bleeding: DOACs Non-variceal upper GI bleeding: DOACs

•Management depends on the severity of bleeding. • bleeding is not severe, temporary drug withdrawal may be the only requirement due to the short half-lives of these drugs •In the absence of renal or hepatic failure, the clearance of DOACs and the subsequent loss of anticoagulation is rapid and predictable, occurring gradually over 12–24 h

Digestive and Liver Disease 47 (2015) 621–627 ESGE guidelines. Gut 2016;65:374–389. Non-variceal upper GI bleeding: DOACs

• Specific reversal agent of DOACs available for clinical use is Praxbind®(idarucizumab), Specific Reversal Agent for Pradaxa®(dabigatran etexilate). •PRAXBIND is a humanized monoclonal antibody fragment (Fab) indicated in patients treated with PRADAXA when reversal of the anticoagulant effects of dabigatran is needed • Routine laboratory tests are not reliable to measure the anticoagulant effect of DOACs. Although a normal PT and aPTT are advocated as useful tool .

Digestive and Liver Disease 47 (2015) 621–627 ESGE guidelines. Gut 2016;65:374–389. Pre-endoscopic management: DOACs •Patients on DOACs •Watch and support • short half-lives • Gastric lavage and oral charcoal • Prevent further absorption • Ingested within 2–3 h •Non specific pro-haemostatic agents: serious bleeding • PCCs and rFVIIa • Haemodialysis: Dabigatran can be used to reduce the plasma concentration of dabigatran rapidly and efficiently (65% at 2–4 h)

Digestive and Liver Disease 47 (2015) 621–627 ESGE guidelines. Gut 2016;65:374–389. Acute GI bleeding

Urgent clinical assessment and resuscitation, including blood type &cross-match for active and significant bleeding Complete blood count / Clotting screen (INR, aPTT, creatinine clearance)

Significant bleeding without haemodynamic Active bleeding / Shock Minor rectal compromise bleeding

Potential outpatient management 1. Stop DOACs 2. Fluid re placement to maintain diuresis 1. Stop DOACs 3. Consider gastric lavage (if overdose < 2-3 hr) 2. Fluid replacement to maintain diuresis Delay or discontinue next dose Consider haemodialysis for clearing dabigatran Consider off -label use of PCC

Consider emergent endoscopy Consider endoscopy preferably after 12-24 hr Consider endoscopy evaluation as appropriate DOACs resumption •Data about DOACs resumption after GI bleeding are lacking. •The pharmokinetics of DOACs make the role of heparin bridge therapy unnecessary in most cases, but also call for prudence in DOACs resumption, which should probably be deferred after the first week following the bleeding event. Resumption of DOACs

APAGE-APSDE: Resume DOACs by day 3 once adequate haemostasis is achieved; no heparin bridging

ASGE/ESGE : Not specified Resumption of DOACs