Use of anticoagulants in AF patients with renal impairment What is the point of view of a cardiologist?

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1 Use of anticoagulants in AF patients with renal impairment What is the point of view of a cardiologist? Prof. Dan Atar, MD Dept. of Cardiology B Oslo University Hospital, Norway Vice-President of the ESC ( ) Member, ESC Media Committee ( ) ESC Congress Program Committee ( ) Tallinn

2 Prof. Dan Atar Disclosures Co-author of the 2010, 2012 and 2016 ESC Guidelines on Atrial Fibrillation and 2012 ESC STEMI Guidelines, as well as the 2018 Universal Definition of AMI GL. Steering Committee member, National Coordinator for Norway, and Co-author of ACTIVE, RELY, ARISTOTLE, AVERROES, APPRAISE, GARFIELD, ENGAGE-AF, XANTUS, RE-ALIGN, RE-VERSE, ARTESIA, NOAH, ENTRUST-AF-PCI, REPORT-AF, RE-SONANCE, REPORT-HF, PARAGON, VICTORIA. Adjudication Committee member for the AVRO and Roxadustat trials, DSMB for the CHILL-MI, OPTIMUM, LUPUS, BETA-3 and HOMAGE trials. Chair of the FIRE and MITOCARE trial (EU-FP7 fundet). Fees, honoraria from Boehringer- Ingelheim, Bayer, BMS/Pfizer, Cardiome, Astra-Zeneca, MSD, Sanofi-Aventis, Amgen.

3 QUIZ

4 Quiz what is the correct answer? How many registered participants were at the ESC congress 2017 in Barcelona? A: B: C: D: E:

5 Quiz what is the correct answer? 5 days before the ESC congressen 2017, Barcelona was targeted by a devastating terrorism event. How many of the registered participants withdrew? A: 30 B: 115 C: 412 D: 731 E: 1316

6 Quiz what is the correct answer? Which country had most participants and abstracts at the ESC congress 2017 in Barcelona? A: Tyskland B: Frankrike C: Japan D: Spania E: USA

7 Prelude on Atrial Fibrillation

8 Differences in 2-year outcomes according to type of AF Professor Dan Atar Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway

9 Background The type of atrial fibrillation (AF) has not been established as a major predictor of stroke or death, with conflicting reports in the literature 1-4 Therefore, AF burden, defined according to each type of AF, has not been factored into the guidance for clinical decision making 5,6 1. Banerjee A. et al Int J Cardiol. 2013; 167: Vanassche T. et al European Heart Journal. 2015; 36: 281-7a 3. Steinberg B.A. et al European Heart Journal. 2015; 36: Senoo K. et al Stroke. 2015; 46: Kirchhof P. et al European Heart Journal. 2016; 37: January C.T. et al Circulation. 2014; 130:

10 Stroke and systemic embolic event (SEE) occurred less frequently in the patients with paroxysmal atrial fibrillation (AF) (1.49%/y), as compared with persistent (1.83%/y; HR, 0.79; 95% CI, ; P=0.015) and permanent AF (1.95%/y; HR, 0.79; 95% CI, ; P=0.004). Mark S. Link et al. Circ Arrhythm Electrophysiol. 2017;10:e Courtesy Prof. M. Rosenkvist

11 Objectives To analyse outcomes over 2 years after diagnosis of AF by type of AF and by antithrombotic therapy Methods We analysed baseline characteristics, antithrombotic therapy, and 2-year incidence of outcomes in patients classified as having paroxysmal, persistent, or permanent AF Cohorts 1 4, N=28,628

12 Clinical characteristics of patients Paroxysmal AF (n=10,473) Persistent AF (n=6020) Permanent AF (n=5117) Age 75 yrs, % Mean (SD) 68.5 (11.7) 69.1 (10.9) 72.6 (10.6) Female, % BMI 30 kg/m 2, % NYHA Class III IV CHF, % ACS, % LVEF <40%, % Prior stroke/tia, % Carotid occlusive disease, % Cohorts 1 4, N=28,628

13 Antithrombotic treatment patterns VKA±AP FXaI±AP DTI±AP Proportion of patients, % ,1 26,8 7,0 13,1 38,0 9,0 8,3 19,7 19,7 7,7 5,8 9,8 9,0 53,9 57,1 0 Paroxysmal AF (n=10,473) Persistent AF (n=6020) Permanent AF (n=5117) AP, antiplatelet; CHF, congestive heart failure; DTI, direct thrombin inhibitor; FXaI, factor Xa inhibitor; VKA, vitamin K antagonists Cohorts 1 4, N=28,628

14 Adjusted HRs for 2-year clinical outcomes according to type of AF HRs were adjusted for anticoagulant treatment and the following baseline factors: age, gender, race, smoking, diabetes, hypertension, stroke/transient ischaemic attack/systemic embolism, history of bleeding, cardiac failure, vascular disease, moderate-to-severe CKD, and heavy alcohol consumption (only for major bleeding)

15 Conclusions Patients with paroxysmal AF were less likely to be prescribed AC therapy (with or without AP therapy) than those with persistent or permanent AF Persistent and permanent AF were associated with higher mortality risk compared with paroxysmal AF, but had similar adjusted risks of stroke/se and major bleeding during 2 years of follow-up

16 Clinical implications The finding of similar adjusted stroke rates in patients with paroxysmal AF as compared to those with persistent or permanent AF has several implications: It emphasises the need for early detection of silent and unnoticed paroxysmal AF It underscores the recommendation to apply the same stroke prevention strategies to paroxysmal AF as to the other types of AF

17 Use of anticoagulants in AF patients with renal impairment

18 ESRD

Renal impairment is common among AF patients and is associated with increased risk of

Anticoagulation Clinic (n=5,039; 1997 2005) 1 AURICULA Registry, Malmö (n=2,603; 2007

2% 80 Using Different egfr Cut-off Values % of Patients 60 40 30.

3% >60 30 60 15 30 0 15 <60 <45 <30 egfr, ml/min/1.73 m 2 (MDRD formula) egfr, ml/min/1.

19 Renal impairment is common among AF patients and is associated with increased risk of adverse outcomes Distribution of patients with AF according to renal function Leiden Anticoagulation Clinic (n=5,039; ) 1 AURICULA Registry, Malmö (n=2,603; ) % 34.2% 80 Using Different egfr Cut-off Values % of Patients % % of Patients % % 0.8% % 4.3% > <60 <45 <30 egfr, ml/min/1.73 m 2 (MDRD formula) egfr, ml/min/1.73 m 2 (MDRD formula) egfr: estimated glomerular filtration rate; MDRD: modification of diet in renal disease. 1 Kooiman et al. J Thromb Haemost 2011;9:1652-3; 2 Jönsson et al. Thromb Res 2011;128:341-5.

20 Chronic kidney disease increases the risk of stroke, bleeding, MI and all-cause death in AF patients Risk of Events in NVAF Patients with Non-end-stage CKD (n=3,587) or with CKD Requiring Renal Replacement Therapy (n=901) vs. NVAF Patients with No Renal Disease (n=127,884) Danish Registry ( ) Reference: Patients with no renal disease HR (95% CI)* Stroke or Systemic Thromboembolism Non-end-stage CKD 1.49 (1.38; 1.59) CKD requiring renal replacement therapy 1.83 (1.57; 2.14) Bleeding Non-end-stage CKD 2.24 (2.10; 2.38) CKD requiring renal replacement therapy 2.70 (2.38; 3.07) Myocardial Infarction Non-end-stage CKD 2.00 (1.86; 2.16) CKD requiring renal replacement therapy 3.00 (2.58; 3.50) Death from Any Cause Non-end-stage CKD 2.37 (2.30; 2.44) CKD requiring renal replacement therapy 3.35 (3.13; 3.58) *Adjusted for baseline characteristics. Adapted from Olesen et al. N Engl J Med 2012;367:

21 Extent of renal excretion varies between the different NOACs which could influence their safety in patients with impaired renal function Heidbuchel et al. Europace 2013; 15: (EHRA guidelines)

22 Chang M et al. Apixaban pharmacokinetics and pharmacodynamics in subjects with renal impairment. Poster presented at ACCP 2012 Eliquis SPC 2013 Eliquis EMA assessment report Sept 2012 Apixaban Concentration Time Profiles Concentration (ng/ml) 1000 Apixaban concentration is fairly similar regardless of renal impairment level Severe renal impairment Moderate renal impairment Mild renal impairment Normal renal function Time (h)

23 Apixaban is the only NOAC to demonstrate superiority vs. warfarin in stroke/se prevention, reduction of major bleeding and all cause mortality (ARISTOTLE) Superior stroke/systemic embolism prevention 21% RRR p=0.01 Superior profile in reducing major bleeding 31% RRR p<0.001 Superior reduction in all-cause mortality 11% RRR p= ,0% Event rate (%/year) 4,0% 3,0% 2,0% 1,0% 1,60% 265/9081 1,27% 212/9120 3,09% 462/9052 2,13% 327/9088 3,94% 669/9081 3,52% 603/9120 0,0% Primary efficacy endpoint Primary safety endpoint Key secondary endpoint Warfarin (target INR ) 1 Adapted from Granger CB et al. N Engl J Med 2011;365: Apixaban

24 ARISTOTLE: The benefits of Apixaban vs. warfarin were maintained in patients with impaired renal function; these patients appeared to show the greatest reduction in major bleeding vs. warfarin Apixaban %/yr (n) Warfarin %/yr (n) Hazard Ratio (95% CI) P Value for Interaction Stroke/SE Cockcroft-Gault (egfr ml/min) > (70) 1.12 (79) > (87) 1.69 (116) (54) 2.67 (69) Major Bleeding Cockcroft-Gault (egfr ml/min) > (96) 1.84 (119) > (157) 3.21 (199) (73) 6.44 (142) NOTE: Patients with calculated creatinine clearance of <25 ml /minute were excluded from ARISTOTLE egfr=estimated glomerular filtration rate. Hohnloser SH et al. Eur Heart J. 2012;: Apixaban Better Warfarin Better

25 ARISTOTLE: In elderly patients ( 75 years) the benefits of Apixaban vs. warfarin were consistent across the range of estimated glomerular filtration rate No. of patients 75 years Apixaban %/yr (n) Warfarin %/yr (n) Hazard Ratio (95% CI) P Value for Interaction Stroke/SE Cockcroft-Gault (egfr ml/min) > (8) 2.16 (11) > (39) 1.70 (45) > (28) 2.69 (44) (3) 5.57 (9) Major Bleeding Cockcroft-Gault (egfr ml/min) > (11) 3.39 (15) > (85) 4.45 (104) > (47) 6.27 (87) (7) 13.4 (17) NOTE: Patients with calculated creatinine clearance of <25 ml /minute were excluded from ARISTOTLE 0,0625 0,125 0,25 0,5 1 2 egfr=estimated glomerular filtration rate. Halvorsen S et al. European Heart J doi: /eurheartj/ehu046 epub February Apixaban Better Warfarin Better

26 AVERROES: The efficacy and safety of Apixaban vs ASA was maintained in patients with NVAF and moderate renal impairment 1 Stroke / SE Apixaban ASA % / yr (No. of events / No. of patients) egfr 60 ml/min 1.7% (34/1917) 2.8% (60/1911) egfr ml/min 1.8% (17/857) 5.6% (51/840) Major Bleeding egfr 60 ml/min 0.9% (19/1917) 0.8% (18/1911) egfr ml 2.5% (24/857) 2.2% (20/840) All-cause mortality egfr 60 ml/min 2.3% (49/1917) 3.3% (71/1911) egfr ml/min 6.2% (59/857) 7.1% (66/840) NOTE: Patients with calculated creatinine clearance of <25 ml /minute were excluded from AVERROES Hazard Ratio (95% CI) Apixaban better ASA better 2.0 P value Interaction: 0.10 Interaction: 0.82 Interaction: 0.39 Event rates for 70 patients with stage IV CKD assigned to apixaban (n =31) versus aspirin (n =39) primary events : 0% per year (n= 0) vs.5% per year (n= 2); major hemorrhage: 3.0% per year (n =1) vs. 2.5% per year (n = 1); Death: 9.1% per year (n =3) vs. 7.4% per year (n =3). egfr, estimated glomerular filtration rate. egfr ml/min/1.73 m 2 : stage III chronic kidney disease (CKD); 1 Adapted from Eikelboom JW et al. J Stroke Cerebrovasc Dis 2012;21:

27 Dabigatran 110mg: Outcomes of RE-LY according to renal function 1 Dabigatran Warfarin 110 mg BID %/yr (no. of events) Hazard ratio (95% CI) P value for interaction Stroke / SE egfr 80 ml/min 0.88 (35) 1.05 (41) egfr 50-<80 ml/min 1.69 (94) 1.83 (103) egfr <50 ml/min 2.32 (52) 2.70 (57) Major bleeding egfr 80 ml/min 1.48 (59) 2.43 (95) egfr 50-<80 ml/min 2.84 (158) 3.70 (209) egfr <50 ml/min 5.45 (122) 5.49 (116) NOTE: Patients with calculated creatinine clearance of <30 ml /minute were excluded from RE-LY GFR: glomerular filtration rate, BID: twice-daily GFR estimation according to Cockcroft-Gault method Dabigatran better Warfarin better 1. Hijazi et al. Circulation Dec 9. [Epub ahead of print]

28 Dabigatran 150mg: Outcomes of RE-LY according to renal function 1 Dabigatran Warfarin 150 mg BID %/yr (no. of events) Hazard ratio (95% CI) P value for interaction Stroke / SE egfr 80 ml/min 0.71 (28) 1.05 (41) egfr 50-<80 ml/min 1.25 (70) 1.83 (103) egfr <50 ml/min 1.53 (36) 2.70 (57) Major Bleeding egfr 80 ml/min 2.04 (81) 2.43 (95) egfr 50-<80 ml/min 3.35 (188) 3.70 (209) egfr <50 ml/min 5.50 (129) 5.49 (116) NOTE: Patients with calculated creatinine clearance of <30 ml /minute were excluded from RE-LY GFR: glomerular filtration rate, BID: twice-daily GFR estimation according to Cockcroft-Gault method Dabigatran better Warfarin better 1. Hijazi et al. Circulation Dec 9. [Epub ahead of print]

29 Rivaroxaban: Outcomes of ROCKET-AF according to renal function 1 Rivaroxaban Warfarin P value for Event rates per 100 patientyears of follow-up Hazard ratio (95% CI) interaction Stroke / SE 0.76 CrCl 50 ml/min * CrCl ml/min Major bleeding 0.48 CrCl 50 ml/min CrCl ml/min Rivaroxaban better Warfarin better NOTE: Patients with calculated creatinine clearance of <30 ml /minute were excluded from ROCKET-AF 1. Fox et al. Eur Heart J. 2011;32:

30 EHRA Practical Guide (2013) Apixaban demonstrated a lower overall rate of major bleeding compared to VKA, and [ ] the increase in the rate of bleeding by renal dysfunction was significantly less than with VKA A similar benefit/risk ratio of NOACs vs. VKAs was seen with a reduced dose rivaroxaban (15 mg qd) in patients with renal impairment (CrCl <50 ml/min) [ ] dabigatran, which is primarily cleared renally, may not be the NOAC of first choice in patients with known CKD, especially stage III or higher Heidbuchel et al. Europace (2013) 15,

31 Stroke/SE and major bleeding risk for subgroups of patients with stage III CKD* from trials comparing NOACs and warfarin Stroke/SE Dabigatran 110 mg bid 0.77 ( ) Dabigatran 150 mg bid Rivaroxaban 15 mg qd Apixaban 2.5/5.0 mg bid 0.55 ( ) 0.86 ( ) 0.79 ( ) Major bleeding Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 15 mg qd Apixaban 2.5/5.0 mg bid 0.99 ( ) 1.03 ( ) 0.95 ( ) 0.50 ( ) New oral anticoagulant better Warfarin better New oral anticoagulant better Warfarin better BID, twice daily; CI, confidence interval CKD chronic kidney disease; qd, once daily *Stage III CKD: estimated creatinine clearances ml/min for dabigatran and rivaroxaban; ml/min for apixaban. The width of the 90% CIs are estimated from published figures for dabigatran Adapted from Hart et al. Canadian Journal of Cardiology 2013;29:S71-S78

32 No dose adjustment of Apixaban is required in patients with mild or moderate impairment only 1 The recommended dose of apixaban is 5 mg taken orally twice daily (BD), swallowed with water, with or without food. Impaired renal function Mild or moderate renal impairment Severe renal impairment (creatinine clearance ml/min) Dialysis Renal failure (creatinine clearance <15 ml/min) SmPC recommendation No dose adjustment required The standard dose reduction to 2.5 mg BD for two or more of the following criteria applies: age 80 years; weight 60 kg; serum creatinine level 1.5 mg/dl (133 µmol/l) Dose reduction to 2.5 mg BD Not recommended Not recommended Note: ESC guidelines do not recommend the use of NOACs in patients with severe renal impairment (CrCl < 30 ml/min) 2 Rivaroxaban requires a dose reduction to 15 mg QD for moderate/severe renal impairment, and is not recommended in renal failure (Cr Cl<15 ml/min) 3 For dabigatran, the SMPC recommendation is that for moderate renal impairment, a dose of 110 mg BD be considered. Dabigatran is contraindicated in severe renal impairment (Cr Cl<30 ml/min) 4 1 Apixaban SmPC. Accessed Jan Camm AJ et al. European Heart Journal 2012;33: Rivaroxaban SmPC accessed Jan Dabigatran SmPC accessed Jan 2014

33 Recommendations in Guidelines?

EHRA guide Practical guidance on how to utilize the NOAC s The focus is on typical situations and challenges faced in clinical practice, such as - renal dysfunction -

35 EHRA guide Practical guidance on how to utilize the NOAC s The focus is on typical situations and challenges faced in clinical practice, such as - renal dysfunction - bleeding events - need for surgery - concomitant CHD - stroke despite adequate SPAF therapy European Heart Journal doi: /eurheartj/ehs253

36 Patients with chronic kidney disease Estimated t ½ and AUC NOAC plasma concentrations compared to healthy controls Heidbuchel et al.: EHRA Practice Guide 2015 Europace doi: /europace/euv309

NOACs in renal dysfunction Practical recommendations for dosing in chronic kidney disease Dabigatran Apixaban Edoxaban * Rivaroxaban When CrCl 30 49 ml/min, 150 mg CrCl 15 29 ml/min: 2.

5 mg/dl in or recommended (GL update)1 combination with age 80 Note: 75 mg BID approved in US years or weight 60 kg only# (SmPC) or with other yellow -If CrCl 15 30 ml/min factor: 2.

37 NOACs in renal dysfunction Practical recommendations for dosing in chronic kidney disease Dabigatran Apixaban Edoxaban * Rivaroxaban When CrCl ml/min, 150 mg CrCl ml/min: 2.5 mg not available 15 mg OD when CrCl BID is possible (SmPC) but 110 mg BID is possible BID if high risk of bleeding (SmPC) Serum creatinine 1.5 mg/dl in or recommended (GL update)1 combination with age 80 Note: 75 mg BID approved in US years or weight 60 kg only# (SmPC) or with other yellow -If CrCl ml/min factor: 2.5 mg BID ml/min -If CrCl ml/min -And other orange factor (e.g. verapamil) *No EMA approval yet. Needs update after finalisation of SmPC; #No EMA indication. FDA recommendation based on pharmacokinetics. Carefully consider benefits and risks of this approach. Note that 75 mg capsules are not available in Europe for AF indication; Australian prescribing information Disclaimer: All NOACS should always be used in accordance with local prescribing authorization, which may or may not be the same as in Europe and the US 1. Camm et al, Eur Heart J 2012;33: ; Heidbuchel et al, Europace 2013;15: ; Heidbuchel et al, Eur Heart J 2013;34:

38 Bleeding risk with CrCL < 50 ml/min 45 J Am Soc Nephrol. 2014; 25:

40 Summary and Conclusions Patients with AF and moderate to severe renal impairment are at increased risk of stroke and also have an increased bleeding risk Studies indicate this population is undertreated Dabigatran, Rivaroxaban and apixaban: The efficacy and safety findings vs. warfarin in the overall population are maintained in patients with moderate renal impairment Also in the elderly, the benefits of apixaban vs. warfarin were consistent across the range of egfr The data suggest that apixaban may be particularly suited to address the unmet need for a more effective and safe stroke prevention in patients with AF and renal dysfunction.

41 Thank you for your attention 41

DIRECT ORAL ANTICOAGULANTS

2017 Cardiovascular Symposium DIRECT ORAL ANTICOAGULANTS ERNESTO UMAÑA, MD, FACC ORAL ANTICOAGULANTS Vitamin K Antagonists (VKAs): Warfarin Non Vitamin K Antagonists Direct oral anticoagulants Novel Oral