New Anticoagulants and GI bleeding

Transcription

1 New Anticoagulants and GI bleeding DR DANNY MYERS MD FRCP(C) CLINICAL ASSISTANT PROFESSOR OF MEDICINE, UBC Conflicts of Interest None I am unbiased in the use of NOAC s vs Warfarin based on risk benefit ratio I am a General Internist though performed <20,000 endoscopies in previous clinical practice

2 81 year old male history of CAD and Hypertension November 2013 TIA secondary to Atrial fibrillation Started on Rivaroxaban 20 mg per day by stroke clinic Jan 2014 Hg 65 acute GI bleed (melena) and CrCl 55 UGI scope, colonoscopy and capsule study all normal How should patient be treated in view of CHADS-2 score of 4? Indications for NOAC s 1) Prevention of systemic embolism (CVA) from Non valvular Atrial Fibrillation 2) treatment of VTE 3) Prophylaxis for VTE

3 Case-fatality rate Cumulative probability of recurrence (%) NOAC 1) Dabigatran 2) Rivaroxaban 3) Apixaban 4) Edoxaban Atrial Fibrillation Patients Have Increased Post-stroke Mortality and Stroke Recurrence Mortality With AF 49.5 Without AF 10 8 Probability of stroke recurrence With AF Without AF p = days 1 year Time since event Months since event AF = atrial fibrillation Marini C, et al. Stroke 2005;36:1115

4 Bedridden patients (%) Ischemic Stroke Associated With Atrial Fibrillation Is Typically More Severe Than Stroke Due to Other Etiologies % % With AF Without AF Odds ratio for bedridden state following stroke due to atrial fibrillation was 2.23 (95% CI: ; p < ) Dulli DA, et al. Neuroepidemiology 2003;22:118 NOAC s in Atrial Fibrillation 1) Rarely use ASA in Atrial fibrillation for stroke prevention 2) NOAC efficacy similar or better than warfarin 3) similar or lower risk of overall bleeding 4) significant reduction of ICH 5) no laboratory monitoring required* and fixed dosing

5 NOAC risk GI bleeding compared to warfarin in Afib trials in approximately 70,000 patients GI bleeding higher with Dabigatran 150 mg, Rivaroxaban 20 mg and Edoxaban 60 mg Dabigatran 110 mg higher GI bleeding >75 years old Apixaban similar bleeding risk to warfarin Differences in clinical trials and real life. Risk of GI bleeding lower in clinical trials 1) age >75 only 31 to 43% of NOAC A-fib trials 47 to 64% in real world afib cohorts 2) increasing age = higher risk (GI) bleeding 3) increasing age = worsening renal function

6 Major Exclusion criteria NOAC Afib trials 1) valvular atrial fibrillation (mitral stenosis or mechanical valves) 2) major surgery within past month and / or planned major surgery 3) Dabigatran GI bleed past year, symptomatic or endoscopic gastroduodenal ulcer past 30 d active liver disease, anemia, CrCl <30, malignancy within 6 months with expected survival < 3 years Apixaban -ASA dose > 165 mg/d or ASA with Clopidogrel or active liver dx, Hg <90, CrCl <25 Rivaroxaban clinically significant bleeding within 6 months, planned invasive procedure with potential for uncontrolled bleeding or use ASA >100 mg/d or ASA+Clopidogrel within 5 d random or anticipated need chronic NSAID's or active liver disease or anemia, CrCl <30, malignancy within 6 months with expected survival < 3 years NOAC s and GI bleeding -Overall increase risk of GI bleeding (>75 years old in particular) compared to warfarin but marked heterogeneity between trials -Meta-analysis of Phase 3 trials 25% increase in GI bleeding compared to warfarin -Rivaroxaban: regional differences in baseline characteristics (older age, PHx GI bleed, anemia) affected risk of GI bleeding rates

7 GI bleeding risk (number per 100 pt/yrs) NOAC Comparator Dabigatran 110 mg bid 1.12 % Warfarin 1.02 % Dabigatran 150 mg bid 1.51 % Rivaroxaban 3.15 % Warfarin 2.16 % Apixaban 0.76 %/year Warfarin 0.86 %/year Apixaban 0.4 % ASA 0.4 % Upper vs Lower GI bleeding More UGI than Lower GI bleeding with all 3 NOAC s Rivaroxaban showed trend towards increase UGI bleeding with RR 1.45 Dabigatran showed trend towards increase Lower GI bleeding with RR 2.52

8 Devil in the details. Heterogeneous data CHADS 2 score higher Rivaroxaban group Clinical trials compared only NOAC to Coumadin (not NOAC to NOAC) Geographical differences in risk / benefit NOAC vs Coumadin What really matters is risk / benefit analysis with proper patient stratification Observational data more representative of the real world -Abrahams assessed risk of GI bleeding with NOAC compared to Warfarin in patients with and without Afib -Propensity scoring used to match patients taking Warfarin: HP infection, PHx GI bleeds, concomitant Anti PLT or NSAID, SSRI or PPI -No significant difference in rate GI bleed between Dabigatran or Rivaroxaban and Warfarin even if divided into upper or lower GI -Risk bleeding increased >75 yo irrespective of OAC

9 Observational data -ORBITAF registry objective to follow 10,000 patients with AF with 3 year follow-up including use of Antiplatelet and Anticoagulant agents -patients often received concomitant ASA with OAC even in the absence of a CV indication. -dual therapy associated with a significantly increased risk of bleeding Risk of Bleeding: Has Bled Score

10 Has Bled risk of Bleeding HAS-BLED SCORE RISK BLEEDING PER YEAR 0 0.9% 1 3.4% 2 4.1% 3 5.8% 4 8.9% 5 9.1% 6-9 INSUFFICIENT DATA Increased GI risk from a Gastroenterologists perspective:it's not just the drug... HASBLED score not enough.. PHx GI Bleed Age differential H Pylori status Concomitant ASA/NSAID or Anti-Platelet use Concomitant Corticosteroid use Diverticular disease Angiodysplasia Other mucosal diseases

11 The dilemma Consequences of CVA high from A-fib vs Risk GI Bleed: Elderly Renal Failure Low BMI Multiple blood thinners The most pressing problem is.. Dual or Triple therapy (Single or Dual anti-plt therapy with OAC)

12 AF and Vascular Disease -Approximately 80% of AF patients have indication for OAC and 30% have co-existent vascular disease -ACS patients with AF are highest risk as require dual Anti- PLT therapy for PCI/Stents -OAC (Oral Anti-coagulants) should not be interrupted in AF patients with ACS -The question is dual vs triple therapy AF and ACS/CAD -Cohort Studies approximately 50% increase bleeding with triple compared dual therapy -both early (<90 day) and delayed (90 to 360 days) bleeding risk increases with triple therapy -WOEST trial

13 NOAC s -AF patients requiring OAC excluded from ACS trials -RELY trial Dabigatran post hoc analysis: 7000/18,000 patients out of 18,000 received concomitant ASA or Clopidogrel at some time during the study ASA 5789 Plavix 351 and both meds 812 with only 27% on concomitant anti PLT at any one time with NOAC -major bleeding increased as expected -Dual Anti PLT therapy increased risk further HR dual anti PLT 2.31 major bleed and 1.60 single anti PLT -Absolute risk per year Dabigatran 110 bid (3.9%) 150 bid (4.4%) Warfarin (4.8%) RR of bleeding in RELY post hoc analysis suggests the relative risk of bleeding with Dabigatran and anti PLT agents similar compared to combination therapy with warfarin Risk 50% higher with single Anti PLT and doubled with dual anti PLT Results may underestimate true risk as anti PLT use not continuous (mean duration of use 66%) No data (yet) on PPI treatment

14 Acute GI Bleeding Unlike warfarin no anecdote available (yet) Usually supportive care, PRBC s and await clearance of NOAC sufficient and majority of time bleeding will stop spontaneously Timing of endoscopy important Use of PCC or other products no data Can dialyze Dabigatran Acute GI bleeding; lab tests unreliable Need to know the following for an estimate of anticoagulant effect 1) time of last dose and dose taken 2) renal function 3) if any drug interactions (few with NOAC s)

15 The future. 1) new generation stents less thrombogenic than 1 st generation stents 2) await new data (Rivaroxaban and Plavix in PIONEER AF-PCI trial) 3) pre selection of higher risk patients 4) LA appendage closure devices 5) reversal agents for thrombin and Xa Inhibitors THE END