Case study - patient presenting with newly diagnosed NVAF with prior CAD

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EUAPI581k; Date of preparation: April 2014

NVAF, non-valvular atrial fibrillation; CAD, coronary artery disease

15.ELI.22.1443NL15PR04188-01

Patient profile – Newly diagnosed NVAF

* Patient is fictitious

MI, myocardial infarction; ECG, electrocardiogram; ASA, acetylsalicylic acid

Personal InformationSex MaleAge 77Weight 85 kg

Blood Pressure 161/92 mmHg

Personal • Retired

Patient: Jürgen*

Patient History

Medical History• MI two years ago• Hypertension• Dyslipidaemia

Medications• ASA• Atorvastatin• Metoprolol

Presentation

• Regular transient mild dyspnoea since a few weeks ago

• Diagnosed with NVAF on ECG during investigation

Jürgen is at significant risk of stroke and major bleeding

CHA2DS2-VASc1 = 4Risk Factors2 Points

C Congestive heart failure/LV dysfunction 1

H Hypertension 1A2 Age ≥75 years 2D Diabetes mellitus 1S2 Stroke/TIA/thromboembolism 2V Vascular diseasea 1A Age 65 to 74 years 1Sc Sex category (female) 1

Maximum score 9

HAS-BLED2 = 3

aVascular disease includes myocardial infarction, complex aortic plaque, and peripheral artery diseasebDefined as uncontrolled hypertension (systolic blood pressure >160 mm Hg)

LV, left ventricular; TIA, transient ischemic attack; INR, international normalized ratio

Clinical Characteristics Points

H Hypertensionb 1

A Abnormal renal or hepatic function (1 point each) 1 or 2

S Stroke 1

B Bleeding history or predisposition 1

L Labile INRs 1

E Elderly (age >65 years) 1

D Drugs or alcohol (1 point each) 1 or 2

1. Lip et al. Chest 2010;137:263–72;2. Pisters et al. Chest 2010;138:1093–100.

Question 1

Jurgen is newly diagnosed with NVAF and has a CHA2DS2-VASc score of 4 and a HAS-BLED score of 3. According to the 2012 ESC guidelines, a NOAC should be considered rather than adjusted-dose VKA (INR 2–3)1

Jurgen has hypertension and prior coronary artery disease

Would ELIQUIS® (apixaban) be a good option for Jürgen’s stroke prevention?

1. Yes

2. No

NOAC(s), novel oral anticoagulant(s); VKA, vitamin K antagonist

1. Camm et al. Eur Heart J 2012;33:2719–47.

Jürgen has a high risk of stroke as well as a high risk of bleeding and may benefit most from a therapy that protects against stroke and limits major bleeding

In ARISTOTLE, ELIQUIS® (apixaban) significantly reduced the rates of stroke/SE and major bleeding as compared to warfarin1

– In addition all-cause mortality was reduced significantly for ELIQUIS® (apixaban) vs warfarin1

Primary safety endpoint 0.00.51.01.52.02.53.03.54.0

2.13%

3.09%

ApixabanWarfarin (Target INR 2.0−3.0)

What about ELIQUIS® (apixban)

1. Granger et al. N Engl J Med 2011;365:981–92.

n=269

Stroke/ systemic embolism1 Major bleeding1

Primary efficacy endpoint 0.0

0.5

1.0

1.5

2.0

1.27%1.6%

n=212/9120

n=265/9081

n=327/9088

n=462/9052

21% RRR p=0.01 31% RRR p<0.001

SE, systemic embolism Adapted from Granger et al. N Engl J Med 2011;365:981–92

Even

t rat

e (%

/yea

r)

Even

t rat

e (%

/yea

r)

B. Major Bleeding1

Subgroup No. of patients Apixaban Warfarin Hazard Ratio (95% CI) P value for

interactionNo. of events (%/yr)

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)

1. Halvorsen et al. Eur Heart J 2014;Feb 20 [epub ahead of print];2. Connolly et al. N Engl J Med 2011;364:806–17.

Jürgen is 77 years old. What do we know about the ELIQUIS® (apixaban) data (ARISTOTLE) in elderly patients?1

0.25 0.50 1.00 2.00

Apixaban better Warfarin better

A. Primary Efficacy Outcome: Stroke and Systemic Embolism1

Subgroup No. of patients Apixaban Warfarin Hazard Ratio (95% CI) P value for

interactionNo. of events (%/yr)

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

*Interaction P-values based on continuous ageAdapted from Halvorsen et al. Eur Hear J 2014;Feb 20 [epub ahead of print]

In addition, in the AVERROES trial the effects of apixaban compared with ASA in the older patient subgroups (age ≤ 75 years) were consistent with the overall study population2

Prevalence in the REACH Registry1

Jürgen is put on ELIQUIS® (apixaban) 5 mg twice-dailyHow does his CAD influence his treatment?

1. Goto et al. Am Heart J 2008;156:855–63.

37,724 stable outpatients with CAD

87.5%

12.5%

Without AFWith AF

The REACH study was a large-scale international, prospective cohort study of 68,236 stable outpatients with established atherothrombosis or >= 3 atherothrombotic risk factors.

Adapted from Goto et al. Am Heart J 2008;156:855–63

Atrial Fibrillation and CAD frequently coincide

CAD patients with AF have a higher rate of major clinical events than CAD patients without AF1

Death / MI / stroke CV death Bleeding0

1

2

3

4

5

6

7

8

6.92%

3.42%

1.49%

4.3%

1.69%

0.81%

With AFWithout AF

Patie

nts (

%)

p<0.0001

p<0.0001

p<0.0001

CV, cardiovascular

1. Goto et al. Am Heart J 2008;156:855–63.

Adapted from Goto et al. Am Heart J 2008;156:855–63

37,724 patients with CAD: 12.5% prevalence of atrial fibrillation1

What data for ELIQUIS® (apixaban) in for stroke preventionin NVAF exist in patients with prior CAD?1

Of the study population in ARISTOTLE, 6,639 (36.5%) of patients had prior CAD

Patients with prior CAD were more often male and were more likely to have prior stroke, diabetes and hypertension as compared with patients without prior CAD

Patients with prior CAD were more likely to be on aspirin at baseline (42.2% vs 24.5%; p<0.001) when compared with patients without prior CAD

1. Bahit et al. Int J Cardiol 2013;170:215–20

Apixaban Warfarin HR (95% CI) No CAD CAD Interaction p value

Efficacy endpointsStroke or systemic embolism

1.15 (121)1.47 (91)

1.63 (171)1.55 (94)

0.704 (0.558, 0.889)0.950 (0.712,1,267) 0.11

Stroke 1.06 (112)1.40 (87)

1.52 (159)1.50 (91)

0.701 (0.550, 0.892)0.937 (0.699, 1.258) 0.14

Death (any cause) 3.11 (335)4.21 (267)

3.68 (395)4.40 (274)

0.847 (0.732, 0.979)0.958 (0.809, 1.133) 0.28

MI 0.29 (31)0.95 (59)

0.39 (41)1.00 (61)

0.755 (0.473, 1.203)0.947 (0.662, 1.354) 0.45

Revascularisation (PCI/CABG)

0.70 (74)1.69 (104)

0.67 (71)1.89 (114)

1.040 (0.751, 1.441)0.890 (0.682, 1.161) 0.47

Safety endpoints

ISTH major bleeding 1.99 (194)2.39 (123)

3.12 (297)3.05 (165)

0.640 (0.534, 0.766)0.784 (0.624, 0.985) 0.17

Intracranial bleeding 0.37 (37)0.27 (15)

0.85 (82)0.73 (40)

0.443 (0.301, 0.654)0.364 (0.201, 0.659) 0.59

Patients with or without prior CAD in ARISTOTLE1

1. Bahit et al. Int J Cardiol 2013;170:215–20

Adapted from Bahit et al. Int J Cardiol 2013;170:215–20

0.1 1 10

Favour apixaban Favour warfarin

MI, myocardial infarction; ISTH, International Society on Thrombosis and Haemostasis

Conclusion of the subanalysis of patients with prior CAD in ARISTOTLE

In patients with NVAF, ELIQUIS® (apixaban) prevents stroke or systemic embolism and causes less major bleeding and death compared with warfarin

These treatment effects were consistent in patients with and without a history of CAD

As the combination of NVAF and CAD commonly occurs and as there are higher rates of CV events and death in these patients, ELIQUIS® (apixaban) may be a better option than warfarin in this high-risk group

1. Bahit et al. Int J Cardiol 2013;170:215–20

Question 2

Jürgen is now on ELIQUIS® (apixaban) for stroke prevention in NVAF and is also still taking aspirin given his prior CAD. His CAD has been stable ever since he has had the MI 2 years ago

Can Jürgen discontinue taking ASA?

1. Yes, ASA can be discontinued

2. No, he still needs ASA

ELIQUIS® (apixaban) and antiplatelet therapy in NVAF patients

In ARISTOTLE, concomitant use of ASA increased the major bleeding risk:1

1. Apixaban SmPC. Available at http://www.ema.europa.eu

OAC alone OAC + ASA0

0.51

1.52

2.53

3.54

4.55

1.8%

3.4%

2.7%

4.6%

Major bleeding in ARISTOTLE1

Apixaban VKA

(%) o

f eve

nts

There was limited (2.1%) use of concomitant dual antiplatelet therapy1

Created from Apixaban SmPC

Concomitant use of ELIQUIS® (apixaban) with antiplatelet agents increases the risk of bleeding1

Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid

In patients with NVAF and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban

1. Apixaban SmPC. Available at http://www.ema.europa.eu

In ARISTOTLE, concomitant ASA use was left to the discretion of the treating physician1

On Day 1, 4434 (24%) of patients were taking ASA1

Event rates for apixaban vs warfarin in patients on ASA vs no ASA:

Apixaban benefits vs warfarin were consistent for patients taking or not taking ASA1

What do we know about the use of concomitant ASA in patients using apixaban?

1. Alexander et al. Eur Heart J 2014;35:224–32

Apixabanevent rate (%/year)

Warfarinevent rate(%/year)

HR (95% CI) ASA No ASA Interaction p value

Stroke or systemic embolism

41 (1.12)127 (1.11)

67 (1.91)149 (1.32)

0.58 (0.39–0.85)0.84 (0.66–1.07) 0.10

Ischaemic stroke 29 (0.79)95 (0.83)

40 (1.14)94 (0.83)

0.69 (0.43–1.11)1.00 (0.75–1.33) 0.19

Myocardial infarction 33 (0.90)46 (0.40)

26 (0.74)58 (0.51)

1.20 (0.71–2.00)0.78 (0.53–1.14) 0.19

Death 71 (1.93)188 (1.64)

64 (1.82)223 (1.97)

1.05 (0.75–1.47)0.83 (0.68–1.00) 0.23

Major bleeding 114 (3.10)211 (1.82)

138 (3.92)317 (2.78)

0.77 (0.60–0.99)0.65 (0.55–0.78) 0.29

Haemorrhagenic stroke 10 (0.27)25 (0.22)

24 (0.68)47 (0.42)

0.40 (0.19–0.83)0.53 (0.33–0.86) 0.52

Major or CRNM bleeding 199 (5.54)410 (3.59)

246 (7.18)620 (5.58)

0.76 (0.63–0.92)0.65 (0.57–0.73) 0.15

Any bleeding 682 (22.64)1657 (16.61)

859 (32.84)2180 (23.72)

0.70 (0.62–0.77)0.71 (0.67–0.76) 0.70

0.1 1 10Favour apixaban Favour warfarin

EHRA guidance on concomitant ASA1

Stable CAD patients developing AF should receive anticoagulation, depending on their CHA2DS2-VASc score

Anticoagulation without additional antiplatelet agents is considered sufficient for most AF patients with stable CAD (acute coronary syndrome ≥1 year ago; elective bare-metal stent ≥1 month; drug-eluting stent ≥6 months)

The advantages of NOACs over VKA are likely to be preserved in stable CAD patients. NOACs may be an appropriate and effective alternative to VKAs

1. Heidbüchel et al. Europace 2013;15:625–51.

Question 2

Jürgen is now on ELIQUIS® (apixaban) for stroke prevention in NVAF and is also still taking aspirin given his prior CAD. His CAD has been stable ever since he has had the MI 2 years ago

Can Jürgen discontinue taking ASA?

1. Yes, ASA can be discontinued

2. No, he still needs ASA

Patient case: Key learnings

1. Bahit et al. Int J Cardiol 2013;170:215–220; 2. Alexander et al. Eur Heart J 2014;35:224–232; 3. Heidbüchel et al. Europace 2013;15:625–651.

This high-risk patient may benefit most from a therapy that protects against stroke while limiting major bleeding

– In ARISTOTLE, ELIQUIS® (apixaban) significantly reduced the risk of stroke/SE and major bleeding as compared to warfarin

The results of the ARISTOTLE trial were consistent in predefined subgroups according to:

– Prior coronary artery disease1

– Use of ASA2

According to the EHRA practical guide on the use of NOACs in NVAF, anticoagulation without additional antiplatelet agents is considered

sufficient for most patients with stable CAD3

ELIQUIS® (apixaban) 2.5 mg & 5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION

SMPC link, click here