Oral anticoagulant agent-associated bleeding events reporting system - PowerPoint PPT Presentation

Oral anticoagulant agent-associated bleeding events reporting system (ORANGE study) Laura Green 1,2,3 , Joan Morris 1 , Raza Alikhan 4 , Nicola Curry 5 , Rhona Maclean 6 , Khalid Saja 7 , Simon Stanworth 3,5 , Campbell Tait 8 , Joachim Tan 1 , Peter MacCallum 1,2 1 Barts and the London School of Medicine and Dentistry, Queen Mary University of London; 2 Barts Health NHS Trust; 3 NHS Blood and Transplant; 4 University Hospital of Wales, Cardiff and Vale University Health Board; 5 Oxford University Hospitals NHS Trust; 6 Sheffield Teaching Hospitals NHS Foundation Trust; 7 Barking, Havering and Redbridge University Hospitals NHS Trust; 8 Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde

Summary Background � Study Objectives � Study progress �

Background NICE Commissioning Guide (2013) extrapolated to UK � Prevalence of AF about 2% of adult population of UK � Currently ≈ 500,000 on oral a/c therapy � Likely to increase towards 1 million with new initiatives � Reflects efficacy of warfarin and NOACs in stroke prevention (2/3 reduction)

Background � New cases of VTE ≈ 100,000 per year in UK � Additional 0.1% of adult population - 50,000 - need long-term oral a/c therapy � Prosthetic heart valves 100,000 � Other indications 100,000 � Total 2.4% of adult population � ≈ 1.2 million people on oral a/c therapy

Overview of anticoagulant therapy properties Laura Green

Safety • Budnitz et al (NEJM 2011) – 100, 000 emergency admissions for adverse drug events in adults ≥ 65 years (2007-9) – 50% in adults ≥ 80 years • Warfarin 33% • Insulin 14% • Antiplatelet agents 13%

Safety • Bleeding – Major bleeding 1-3% per year – If 1.2 million people on oral a/c therapy • ≈24,000 major bleeds per year in UK • ≈ 500 per week, 2 or 3 per week per acute Trust

Safety • Warfarin-related bleeds – management guidelines so must be ok?? – how good are we at managing warfarin- or NOAC- related bleeds??

Correction of warfarin-associated major bleeding (Toth et al; Blood Transf 2013) • Retrospective audit of emergency warfarin reversal • 131 consecutive patients • Median PCC dose 26.8 IU/kg, INR reduced 3.1 to 1.2 • Vitamin K (5 mg) given in 91.6% • Median time from presentation to – INR result 2.0 h (1.3 h in ICH) – Vit K administration 3.6 h (2.7 h in ICH) – PCC administration 5.2 h (3.0 h in ICH) • Mortality 7.6% (ICH 22.8%) • Thrombosis by 7 days 1.5%

Meta-analysis of bleeding on NOACs Chai-Adisaksopha et al. Blood 2014;124:2450-8

Meta-analysis of bleeding on NOACs Chai-Adisaksopha et al. Blood 2014;124:2450-8 Intracranial bleeds

Meta-analysis of bleeding on NOACs Chai-Adisaksopha et al. Blood 2014;124:2450-8 Fatal bleeds

30-day mortality after major bleeding Dabigatran v warfarin (Majeed et al Circulation 2013;128:2325-32)

Management of major bleeding dabigatran v warfarin (Majeed et al Circulation 2013;128:2325-32)

Mortality in warfarin-related major bleeding – PCC v FFP Johansen M et al. Cochrane Review 2015

Safety in clinical practice Outcomes of major bleeding Dresden NOAC registry (Bayer-Westendorf J et al. Blood 2014;124:955-62) • 1776 patients (67.5% AF; 32.5% VTE) • Major bleeding per 100 py – 3.1% AF; 4.1% VTE • 1082 all bleeds – 59% minor, 35% clinically relevant, 6% major • 66 major bleeds – 25 (38%) procedural intervention • 6 PCC – 5 showed stabilisation, 1 death from ICH with delayed and underdosed PCC • Bleeding mortality at 90 days after major bleed 5.1% – (15-20% for VKA in literature)

ORANGE study Design � Prospective, multicentre, observational 3-year study � Collect data on the current management and outcomes of patients who develop major bleeding while on OAC warfarin, rivaroxaban, dabigatran, apixaban and o others ( as they become available ) Primary Objectives � Proportion of patients who develop major bleeding and: present with ICH o die within 30 days of presentation o

Secondary Objectives � Estimate the effectiveness of products (PCC, rFVIIa or FEIBA, FgC) in treating major bleeding � Characterise coagulation abnormalities of major bleeding associated with the new OAC � Examine associations between clinical outcomes and: transfusion requirements (RBC to FFP ratio) o correction of coagulation abnormalities resulting from o blood transfusion and/or other products

ORANGE study • Major bleeding – Bleeding leading to hospital admission and resulting in • Death • Transfusion of ≥ 2 units red cells • Transfusion of FFP • Administration of other products (PCC, rFVIIa, FEIBA, fibrinogen) • Bleeding into a critical organ

Milestones � REC approval obtained (REC reference: 12/EE/0431) � NIHR CRN Portfolio adopted (UKCRN ID: 15322) � Recruitment began: October 2013 � Study ends: December 2016 � Number of sites: 31 recruiting; 2 pending R&D � Quarterly newsletter � Yearly reporting of results at BSH meetings

Demographics � 1059 cases have been reported between October 2013 and August 2015 N = 1059 Characteristics Female / Male 520/539 Median age (yrs) 79 [IQR 70-85] N (%) Warfarin (Vitamin K antagonists) 909 (85.8) NOAC 150 (14.2) - Rivaroxaban 106 (10.0) - Apixaban 24 (2.3) - Dabigatran 20 (1.9)

Indications for OAC ( % of total indications, not patients ) Heart valve 10% DVT 11% PE AF 10% 59% Other 5% Stroke 5%

Age distribution by gender

Site of bleeding by OAC type Warfarin/VKA NOAC N = 909 N = 150 % Intracranial 43.0 28.7 Gastrointestinal 29.8 46.7 Other 27.2 24.6

Hb (g/dL)

INR

Management of Bleeding 1 Intervention Number Vitamin K 269 5 mg 86 IV 254 10 mg 145 Oral 8 Dose Route Other 26 unspec. 7 unspec. 12 Tranexamic acid 25 Haemodialysis 3 Surgery/Procedure 63 Neuro-surgical 19 intervention GI tract endoscopic 23 investigation/procedure Other 18

Management of Bleeding 2 PCC, FEIBA

Management of Bleeding 3 RBC, FFP, Platelets & Cryoprecipitate

Outcomes at 30 days Pending 5.5% Died 19.8% Discharged 62.2% Still inpatient 12.5% % Discharged Inpatient Died Report pending* VKA (n= 909) 62.7 12.4 19.8 5.1 NOAC (n=150) 59.3 12.7 20.0 8.0 Overall 62.2 12.5 19.8 5.5 (n=1059)

Length of hospitalisation (for discharged patients)

Summary � 85.8% warfarin; 14.2% NOAC. � Median age: 79 yrs � 41% ICH; 32.2% G-I bleeds overall, however: Rate of ICH is higher with VKA than NOAC o Rate of G-I bleed is higher with NOAC than VKA o � Overall mortality rate at 30 days is 19.8%.