1. The use of ELIQUIS® (apixaban) in various clinical populations
Full Prescribing Information is provided at the end of this presentation
EUAPI581c, April 2014
15.ELI.22.7
43NL15PR

2. ELIQUIS® (apixaban) has demonstrated superiority vs warfarin in the following three key outcomes1
Superior stroke / systemic embolism prevention
Superior profile in reducing
major bleeding
Superior reduction in
all-cause mortality
21% RRR p=0.01
31% RRR p<0.001
11% RRR p=0.047
3.94%
669/9,081
3.52%
603/9,120
3.09%
462/9,052
Apixaban was superior to warfarin in reducing the rates of the three key outcomes of the ARISTOTLE study, i.e., stroke or systemic embolism, major bleeding and death from any cause.
Abbreviations
RRR: Relative risk reduction.
References
Granger CB et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:
2.13%
327/9,088
1.60%
265/9,081
1.27%
212/9,120
Median duration of follow-up 1.8 years
eGFR: estimated glomerular filtration rate; MDRD: modification of diet in renal disease; RRR: relative risk reduction; INR: international normalised ratio
Adapted from Granger et al. N Engl J Med 2011;365:981–92.
1. Granger et al. N Engl J Med 2011;365:981–92.

3. Introduction on sub analyses
The overall outcomes of a study provide the best evidence for the direction of the effect of two interventions in an RCT
Subgroup analyses assess the consistency of the outcomes in a subgroup with the overall trial results
Tests for interaction between treatment and subgroup are key to assess the statistical relevance of the outcome in a subgroup1
If p-value for interaction is not significant (p>0.05), the results in the subgroup can be considered as consistent with the results in the overall population1
RCT: randomized controlled trial
1. Rothwell. Lancet 2005;365:176–86.

4. The efficacy and major bleeding results of ELIQUIS® vs warfarin in key subgroups in ARISTOTLE were consistent with the overall trial results1
ELIQUIS® (apixaban) has clinical benefits over warfarin
that are maintained irrespective of renal function2
that are maintained irrespective of age3
that are consistent across patient risk of stroke and bleeding as assessed by the CHADS2, CHA2DS2-VASc, and HAS-BLED risk scores4
Abbreviations
CHADS2: assigns one point each for congestive heart failure (C), high blood pressure (H), age 75 or older (A), and diabetes (D), and two points for a previous stroke (S2) or transient ischaemic attack
CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex category (female) HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; ICH: Intracranial Haemorrhage; INR: International normalised ratio
1. Apixaban SmPC. Available at 2. Hohnloser et al. Eur Heart J 2012;22:2821–30; 3. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print]; 4. Lopes et al. Lancet 2012;380:1749–58.

5. Chronic kidney disease is common among AF patients
Leiden Anticoagulation Clinic (n=5,039; 1997–2005)1
40.4%
16.3%
% of Patients
100 80 60 40 20
4.3%
<60
<45
<30
eGFR, mL/min/1.73 m2 (MDRD formula)
AURICULA Registry, Malmö (n=2,603; 2007–2008)2
Adapted from Jönsson et al. Thromb Res 2011;128:341–5.
100 80
65.8%
34.2% 60
% of Patients
In a multicenter retrospective cohort study the medical charts of AF patients from the Leiden anticoagulation clinic starting anticoagulant therapy between January 1997 and April 2005 were scrutinised for creatinine levels. Patients were included if serum creatinine values were available within 6 months before or after the diagnosis of AF (n=5039).1 The eGFR was calculated using the abbreviated MDRD formula because our study population was comprised of elderly patients, in whom the MDRD is more accurate in estimating the GFR in the lower ranges than the Cockroft–Gault formula. The incidence of chronic kidney disease in AF patients was 34.2%.1
Using AURICULA, a Swedish registry for anticoagulation, eGFR was investigated in AF patients on warfarin treatment (n=2,603). The study group was compared with a healthy sample from the population (n=2,261). Two different creatinine prediction equations were used for calculating eGFR: the Lund-Malmö and MDRD Study equation. The fraction of AF patients with eGFR <30, <45 and <60 ml/min/1.73 m2 were 4.3%, 16.3% and 40.4% with the MDRD equation, respectively, and significantly higher than corresponding values in the reference population2.
Abbreviations
AF: Atrial fibrillation
eGFR: estimated glomerular filtration rate
MDRD: Modification of diet in renal disease
References
1. Kooiman J, et al. Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs. J Thromb Haemost 2011;9:
2. Jönsson KM, et al. Glomerular filtration rate in patients with atrial fibrillation on warfarin treatment: a subgroup analysis from the AURICULA registry in Sweden. Thromb Res 2011;128:341-5. 40
30.9% 20
2.5%
0.8%
>60
30–60
15–30
0–15
eGFR, mL/min/1.73 m2 (MDRD formula)
Adapted from Kooiman et al. J Thromb Haemost 2011;9:1652–3.
AF: atrial fibrillation
1. Kooiman et al. J Thromb Haemost 2011;9:1652–3;
2. Jönsson et al. Thromb Res 2011;128:341–5.

6. Reference: Patients with no renal disease
Chronic kidney disease increases the risk of stroke, bleeding, MI and all-cause death in AF patients1
Risk of Events in NVAF Patients with Non-end-stage CKD (n=3,587) or with CKD Requiring Renal Replacement Therapy (n=901) Compared with NVAF Patients with No Renal Disease (n=127,884) – Danish Registry (1997–2008)
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
2.24 (2.10; 2.38)
2.70 (2.38; 3.07)
Myocardial infarction
2.00 (1.86; 2.16)
3.00 (2.58; 3.50)
Death from any cause
2.37 (2.30; 2.44)
3.35 (3.13; 3.58)
Using Danish national registries, all patients discharged from the hospital with a diagnosis of non-valvular atrial fibrillation between 1997 and 2008 were identified. The risk of stroke or systemic thromboembolism and bleeding associated with non-end-stage chronic kidney disease and with end-stage chronic kidney disease (i.e., disease requiring renal-replacement therapy) was estimated with the use of time-dependent Cox regression analyses.
Of 132,372 patients included in the analysis, 3587 (2.7%) had non–end-stage chronic kidney disease and 901 (0.7%) required renal-replacement therapy at the time of inclusion.
As compared with patients who did not have renal disease, patients with non-end-stage chronic kidney disease had an increased risk of stroke or systemic thromboembolism (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to 1.59; P<0.001), as did those requiring renal-replacement therapy (hazard ratio, 1.83; 95% CI, 1.57 to 2.14; P<0.001). The risk of bleeding, myocardial infarction or all-cause death was also increased among patients who had non-end-stage chronic kidney disease or required renal replacement therapy.
Abbreviations
AF: atrial fibrillation
CKD: chronic kidney disease
NVAF: non-valvular atrial fibrillation
References
Olesen JB, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:
1.00
1.5
2.0
2.5
3.0
3.5
*Adjusted for baseline characteristics
MI: myocardial infarction; NVAF: non-valvular atrial fibrillation; CKD: chronic kidney disease; HR: hazard ratio; CI: confidence interval
Adapted from Olesen et al. N Engl J Med 2012;367:
1. Olesen et al. N Engl J Med 2012;367:625–35.

7. Imagine this patient*:
Question 1
Imagine this patient*:
Male
Newly diagnosed with persistent NVAF
Age: 66 years
Hypertension
Creatinine clearance 45 ml/min
Would you treat this patient with ELIQUIS® (apixaban)?
Yes No
*Patient is fictitious

8. ELIQUIS® (apixaban) is eliminated from the body via multiple routes
Only ~27% of apixaban is eliminated by the kidneys1
Renal elimination (27%)
Direct intestinal excretion
Biliary elimination
Liver metabolism
References
Apixaban, SmPC 2012.
In ARISTOTLE, the classification according to Cockcroft-Gault was the following:2
7,518 patients (42%) had an eGFR of >80 mL/min
7,587 patients (42%) had an eGFR of >50 – 80 mL/min
3,017 patients (15%) had an eGFR of ≤50 mL/min
Patients with severe renal insufficiency (calculated creatinine clearance of <25 mL/min) were excluded from the study2
1. Apixaban SmPC. Available at
2. Hohnloser et al. Eur Heart J 2012;22:2821–30.

9. p value for interaction
ELIQUIS® (apixaban) was more effective and was associated with less major bleeding events than warfarin irrespective of renal function1
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction
%/yr (No. of Events)
Stroke / SE
0.705
eGFR >80 mL/min1
0.99% (70)
1.12% (79)
eGFR >50-80 mL/min2
1.24% (87)
1.69% (116)
eGFR ≤50 mL/min3
2.11% (54)
2.67% (69)
Major bleeding
0.03
1.46% (96)
1.84% (119)
2.45% (157)
3.21% (199)
3.21% (73)
6.44% (142)
All-cause death
0.627
2.33% (169)
2.71% (195)
3.41% (244)
3.56% (251)
7.12% (188)
8.30% (221)
0.25
0.5
1.00
2.0
Apixaban Better
Warfarin Better
Apixaban was more effective than warfarin in preventing stroke or systemic embolism and reducing mortality irrespective of renal function. These results were consistent, regardless of methods for GFR estimation.
In addition, apixaban was associated with less major bleeding events across all ranges of eGFRs. The relative risk reduction in major bleeding was greater in patients with an eGFR of ≤50 mL/min using Cockcroft-Gault (HR 0.50; 95% CI ), interaction p=0.005) or CKD-EPI equations (HR 0.48; 95% CI ), interaction p=0.003], indicating that patients with impaired renal function seemed to have the greatest reduction in major bleeding with apixaban.
Abbreviations
AF: Atrial fibrillation
CI: Confidence interval
CKD-EPI: chronic kidney disease epidemiology collaboration method
eGFR: estimated glomerular filtration rate
HR: Hazard ratio
References
Hohnloser SH, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012; e-published August 29, doi: /eurheartj/ehs274.
1n=7,518 (41%); 2n=7,587 (42%); 3n=3,017 (17%)
Results were consistent regardless of methods for GFR estimation
Adapted from Hohnloser et al. Eur Heart J 2012;22:2821–30.
1. Hohnloser et al. Eur Heart J 2012;22:2821–30.

10. Stroke or Systemic Embolism
ELIQUIS® (apixaban) was more effective & was associated with less major bleeding events than warfarin in patients with impaired renal function1
Stroke or Systemic Embolism
Major Bleeding
p value for interaction: 0.57
p value for interaction: 0.005
1-year Event Rate
1-year Event Rate
Apixaban was more effective than warfarin in preventing stroke or systemic embolism irrespective of renal function. In addition, apixaban was associated with less major bleeding events across all ranges of eGFRs.
Abbreviations
AF: Atrial fibrillation
CI: Confidence interval
eGFR: estimated glomerular filtration rate
References
Hohnloser SH, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012; e-published August 29, doi: /eurheartj/ehs274.
Baseline Cockcroft-Gault eGFR mL/min
Baseline Cockcroft-Gault eGFR mL/min
Warfarin
95% CI
Apixaban
95% CI
Adapted from Hohnloser et al. Eur Heart J 2012;22:
1. Hohnloser et al. Eur Heart J 2012;22:2821–30.

11. How to use ELIQUIS® (apixaban) in patients with renal impairment
The recommended dose of ELIQUIS® (apixaban) is 5 mg taken orally twice-daily, swallowed with water, with or without food1
Impaired renal function SmPC recommendation
Mild or moderate renal impairment
No dose adjustment required unless the patient fulfils criteria for dose reduction* to 2.5 mg twice-daily based on age, body weight and/or serum creatinine1
Severe renal impairment (creatinine clearance mL/min)
Dose reduction to 2.5 mg twice-daily1
Dialysis
Not recommended1
Renal failure
(creatinine clearance <15 mL/min)
As there is no clinical experience in patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, apixaban is not recommended in these patients.
No dose adjustment is necessary in patients with mild or moderate renal impairment.
Patients with serum creatinine ≥ 1.5 mg/dL (133 micromol/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of apixaban 2.5 mg twice daily.
Patients with exclusive criteria of severe renal impairment (creatinine clearance mL/min) should also receive the lower dose of apixaban 2.5 mg twice daily.
Prior to initiating apixaban, liver function testing should be performed.
Abbreviations
BD: Twice daily
ALT: Alanine aminotransferase
AST: Aspartate aminotransferase
ULN: Upper limit of normal
References
Apixaban, SmPC 2012.
*The criteria for dose reduction are two or more of the following:1
age ≥80 years,
weight ≤60 kg
serum creatinine level ≥1.5 mg/dL (133 µmol/L)
1. Apixaban SmPC. Available at

12. Imagine this patient*:
Question 2
Imagine this patient*:
Female
Permanent NVAF: was on aspirin and wants to be put on OAC
Age: 75 years
Hypertension
Creatinine clearance 75 ml/min
Would you treat this patient with ELIQUIS® (apixaban)?
Yes No
*Patient is fictitious

13. Age distribution in ARISTOTLE1
The risk of stroke in atrial fibrillation increases with age1
Warfarin is particularly underused in elderly patients2,3
39%
Patient number
30%
31%
n = 18,201
Range yrs
2,436 patients (13%) were ≥80 yrs
Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J 2014.Feb 20 [epub ahead of print]; 2. Hylek et al. Circulation 2007;115:2689–96;
3. Waldo et al. J Am Coll Cardiol 2005;46:1729–36.

14. In the ARISTOTLE trial, age was a risk factor for various efficacy and safety outcomes1
Stroke /SE
Death
Efficacy and Safety Outcomes According to Age Category
Shown are the primary efficacy and safety outcomes according to age category.
Based on the ARISTOTLE population, with increased age there is increased risk of stroke, death, intracranial hemorrhage.
Major bleeding
ICH
<65
65–74
≥75
ICH: Intracranial haemhorrage; SE: systemic embolism
Adapted from Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

15. Efficacy and safety outcomes according to age1
A. Primary Efficacy Outcome: Stroke and Systemic Embolism
Subgroup
No. of patients
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction
No. of events (%/yr)
All patients
18,201
212 (1.27)
265 (1.60)
Age
0.11*
< 65 yr
5,471
51 (1.00)
44 (0.86)
65 to < 75 yr
7,052
82 (1.25)
112 (1.73)
≥ 75 yr
5,678
79 (1.56)
109 (2.19)
0.25
0.50
1.00
2.00
Apixaban better
Warfarin better
B. Major Bleeding
Subgroup
No. of patients
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction
No. of events (%/yr)
All patients
18,140
327 (2.13)
462 (3.09)
Age
0.63*
< 65 yr
5,455
56 (1.17)
72 (1.51)
65 to < 75 yr
7,030
120 (1.99)
166 (2.82)
≥ 75 yr
5,655
151 (3.33)
224 (5.19)
0.25
0.50
1.00
2.00
Apixaban better
Warfarin better
*Interaction p-values based on continuous age
Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].

16. ELIQUIS® (apixaban) vs. warfarin in patients ≥80 years1
ARISTOTLE
ELIQUIS® (apixaban) vs. warfarin in patients ≥80 years1
Apixaban vs Warfarin in Patients ≥80 vs <80 Years
Shown is a comparison of bleeding, primary efficacy, and all-cause mortality results in patients who were <80 years old and patients who were ≥80 years old in the ARISTOTLE trial.
2,436 (13%) patients were ≥80 years of age in ARISTOTLE
Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

17. Stroke or systemic embolism and major bleeding in patients ≥75 years
Stroke or systemic embolism and major bleeding in patients ≥75 years* in relation to apixaban dose1
Subgroup
No. of patients
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction**
No. of events (%/yr)
Stroke or systemic embolism (n=5,678)
0.52
2.5 mg twice daily
790
11 (1.65)
20 (3.13)
5 mg twice daily
4888
68 (1.54)
89 (2.05)
Major bleeding (n=5,655)
0.48
786
20 (3.29)
35 (6.54)
4869
131 (3.21)
189 (5.00)
0.25
0.50
1.00
2.00
Apixaban better
Warfarin better
Apixaban vs Warfarin in Patients ≥80 vs <80 Years
Shown is a comparison of bleeding, primary efficacy, and all-cause mortality results in patients who were <80 years old and patients who were ≥80 years old in the ARISTOTLE trial.
* A reduced dose of 2.5 mg twice-daily or placebo were administered to a total of 831 patients; 790 of these patients were ≥75 years
** Interaction among treatment, dose, and age based on randomized or treated population
Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

18. p value for interaction*
Primary outcomes in the elderly (≥75 years) in relation to renal function1
Subgroup
No. of patients ≥75 years
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction*
No. of events (%/yr)
Stroke or systemic embolism
0.4954
eGFR >80 mL/min
597
8 (1.41)
11 (2.16)
0.65 (0.26, 1.62)
eGFR >50-80 mL/min
2,922
39 (1.45)
45 (1.70)
0.86 (0.56, 1.32)
eGFR >30-50 mL/min
1,906
28 (1.74)
44 (2.69)
0.65 (0.40, 1.04)
eGFR ≤30 mL/min
222
3 (1.70)
9 (5.57)
0.29 (0.08, 1.07)
Major bleeding
0.1635
596
11 (2.10)
15 (3.39)
0.6 (0.28, 1.32)
2,912
85 (3.53)
104 (4.45)
0.79 (0.60, 1.06)
1,898
47 (3.32)
87 (6.27)
0.53 (0.37, 0.76)
221
7 (4.64)
17 (13.4)
0.35 (0.14, 0.86)
Apixaban vs Warfarin in Patients ≥80 vs <80 Years
Shown is a comparison of bleeding, primary efficacy, and all-cause mortality results in patients who were <80 years old and patients who were ≥80 years old in the ARISTOTLE trial.
eGFRs according to Cockcroft-Gault method
* Interaction P-values are based on categorical eGFR
Adapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print].
1. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print].
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

19. Imagine this patient*:
Question 3
Imagine this patient*:
68 year old male
Newly diagnosed with asymptomatic, paroxysmal NVAF
Hypertension: blood pressure 145 / 92 mmHg
Anaemia
Regularly uses ibuprofen for back pain
CHADS2 score = 1; CHA2DS2-VASc score = 2; HAS-BLED score = 3
Would you treat this patient with ELIQUIS® (apixaban)?
Yes No
*Patient is fictitious

20. Many stroke risk factors are also risk factors for bleeding
Higher stroke risk = higher bleeding risk (overlapping factors)
The relationship between stroke risk and bleeding risk complicates the evaluation of benefit-risk
CHA2DS2-VASc criteria1
Congestive heart failure/LV dysfunction
Hypertension
Aged ≥75 years 
Diabetes mellitus
Stroke/TIA/TE
Vascular disease (prior MI, PAD, or aortic plaque)
Aged years
Sex category (i.e. female gender)
HAS-BLED criteria2
Hypertension
Abnormal renal / liver function
Stroke 
Bleeding
Labile INRs
Elderly (above 65 years)
Drugs or alcohol
LV: left ventricle; TE: thromboembolism; TIA: transient ischemic attack; VKA: vitamin K antagonist; PAD: peripheral arterial disease
1. Lip et al. Chest 2010;137:263–72;
2. Pisters et al. Chest 2010;138:1093–100.

21. ARISTOTLE enrolled patients across a broad range of stroke and bleeding risk1
Patients with non-valvular AF and at least 1 risk factor for stroke were enrolled1
CHADS2 and HAS-BLED scores were correlated in ARISTOTLE:2
HAS-BLED score
0-1 2 ≥3
Total
CHADS2
score 1
3,203 (18%)
2,051 (11%)
929 (5%)
6,183 (34%)
2,807 (15%)
2,461 (14%)
1,248 (7%)
6,516 (36%)
1,451 (8%)
2,056 (11%)
1,995 (11%)
5,502 (30%)
7,461 (41%)
6,568 (36%)
4,172 (23%)
18,201 (100%)
Adapted from Lopes et al. Lancet 2012;380:1749–58.
1. Granger et al. N Engl J Med 2011;365:981–92;
2. Lopes et al. Lancet 2012;380:1749–58.

22. Stroke or systemic embolism according to baseline risk scores1
ARISTOTLE
Stroke or systemic embolism according to baseline risk scores1
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value
No. of patients
%/yr (No. of events)
CHADS Interaction: 1
6,183
0.74% (44)
0.87% (51) 2
6,516
1.24% (74)
1.37% (82) ≥3
5,502
1.95% (94)
2.80% (132)
CHA2DS2VASc Interaction:
1,604
0.62% (10)
0.53% (8)
3,771
0.85% (30)
0.67% (24)
12,826
1.48% (172)
2.03% (233)
HAS-BLED Interaction:
0–1
7,461
0.92% (65)
1.14% (79)
6,568
1.39% (83)
1.81% (109)
4,172
1.73% (64)
2.14% (77)
Overall
18,201
1.27% (212)
1.60% (265)
0.0144
Apixaban vs Warfarin in Patients ≥80 vs <80 Years
Shown is a comparison of bleeding, primary efficacy, and all-cause mortality results in patients who were <80 years old and patients who were ≥80 years old in the ARISTOTLE trial.
0.25
0.50
1.00
2.00
4.00
Favours apixaban
Favours warfarin
Adapted from Lopes et al. Lancet 2012;380:1749–58.
1. Lopes et al. Lancet 2012;380:1749–58.
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

23. Major bleeding according to baseline risk scores1
ARISTOTLE
Major bleeding according to baseline risk scores1
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value
No. of patients
%/yr (No. of events)
CHADS2
Interaction: 1
6,169
1.38% (76)
2.34% (126) 2
6,492
2.30% (125)
3.03% (163) ≥3
5,479
2.88% (126)
4.15% (173)
CHA2DS2VASc
Interaction:
1,602
0.80% (12)
1.21% (17)
3,759
1.26% (42)
2.48% (82)
12,779
2.60% (273)
3.55% (363)
HAS-BLED
Interaction:
0–1
7,433
1.36% (89)
2.16% (137)
6,544
2.25% (123)
3.23% (175)
4,163
3.46% (115)
4.70% (150)
Overall
18,140
2.13% (327)
3.09% (462)
<0.0001
0.25
0.50
1.00
2.00
4.00
Favours apixaban
Favours warfarin
Adapted from Lopes et al. Lancet 2012;380:1749–58.
1. Lopes et al. Lancet 2012;380:1749–58.
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

24. Intracranial bleeding according to baseline risk scores1
ARISTOTLE
Intracranial bleeding according to baseline risk scores1
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value
No. of patients
%/yr (No. of events)
CHADS Interaction: 1
6,169
0.27% (15)
0.60% (33) 2
6,492
0.38% (21)
0.64% (35) ≥3
5,479
0.36% (16)
1.27% (54)
CHA2DS2VASc Interaction:
1,602
0.20% (3)
0.35% (5)
3,759
0.27% (9)
0.57% (19)
12,779
0.37% (40)
0.94% (98)
HAS-BLED Interaction:
0–1
7,433
0.35% (23)
0.53% (34)
6,544
0.96% (53)
4,163
0.23% (8)
1.07% (35)
Overall
18,140
0.33% (52)
0.80% (122)
<0.0001
0.01
0.1
1.00
10.00
Favours apixaban
Favours warfarin
Adapted from Lopes et al. Lancet 2012;380:1749–58.
1. Lopes et al. Lancet 2012;380:1749–58.
Halvorsen S, on behalf of the ARISTOTLE Investigators and Committees. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation. American College of Cardiology; March 9-11, 2013; San Francisco, California.

25. p value for interaction
Primary efficacy results for apixaban were consistent across pre-specified major subgroups in ARISTOTLE1
Characteristics
No. of patients
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction
No. of events (%/yr)
All patients
18,201
212 (1.27)
265 (1.60)
Prior warfarin/VKA
Yes
10,401
102 (1.1)
138 (1.5)
0.39 No
7,800
110 (1.5)
127 (1.8)
Age
< 65 yrs
5,471
51 (1.0)
44 (0.9)
0.12
65 to < 75 yrs
7,052
82 (1.3)
112 (1.7)
≥ 75 yrs
5,678
79 (1.6)
109 (2.2)
Sex
Male
11,785
132 (1.2)
160 (1.5)
0.60
Female
6,416
80 (1.4)
105 (1.8)
Weight
≤ 60 kg
1,985
34 (2.0)
52 (3.2)
0.26
> 60 kg
16,154
177 (1.2)
212 (1.4)
Type of AF
Permanent/Persistent
15,412
191 (1.4)
235 (1.7)
0.70
Paroxysmal
2,786
21 (0.8)
30 (1.1)
Prior stroke or TIA
3,436
73 (2.5)
98 (3.2)
0.71
14,765
139 (1.0)
167 (1.2)
Diabetes mellitus
4,547
57 (1.4)
75 (1.9)
13,654
155 (1.2)
190 (1.5)
Table has been redesigned slightly to accommodate 16:9 dimensions. The original table is hidden on the next slide (29)
Primary efficacy endpoint: stroke or systemic embolism
0.25
0.50
1.00
2.00
Adapted from Granger et al. N Engl J Med 2011;365:981–92.
Apixaban better
Warfarin better
1. Granger et al. N Engl J Med 2011;365:981–92.

26. p value for interaction
Primary safety results for apixaban were consistent across pre-specified major subgroups in ARISTOTLE1
Characteristics
No. of patients
Apixaban
Warfarin
Hazard Ratio (95% CI)
p value for interaction
No. of events (%/yr)
All patients
18,140
327 (2.13)
462 (3.09)
Prior warfarin/VKA
Yes
10,376
185 (2.1)
274 (3.2)
0.50 No
7,764
142 (2.2)
188 (3.0)
Age
< 65 yrs
5,455
56 (1.2)
72 (1.5)
0.64
65 to < 75 yrs
7,030
120 (2.0)
166 (2.8)
≥ 75 yrs
5,655
151 (3.3)
224 (5.2)
Sex
Male
11,747
225 (2.3)
294 (3.0)
0.08
Female
6,393
102 (1.9)
168 (3.3)
Weight
≤ 60 kg
1,978
36 (2.3)
62 (4.3)
0.22
> 60 kg
16,102
290 (2.1)
398 (3.0)
Type of AF
Permanent/Persistent
15,361
283 (2.2)
402 (3.2)
0.75
Paroxysmal
2,776
44 (1.9)
60 (2.6)
Prior stroke or TIA
3,422
77 (2.8)
106 (3.9)
0.71
14,718
250 (2.0)
356 (2.9)
Diabetes mellitus
4,526
112 (3.0)
114 (3.1)
0.003
13,614
215 (1.9)
348 (3.1)
Table has been redesigned slightly to accommodate 16:9 dimensions. The original table is hidden on the next slide (31)
Adapted from Granger et al. N Engl J Med 2011;365:981–92.
0.25
0.50
1.00
2.00
Apixaban better
Warfarin better
1. Granger et al. N Engl J Med 2011;365:981–92.

27. ARISTOTLE subanalyses to date
Topic
Author/year
Warfarin naïve/experienced
Garcia et al
Drug dosing errors
Alexander et al
Concomitant ASA treatment
Alexander et al
Cardioversion
Flaker et al
Prior MI/coronary artery disease
Bahit et al
Biomarker hs-troponin I
Hijazi et al
Previous stroke/TIA
Easton et al
Renal function
Hohnloser et al
CHADS2/CHA2DS2VASc/HAS-BLED
Lopes et al
Topic
Author/year
Biomarker NT-proBNP
Hijazi et al
Heart failure
McMurray et al
Type of AF
Al-Khatib et al
TTR/INR
Wallentin et al
Biomarker hs-troponin T
Hijazi et al
Age
Halvorsen et al
Concomitant amiodarone treatment
Flaker et al
Major bleeding
Hylek et al
ASA: aspirin; CAD: coronary artery disease; TTR: time in therapeutic range
1. Garcia et al. Am Heart J 2013;0:1-10; 2. Alexander et al. Am Heart J 2013 Sep;166(3):559-65; 3. Alexander et al. Eur Heart J 2014;35:224–232; 4. Flaker et al. J Am Coll Cardiol 2013; doi: /j.jacc ; 5. Bahit et al. Int J Cardiol 2013;170(2):215-20; 6. Hijazi et al. Circulation 2014;129(6):625-34; 7. Easton et al. Lancet Neurol 2012;11(6):503-11; 8. Hohnloser et al. Eur Heart J 2012;33(22): ; 9. Lopes et al. Lancet 2012;380(9855): ; 10. Hijazi et al. J Am Coll Cardiol 2013;61(22): ; 11. McMurray et al. Circ Heart Fail 2013;6(3):451-60; 12. Al-Khatib et al. Eur Heart J 2013;34(31): ; 13. Wallentin et al. Circulation 2013;127: ; 14. Hijazi et al. J Am Coll Cardiol 2014;63(1):52-61; 15. Halvorsen et al. Eur Heart J 2014 [Epub ahead of print]; 16. Flaker et al. Poster presented at ACC Congress Hylek et al. J Am Coll Cardiol pii: S (14)01386–2.

28. AVERROES subanalyses to date
Topic
Author/year
Bleeding
Flaker et al
Previous stroke / TIA
Diener et al
Renal function
Eikelboom et al
CHADS2/CHA2DS2-VASc
Lip et al
Hospitalizations
Hohnloser et al
Previous VKA treatment
Coppens et al
1. Flaker et al. Stroke 2012;43(12):3291-7; 2. Diener et al. Lancet Neurol 2012;11(3):225-31; 3. Eikelboom et al. J Stroke Cerebrovasc Dis 2012;21(6):429-35; 4. Lip et al. Circ Arrhythm Electrophysiol 2013;6:31-38; 5. Hohnloser et al. Eur Heart J 2013;34(35):2752-9; 6. Coppens et al. Eur Heart J 2014;Feb 25 [epub ahead of print]

29. The efficacy and major bleeding results of ELIQUIS® vs
The efficacy and major bleeding results of ELIQUIS® vs. warfarin in key subgroups in ARISTOTLE were consistent with the overall trial results1
ELIQUIS® (apixaban) has clinical benefits over warfarin
that are maintained irrespective of renal function2
that are maintained irrespective of age3
that are consistent across patient risk of stroke and bleeding as assessed by the CHADS2, CHA2DS2-VASc, and HAS-BLED risk scores4
Abbreviations
CHADS2: assigns one point each for congestive heart failure (C), high blood pressure (H), age 75 or older (A), and diabetes (D), and two points for a previous stroke (S2) or transient ischaemic attack
CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex category (female) HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; ICH: Intracranial Haemorrhage; INR: International normalised ratio
1. Apixaban SmPC. Available at 2. Hohnloser et al. Eur Heart J 2012;22:2821–30; 3. Halvorsen et al. Eur Hear J Feb 20 [epub ahead of print]; 4. Lopes et al. Lancet 2012;380:1749–58.

30. ELIQUIS® (apixaban) 2.5 mg & 5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION
SMPC link, click here