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

SLIDE 1

The Risk of Permanent Discontinuation

f 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

SLIDE 2

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Unpublished Data

SLIDE 3

57,262 patients from over 1000 sites in 35 countries

EUROPE

Austria
Belgium
Czech Republic
Denmark
Finland
France
Germany
Hungary
Italy
Netherlands
Norway
Poland
Russia
Spain
Sweden
Switzerland
Ukraine
United Kingdom

ASIA & MIDDLE EAST & OCEANIA

Australia
China
Egypt
India
Japan
Singapore
South Korea
Thailand
Turkey
United Arab Emirates

AMERICAs

Argentina
Brazil
Canada
Chile
Mexico
USA

AFRICA

Egypt
South Africa

SLIDE 4

Patients are consecutively recruited into 5

sequential cohorts

≥18 years of age
with newly diagnosed non-valvular AF

(≤6 weeks’ duration)

≥1 investigator-determined stroke risk

factor(s)

Follow-up: 2 yrs (minimum) and up to 8 yrs

2010 2011 2012 2013 2014 2015 2016 2017 2018 Cohort 1 Dec-09 Oct-13 Aug-18 Cohort 2 Jun-15 Aug-18 Cohort 3 Aug-16 Aug-18 Cohort 4 Aug-17 Aug-18 Cohort 5 Aug-18 Extended follow-up Recruitment 1-year follow-up 2-year follow-up

Key

GARFIELD-AF Design

SLIDE 5

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

SLIDE 6

Discontinuation according to OAC Treatment

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%

VKA: Vitamin K Antagonist; DTI: Direct Thrombin Inhibitor; AP: Antiplatelet therapy

Discontinuation rates according to type of OAC: VKA 9.1% Factor Xa-I 9.0% DTI 13.3% Type of OAC started at baseline: VKA 49.8% Factor Xa-I 39.1% DTI 11.1%

Unpublished Data

SLIDE 7

Baseline Characteristics

Discontinuation (N=2170) No Discontinuation (n=20640) Female 40.8% 45.3% Age, mean (SD) 69 (60,77) 72 (64,79) <65 yr 37.3% 25.1% 65-74 yr 29.8% 35.1% ≥75 yr 32.9% 39.8% Diabetes 20.4% 23.6% Stroke/TIA 7.9% 11.9% Coronary disease 20.4% 20.1% Heart failure 19.6% 19.2%

*Mean CHA2DS2-VASc and HAS-BLED score, SD: Standard deviation

Discontinuation (N=2170) No Discontinuation (n=20640) Type of AF Permanent 8.7% 14.6% Persistent 16.6% 16.9% Paroxysmal 29.6% 27.2% New 45.1% 41.3% Bleeding history 2.8% 1.6% CKD Stage 3-5 12.6% 11.4% CHA2DS2-VASc, (SD)* 2.9 (1.6) 3.3 (1.5) HAS-BLED, (SD)* 1.2 (0.9) 1.3 (0.9)

Unpublished Data

SLIDE 8

950 441 292 206 152 84 43

5 10 15 20 25 30 35 40 45 50

0 - 4 4 - 8 8 - 12 12 - 16 16 - 20 20 - 24 > 24

Percent of Patients

Months

Months from Start of Treatment to Discontinuation

Time to Discontinuation after Start of Treatment

43.9% of discontinuations were within the first 4 months of the start of treatment

Unpublished Data

SLIDE 9

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

SLIDE 10

Baseline Characteristics associated with Discontinuation

Odds ratio History of bleeding 1.80 p<0.001 Caucasian vs. other races 1.60 p<0.001 Heart Rate# 1.05 p=0.003 Paroxysmal vs. persistent AF 1.20 p=0.011 Antiplatelet use 1.18 p=0.009 Higher risk care setting (emergency room vs. office) 1.35 p<0.001 Odds ratio Increasing age# 0.97 p<0.001 History of stroke / TIA 0.72 p<0.001 History of hypertension 0.83 p=0.001 Increasing BMI# 0.89 p=0.012 Permanent vs. persistent AF 0.68 p<0.001 Cardiology vs. primary care 0.82 p=0.046 Factors with a higher risk of discontinuation Factors with a lower risk of discontinuation

# OR are for a 10 unit increase in heart rate, age and BMI BMI: Body mass index; TIA: Transient ischemic attack

Unpublished Data

SLIDE 11

Time-dependent Characteristics associated with 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 Factors with a higher risk of discontinuation

CRNM: Clinically relevant non-major bleeding; NH-Stroke: non-hemorrhagic stroke, SE: systemic embolism *NH-Stroke or SE, MI when not a component of the endpoint

Unpublished Data

SLIDE 12

Impact of Discontinuation on Outcomes over 2-yr follow-up

Hazard ratio (95% CI)*

*Reference no discontinuation *After adjusting for variables, both baseline and time-dependent, that are associated with both clinical endpoint and treatment discontinuation

Unpublished Data

SLIDE 13

Other Outcome Studies on OAC Compliance

N Follow-up Pro/Retro parameter results

Gallego1 529 2.2 yr. P/R discontinuation mortality, stroke, CV events Shore2 5376 0.67 yr. R adherence mortality and stroke Yao3 64661 1.1 yr. R adherence stroke risk, increasing with higher CHA2DS2-VASc score Rivera- Caravaca4 1361 6.5 yr. P/R discontinuation mortality, stroke, CV events Jackevicius5 15857 0.5 yr. R nonpersistence CVA/TIA Borne6 2882 1 yr. R adherence mortality and stroke

1Gallego et al. Thromb Haemost 2017;117:1448-1454, 2Shore et al. Am Heart J 2014;167:810-17, 3Yao et al. J Am Heart Assoc 2016;5:e003074, 4Rivera-Caravaca et al. Thromb Haemost 2017;117: 1448-1454, 5Jackevicius et al. Heart 2017;103:1331-1338, 6Borne et al. BMC Cardiovasc Dis 2017;17:236 Unpublished Data

SLIDE 14

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

*Fox et al. Eur Heart J Qual Care Clin Outcomes 2017; 3: 114-122

Unpublished Data

SLIDE 15

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