Increased Levels of D-dimer in Atrial Fibrillation Identify Patients With Higher Risk of Thromboembolic Events and Death

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1 Increased Levels of D-dimer in Atrial Fibrillation Identify Patients With Higher Risk of Thromboembolic Events and Death Christina Christersson, Malin Schollin, John H. Alexander, Bernand J. Gersh, John Horowitz, Elaine M. Hylek, Puneet Mohan, Christopher B. Granger, Lars Wallentin, Agneta Siegbahn The ARISTOTLE trial was sponsored by Bristol-Myers Squibb and Pfizer

2 I have nothing to disclose

3 Background Patients with atrial fibrillation have an increased risk of thromboembolic events and death The risk of thromboembolic events and death is related to the CHADS 2 score In the ARISTOTLE trial patients with atrial fibrillation and at least one risk factor for stroke were randomized to apixaban or warfarin treatment Apixaban was superior to warfarin in preventing stroke/ systemic embolism (SE), reduced mortality and caused less major bleeds

4 Background D-dimer is a coagulation activity marker reflecting thrombin generation and fibrin turnover High D-dimer levels are associated with left appendage thrombi in atrial fibrillation and might be related to stroke (EHJ 2007: , JACC 2010: ) Warfarin treatment reduces D-dimer levels in patients with atrial fibrillation (Circulation 1996;94:425-31)

5 Aims To evaluate D-dimer at baseline, before initiation of study treatment, as an independent risk marker for stroke/se and death in patients with atrial fibrillation without or with oral vitamin K antagonist (VKA) before randomization To evaluate the effect of apixaban or warfarin across quartiles of D-dimer at baseline without or with VKA before randomization

6 Methods In the ARISTOTLE trial patients with atrial fibrillation were randomized to apixaban 5 mg twice daily or warfarin for a mean follow up of 1.8 years In the biomarker sub study blood samples were collected in patients before starting study treatment. Plasma was stored at - 80 C until analysis D-dimer was centrally analysed with ELISA (Asserachrome, Stago, France) in the Uppsala Clinical Research Center (UCR) laboratory, Sweden. D-dimer reference limit of normal; < 500 µg/l The patient cohort was separated into two groups in relation to whether treated with VKA within 7 days of randomization to study treatment (On VKA at randomization) or not (No VKA at randomization)

7 D-dimer levels at baseline D-dimer ( g/l) Reference limit 0 No VKA at randomization On VKA at randomization

8 Baseline characteristics biomarker sub study No VKA at randomization (n=6867) On VKA at randomization (n=7982) Age (mean±sd) 68.5± ±9.3 Sex, female (%) Atrial fibrillation, permanent or persistent (%) Congestive heart failure/ LVEF 40% (%) Hypertension (%) Diabetes mellitus (%) Previous stroke/tia (%) CHADS 2 1 (%) CHADS 2 = 2 (%) CHADS 2 3 (%)

9 Primary endpoint Stroke/SE related to D-dimer levels at baseline No VKA at randomization On VKA at randomization Interaction p=0.30 Effect of D-dimer level p= Cox models adjusted for CHADS 2 score and study treatment.

10 Stroke/SE (%/year) Stroke/SE (%/year) Stroke/SE - D-dimer levels at baseline and CHADS 2 score No VKA at randomization On VKA at randomization 3,5 3, ,5 2 1,5 1 2,5 2 1,5 1 0,5 0 > D-dimer quartiles < CHADS 2 score 0,5 0 > D-dimer quartiles p=0.029 for comparison of c-statistic with and without adding D-dimer to CHADS 2 score < CHADS 2 score

11 Stroke/SEE D-dimer levels and randomized treatment No VKA at randomization On VKA at randomization Cox proportional hazards model with biomarker level, CHADS 2 score, treatment and interaction between treatment and biomarker as covariates

12 Death related to D-dimer at baseline No VKA at randomization On VKA at randomization Interaction p=0.36 Effect of D-dimer level p< Cox models adjusted for CHADS 2 score and study treatment

13 Death (%/year) Death (%/year) Death - D-dimer levels at baseline and CHADS 2 score No VKA at randomization On VKA at randomization > < CHADS 2 score 0 > < CHADS 2 score D-dimer quartiles D-dimer quartiles P< for comparison of c-statistic with and without adding D-dimer to CHADS 2 score

14 Death D-dimer levels and randomized treatment No VKA at randomization On VKA at randomization Cox proportional hazards model with biomarker level, CHADS 2 score, treatment and interaction between treatment and biomarker as covariates

15 Conclusion About 70% of the patients without VKA treatment and 40% with VKA treatment at randomization have D-dimer levels above the upper reference limit of normal Higher D-dimer levels are associated with the risk of stroke and mortality The prognostic value of D-dimer is seen both in patients without and with VKA treatment at randomization The relative effect of apixaban versus warfarin is similar across the range of D-dimer levels therefore the absolute benefit of apixaban may be larger at higher D-dimer levels.

16 Back up slides

17 Interaction between VKA treatment at randomization and D-dimer level at baseline. Outcome D-dimer (µg/l) No VKA at randomization (%/year) On VKA at randomization (%/year) HR No vs On VKA at randomization (95% CI) P-interaction VKA trt*d-dimer Stroke/SE ( ) 0.30 > , ( ) > ( ) > ( ) Death ( ) 0.36 > ( ) > ( ) > ( ) Cox proportional hazards model with biomarker level, treatment and interaction between treatment and biomarker level as covariates