Atrial Fibrillation: Data from the GARFIELD-AF Registry Dr Frank - PowerPoint PPT Presentation

The Risk of Permanent Discontinuation of Oral Anticoagulation in Patients with Atrial Fibrillation: Data from the GARFIELD-AF Registry Dr Frank Cools (AZ Klina, Brasschaat, Belgium) A. John Camm, Jean-Pierre Bassand, Freek W.A. Verheugt, Shu Yang, Anastasio Tsiatis, David A. Fitzmaurice, Samuel Z. Goldhaber, Shinya Goto, Sylvia Haas, Frank Misselwitz, Alexander G.G. Turpie, Keith A.A. Fox, Ajay K. Kakkar for the GARFIELD-AF Investigators

Background • Oral anticoagulant therapy (OAC) is important for patients with atrial fibrillation (AF) who have an increased risk of stroke • Discontinuation rates of OAC are high:  VKA: 25-60% after one year  NOACs: 21-34% in phase 3 trials, 19-53% in Real World Studies • There are few prospective global data on the rate of OAC discontinuation and its impact on outcomes • Aim of this study:  Describe OAC discontinuation patterns  Describe impact of OAC discontinuation on clinical outcome Unpublished Data

57,262 patients from over 1000 sites in 35 countries AFRICA EUROPE AMERICAs • • • Egypt Austria Argentina • • • South Africa Belgium Brazil • • Czech Republic Canada • • Denmark Chile • • Finland Mexico ASIA & MIDDLE EAST & • • France USA OCEANIA • Germany • Australia • Hungary • China • Italy • Egypt • Netherlands • India • Norway • Japan • Poland • Singapore • Russia • South Korea • Spain • Thailand • Sweden • Turkey • Switzerland • United Arab Emirates • Ukraine • United Kingdom

GARFIELD-AF Design 2010 2011 2012 2013 2014 2015 2016 2017 2018 Cohort 1 Dec-09 Oct-13 Aug-18 • Patients are consecutively recruited into 5 sequential cohorts Cohort 2 Jun-15 Aug-18 • ≥18 years of age • with newly diagnosed non-valvular AF (≤6 weeks’ duration) Cohort 3 Aug-16 Aug-18 Key • ≥1 investigator -determined stroke risk Recruitment factor(s) Cohort 4 Aug-17 Aug-18 1-year follow-up • Follow-up: 2 yrs (minimum) and up to 8 yrs 2-year follow-up Extended Cohort 5 Aug-18 follow-up

Methods • 22,810 patients received OAC at the time of inclusion (enrolled Apr-2013 – Aug-2016) • Discontinuation = OAC stopped for at least 7 days whether or not restarted later on  Sensitivity analysis with 30 day discontinuation window  Sensitivity analysis for patients that do not restart any OAC afterwards • Logistic regression model assessed the association between baseline characteristics and discontinuation • Dynamic treatment regime marginal structural models estimated the effect of discontinuation on the following endpoints  Death, Non-Hemorrhagic Stroke + Systemic Embolism (NHS+SE), Myocardial Infarction (MI)  Death, NHS+SE  Death  NHS+SE  MI Unpublished Data

Discontinuation according to OAC Treatment Type of OAC started at baseline: VKA 49.8% Factor Xa-I 39.1% DTI 11.1% • Overall discontinuation rate: 9.5% (23.5% restarted at some point) • Median follow-up: 710 days (IQR 487-731) • Treatment persistence: at 1 year 88%, at 2 years 83% Discontinuation rates according to type of OAC: VKA 9.1% Factor Xa-I 9.0% DTI 13.3% Unpublished Data VKA: Vitamin K Antagonist; DTI: Direct Thrombin Inhibitor; AP: Antiplatelet therapy

Baseline Characteristics Discontinuation No Discontinuation Discontinuation No Discontinuation (N=2170) (n=20640) (N=2170) (n=20640) Female 40.8% 45.3% Type of AF Age, mean (SD) 69 (60,77) 72 (64,79) Permanent 8.7% 14.6% <65 yr 37.3% 25.1% Persistent 16.6% 16.9% 65-74 yr 29.8% 35.1% Paroxysmal 29.6% 27.2% ≥75 yr 32.9% 39.8% New 45.1% 41.3% Diabetes 20.4% 23.6% Bleeding history 2.8% 1.6% Stroke/TIA 7.9% 11.9% CKD Stage 3-5 12.6% 11.4% Coronary disease 20.4% 20.1% CHA 2 DS 2 -VASc, (SD)* 2.9 (1.6) 3.3 (1.5) Heart failure 19.6% 19.2% HAS-BLED, (SD)* 1.2 (0.9) 1.3 (0.9) Unpublished Data *Mean CHA 2 DS 2 -VASc and HAS-BLED score, SD: Standard deviation

Time to Discontinuation after Start of Treatment Months from Start of Treatment to Discontinuation 50 45 40 Percent of Patients 35 30 25 20 15 10 5 950 441 292 206 152 84 0 43 0 - 4 4 - 8 8 - 12 12 - 16 16 - 20 20 - 24 > 24 Months 43.9% of discontinuations were within the first 4 months of the start of treatment Unpublished Data

Reasons for Discontinuation N % Physician decision 940 43.3 Patient decision 365 16.8 Cost and reimbursement issues 26 1.2 Pregnancy or adverse events 57 2.6 End of planned treatment 137 6.3 ‘Other’ or ‘No reason’ listed 645 29.7 Unpublished Data

Baseline Characteristics associated with Discontinuation Factors with a higher risk of discontinuation Factors with a lower risk of discontinuation Odds ratio Odds ratio Increasing age # History of bleeding 1.80 p<0.001 0.97 p<0.001 Caucasian vs. other races 1.60 p<0.001 History of stroke / TIA 0.72 p<0.001 Heart Rate # 1.05 p=0.003 History of hypertension 0.83 p=0.001 Paroxysmal vs. persistent AF 1.20 p=0.011 Increasing BMI # 0.89 p=0.012 Antiplatelet use 1.18 p=0.009 Permanent vs. persistent AF 0.68 p<0.001 Higher risk care setting Cardiology vs. primary care 0.82 p=0.046 1.35 p<0.001 (emergency room vs. office) # OR are for a 10 unit increase in heart rate, age and BMI Unpublished Data BMI: Body mass index; TIA: Transient ischemic attack

Time-dependent Characteristics associated with Discontinuation Factors with a higher risk of discontinuation Odds ratio Major bleeding 2.52 p<0.001 CRNM bleeding 2.63 p<0.001 Minor bleeding 5.22 p<0.001 NH-Stroke or SE* 2.92 p<0.001 Myocardial infarction* 2.33 p<0.001 Left atrial appendage procedure 5.71 p<0.001 CRNM: Clinically relevant non-major bleeding; NH-Stroke: non-hemorrhagic stroke, SE: systemic embolism Unpublished Data *NH-Stroke or SE, MI when not a component of the endpoint

Impact of Discontinuation on Outcomes over 2-yr follow-up Hazard ratio (95% CI)* * Reference no discontinuation Unpublished Data *After adjusting for variables, both baseline and time-dependent, that are associated with both clinical endpoint and treatment discontinuation

Other Outcome Studies on OAC Compliance N Follow-up Pro/Retro parameter results Gallego 1 529 2.2 yr. P/R discontinuation mortality, stroke, CV events Shore 2 5376 0.67 yr. R adherence mortality and stroke stroke risk, increasing with Yao 3 64661 1.1 yr. R adherence higher CHA 2 DS 2 -VASc score Rivera- 1361 6.5 yr. P/R discontinuation mortality, stroke, CV events Caravaca 4 Jackevicius 5 15857 0.5 yr. R nonpersistence CVA/TIA Borne 6 2882 1 yr. R adherence mortality and stroke 1 Gallego et al. Thromb Haemost 2017;117:1448-1454, 2 Shore et al. Am Heart J 2014;167:810-17, 3 Yao et al. J Am Heart Assoc 2016;5:e003074, 4 Rivera-Caravaca et al. Thromb Haemost 2017;117: 1448-1454, 5 Jackevicius et al. Heart 2017;103:1331-1338, 6 Borne et al. BMC Cardiovasc Dis 2017;17:236 Unpublished Data

Strengths and Limitations • Limitations:  Observational research  Lot of ‘other’ or ‘no reason’ reasons for discontinuations • Strengths:  Rigorous prospective follow-up, exact dates of treatment changes known  Significant source data verification*  Novel statistical method Unpublished Data *Fox et al. Eur Heart J Qual Care Clin Outcomes 2017; 3: 114-122

Conclusions • The rate of discontinuation in this study was 9.5% over a 2-year follow-up • When OAC treatment was stopped for at least 7 days, the clinical outcome was significantly worse, and associated with a higher chance of dying, whether or not an OAC was restarted afterwards • These results imply that permanent discontinuation of OAC treatment in AF patients should be discouraged, even if there seems to be a ‘valid’ reason to do so • Starting OAC treatment implies continuous follow-up and counseling, also with NOACs Unpublished Data