UK/CVS-121035(1) | February 2013 Emerging technologies for stroke prevention in atrial fibrillation UK/CVS-121035(1) | Date of preparation: February 2013

UK/CVS-121035(1) | February 2013UK/CVS-121035(1) | February 2013

Emerging technologies for stroke prevention in atrial fibrillation

UK/CVS-121035(1) | Date of preparation: February 2013

Developed and funded by

Clinical trial data indirect comparisons

Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.

Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: http://www.medicines.org.uk/EMC/medicine/25586/SPCXarelto 15 mg: http://www.medicines.org.uk/EMC/medicine/25592/SPC

Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at:Pradaxa 150 mg: http://www.medicines.org.uk/EMC/medicine/24839/SPCPradaxa 110 mg: http://www.medicines.org.uk/EMC/medicine/20760/SPC

Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: http://www.medicines.org.uk/EMC/medicine/27220/SPCEliquis 2.5 mg: http://www.medicines.org.uk/EMC/medicine/24988/SPC


Emerging technologies for stroke prevention in atrial fibrillation

Clinical trial data indirect comparisons


Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: http://www.medicines.org.uk/EMC/medicine/25586/SPCXarelto 15 mg: http://www.medicines.org.uk/EMC/medicine/25592/SPC

Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at:Pradaxa 150 mg: http://www.medicines.org.uk/EMC/medicine/24839/SPCPradaxa 110 mg: http://www.medicines.org.uk/EMC/medicine/20760/SPC

Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: http://www.medicines.org.uk/EMC/medicine/27220/SPCEliquis 2.5 mg: http://www.medicines.org.uk/EMC/medicine/24988/SPC

UK/CVS-121035(1) | February 2013

Clinical data indirect comparisons

• No direct head-to-head clinical trials comparing the novel oral agents have been conducted to date

• The following data for the novel agents has been presented using warfarin as the common comparator

• Please note that differences exist across trial design and patient populations studied

• Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.


Pharmacology

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159:340-347; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365:981-92.


Dabigatran1-3 Rivaroxaban4,5 Apixaban6,7

Mode of action Factor II Factor X Factor X

Half life 12-14 hrs 7-11 hrs 12 hrs

Dosing

(in atrial fibrillation)

B.D. O.D. B.D.

MetabolismEsterase catalysed hydrolysis

CYP P450 dependant and independent mechanisms

CYP P450

Excretion 80% Renal1/3 Renal

2/3 Hepatic

1/4 Renal

3/4 Non Renal

Form Capsule Tablet Tablet

Dose

150 mg

110 mg (>80 yrs, verapamil or increased bleeding risk)

20 mg

15 mg (CrCL 30-49 ml/min)

5 mg

2.5 mg (2 or more:

>80yr; weight <60 kg;

Cr >1.5 mg/dL)

B.D. = twice daily; O.D. = once daily


SPAF trials versus warfarin

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159:340-347; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365:981-92.


Dabigatran1-3 Rivaroxaban4,5 Apixaban6,7

Study RE-LY ROCKET-AF ARISTOTLE

Design PROBE Double Blind Double Blind

Follow up 2 yrs 1.5 yrs 1.5 yrs

Population size >18,000 >14,000 >18,000

InclusionNonvalvular AF + 1 risk factor

Nonvalvular AF + 2 risk factors (i.e. moderate to high risk)

Nonvalvular AF + 1 risk factor

Inclusion (CHADS) 2.1 3.5 2.1

Primary EndpointStroke and systemic embolism

Stroke and systemic embolism

Stroke and systemic embolism

Warfarin comparator INR control (mean TTR)

64% 55% 62%

PROBE = prospective randomised open blinded end-point; INR = international normalised ratio; TTR = time in therapeutic range


Dabigatran 110 mgvs Warfarin(D110 N=6015)


Warfarin(N=6022)

D110

#

D110%/yr

ARR HR P =

D150

#

D150 %/yr

ARR HR P =Warf #

Warf %/yr

Stroke or systemic embolism

183 1.54 0.17 0.900.29 (sup)

134 1.11 0.600.65

<0.001 (sup)

202 1.71

RE-LY: Stroke, systemic embolism*

Connolly SJ et al. N Engl J Med 2009;361:1139–51.Connolly SJ et al. N Engl J Med 2010;363:1875–6.


Fig: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic

Embolism, According to Treatment Group

RE-LY: The primary endpoint was stroke or systemic embolism.

*Intention-to-Treat population


RE-LY: Stroke (ischaemic, haemorrhagic, disabling or fatal)*

Connolly SJ et al. N Engl J Med 2009;361:1139–51.Connolly SJ et al. N Engl J Med 2010;363:1875–6.Pradaxa® 150 mg hard capsules Summary of Product Characteristics. Available at http://www.medicines.org.uk/EMC/medicine/24839/SPC




Warfarin(N=6022)

D110

#

D110%/yr

ARR HR P =

D150

#

D150 %/yr

ARR HR P =Warf #

Warf %/yr

Ischaemic stroke

152 1.28 -0.14 1.13 0.31 103 0.86 0.280.75

0.03 134 1.14

Haemorrhagic stroke

14 0.12 0.26 0.31<0.001

12 0.10 0.280.26

<0.001

45 0.38

Disabling or fatal stroke

112 0.94 0.07 0.93 0.61 80 0.66 0.350.66

0.004 119 1.01



RE-LY: Myocardial infarction, vascular mortality, all cause mortality*





Warfarin(N=6022)

D110

#

D110%/yr

ARR HR P =

D150

#

D150 %/yr

ARR HR P =Warf #

Warf %/yr

Myocardial infarction

98 0.82 -0.181.29

0.09 97 0.81 -0.17 1.27 0.12 75 0.64

Vascular mortality

289 2.43 0.260.90

0.21 274 2.28 0.41 0.85 0.04 317 2.69

All cause mortality

446 3.75 0.380.91

0.13 438 3.64 0.49 0.88 0.051 487 4.13



RE-LY: Safety endpoints*





Warfarin(N=6022)

D110

#

D110%/yr

ARR HR P =D150

#

D150 %/yr

ARR HR P =Warf #

Warf %/yr

Major

Bleeding342 2.87 0.70

0.80

0.003 (sup)

399 3.32 0.250.93

0.31 (sup)

421 3.57

Gastro-intestinal bleeding

137 1.15-0.08

1.08

0.52 188 1.56 -0.491.48

0.001 126 1.07

Intracranial bleeding

27 0.23 0.530.30

<0.001

38 0.32 0.440.41

<0.001

90 0.76

Any

bleeding† 1754

14.74

3.630.78

<0.001

1993 16.56 1.810.91

0.0022166

18.37

RELY: Major bleeding was defined as a reduction in the haemoglobin level of at least 20 g per litre, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the haemoglobin level of at least 50 g per litre, or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery. All other bleeding was considered minor.

*Intention-to-Treat population, †Any bleeding = major and minor bleeding


ROCKET-AF: Stroke, systemic embolism

Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix.


Rivaroxaban(SAT N=7061, ITT N=7081)

Warfarin(SAT N=7082, ITT N=7090)

Rivaroxaban vs Warfarin

Stroke, systemic embolism

#No. / 100

pts yrs#

No. / 100

pts yrsARR HR P =

Safety, as treated (SAT)

189 1.7 243 2.2 0.50.79 (0.65-0.95)

0.02 (sup)

Intention to treat (ITT)

269 2.1 306 2.4 0.30.88 (0.75-1.03)

0.12 (sup)

Fig: Cumulative Rates of the Primary End

Point (Stroke or Systemic Embolism) in the

Intention-to-Treat Population

ROCKET-AF: The primary efficacy end point was the composite of stroke (ischaemic or haemorrhagic) and systemic embolism.


ROCKET-AF: Stroke (ischaemic, haemorragic, disabling, fatal)



Rivaroxaban(N=7061)

Warfarin(N=7082)


#No. / 100

pts yrs#

No. / 100

pts yrsARR HR P =

Ischaemic stroke

149 1.34 161 1.42 0.08 0.94 0.581

Haemorrhagic stroke

29 0.26 50 0.44 0.18 0.59 0.024

Disabling stroke

43 0.39 57 0.50 0.11 0.77 0.188

Fatal stroke 47 0.42 67 0.59 0.17 0.71 0.075

Based on Safety on Treatment population


ROCKET-AF: Myocardial infarction, vascular mortality, all cause mortality



Rivaroxaban(N=7061)

Warfarin(N=7082)


#No. / 100

pts yrs#

No. / 100

pts yrsARR HR P =


101 0.91 126 1.12 0.21 0.81 0.121

Vascular mortality

170 1.53 193 1.71 0.18 0.89 0.289

All cause mortality

208 1.87 250 2.21 0.34 0.85 0.073

Based on Safety on Treatment population


ROCKET-AF: Safety endpoints



Rivaroxaban(N = 7111)

Warfarin(N=7125)


# (%) %/yr # (%) %/yr ARR HR (95% CI) P=

Major bleeding 395 (5.6) 3.6 386 (5.4) 3.4 -0.2 1.04 (0.90-1.20) 0.58

Gastrointestinal bleeding

224 (3.2) n/a 154 (2.2) n/a n/a n/a* <0.001


55 (0.8) 0.5 84 (1.2) 0.7 0.2 0.67 (0.47-0.93) 0.02

Any bleeding†1475 (20.7)

14.91449 (20.3)

14.5 -0.4 1.03 (0.96-1.11) 0.44

*HR and 95% CI not available in publication, †Any bleeding = major and non-major clinically relevant bleeding (excludes minimal bleeding)

Based on Safety on Treatment Population.

ROCKET AF: Major bleeding was defined as clinically overt bleeding associated with any of the following: fatal outcome, involvement of a critical anatomic site (intracranial, spinal, ocular, pericardial, articular, retroperitoneal, or intramuscular with compartment syndrome), fall in haemoglobin concentration ≥2 g/dL, transfusion of ≥2 units of whole blood or packed red blood cells, or permanent disability.


ARISTOTLE: Stroke, systemic embolism*

Granger et al. N Eng J Med 2011;365:981-92.


Apixaban(N=9120)

Warfarin(N=9081)

Apixaban vs Warfarin

# %/yr # %/yr ARR HR P =

Stroke, systemic embolism

212 1.27 265 1.60 0.33 0.790.01 (sup)

ARISTOTLE: The primary endpoint was ischaemic or haemorrhagic stroke or systemic embolism.



ARISTOTLE: Stroke (ischaemic or uncertain, haemorrhagic, disabling or fatal)*



Apixaban(N=9120)

Warfarin(N=9081)



Ischaemic or uncertain stroke

162 0.97 175 1.05 0.08 0.92 0.42

Haemorrhagic stroke

40 0.24 78 0.47 0.23 0.51 <0.001

Disabling or fatal stroke

84 0.50 117 0.71 0.21 0.71 n/a†

†p-value not available in publication.



ARISTOTLE: Myocardial infarction, vascular mortality, all cause mortality*



Apixaban(N=9120)

Warfarin(N=9081)




90 0.53 102 0.61 0.08 0.88 0.37

Vascular mortality† n/a‡ 1.80 n/a‡ 2.02 0.22 0.89 n/a‡

All cause mortality

603 3.52 669 3.94 0.42 0.89 0.047

†Cardiovascular mortality; ‡p-value not available in publication.



ARISTOTLE: Safety endpoints*



Apixaban(N=9088)

Warfarin(N=9052)



Major bleeding 327 2.13 462 3.09 0.960.69 (0.60-0.80)

<0.001

Gastrointestinal bleeding

105 0.76 119 0.86 0.100.89 (0.70-1.15)

0.37


52 0.33 122 0.80 0.470.42 (0.30-0.58)

<0.001

Any bleeding 2356 18.1 3060 25.8 7.70.71 (0.68-0.75)

<0.001

ARISTOTLE: Major bleeding, which was defined, according to the ISTH criteria, as clinically overt bleeding accompanied by a decrease in the haemoglobin level of at least 2 g per decilitre or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death.



Novel agents: Stroke, systemic embolism vs warfarin

SSE vs warfarin (ITT population)

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

1.11 1.710.65 (0.52-

0.81)

Dabigatran 110 mg

1.54 1.710.90 (0.74-

1.10)

Rivaroxaban 2.1 2.40.88 (0.75-

1.03)

Apixaban 1.27 1.600.79 (0.66-

0.95)

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;4. Granger et al. N Eng J Med 2011;365:981-92.


Favours novel orals Favours warfarin

0.5

1 1.5

SSE = stroke and systemic embolism


Novel agents: Ischaemic stroke vs warfarin

0.5

1

Ischaemic stroke vs warfarin

%/yrWarfari

n%/yr

HR

(95% CI)

Dabigatran 150 mg

0.86 1.140.75 (0.58-

0.97)

Dabigatran 110 mg

1.28 1.141.13 (0.89-

1.42)

Rivaroxaban 1.34 1.420.94 (0.75-

1.17)

Apixaban* 0.97 1.050.92 (0.74-

1.13)




1.5

*Ischaemic or uncertain type of stroke


Novel agents: Haemorrhagic stroke vs warfarin




Haemorrhagic stroke vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

0.10 0.380.26 (0.14-

0.49)

Dabigatran 110 mg

0.12 0.380.31 (0.17-

0.56)

Rivaroxaban 0.26 0.440.59 (0.37-

0.93)

Apixaban 0.24 0.470.51 (0.35-

0.75)

0 1 2.0


Novel agents: Disabling or fatal stroke vs warfarin


0.5

1



Disabling or fatal stroke vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg 0.66 1.010.66 (0.50-

0.87)

Dabigatran 110 mg 0.94 1.010.93 (0.72‐

1.21)

Rivaroxaban*

Disab

0.39 0.500.77 (0.52-

1.14)

Fatal

0.42 0.590.71 (0.49-

1.03)

Apixaban 0.50 0.710.71 (0.54-

0.94)* Disabling and fatal stroke reported separately 1.

5


Novel agents: Myocardial infarction vs warfarin

0.2

1 1.8



Myocardial infarction vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

0.81 0.641.27 (0.94-

1.71)

Dabigatran 110 mg

0.82 0.641.29 (0.96-

1.75)

Rivaroxaban 0.91 1.120.81 (0.63-

1.06)

Apixaban 0.53 0.610.88 (0.66-

1.17)



Novel agents: Vascular mortality vs warfarin


Vascular mortality vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

2.28 2.690.85 (0.72-

0.99)

Dabigatran 110 mg

2.43 2.690.90 (0.77-

1.06)

Rivaroxaban 1.53 1.710.89 (0.73-

1.10)

Apixaban* 1.80 2.020.89 (0.76-

1.04)

0.5

1Favours novel orals Favours warfarin

1.5

* Cardiovascular mortality



Novel agents: All cause mortality vs warfarin



All cause mortality vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

3.64 4.130.88 (0.77-

1.00)

Dabigatran 110 mg

3.75 4.130.91 (0.80-

1.03)

Rivaroxaban 1.87 2.210.85 (0.70-

1.02)

Apixaban 3.52 3.940.89 (0.80-

0.99)

0.5

1Favours novel orals Favours warfarin

1.5


Novel agents: Major bleeding vs warfarin

0.5

1




Major bleeding vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

3.32 3.570.93 (0.81-

1.07)

Dabigatran 110 mg

2.87 3.570.80 (0.70-

0.93)

Rivaroxaban 3.6 3.41.04 (0.90-

1.20

Apixaban 2.13 3.090.69 (0.60-

0.80)

1.5


Novel agents: Gastrointestinal major bleeding vs warfarin


1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Nessel C et al. Chest 2012;142(4):84A.4. Granger et al. N Eng J Med 2011;365:981-92.

Gastrointestinal major bleeding vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

1.56 1.071.48 (1.18-

1.85)

Dabigatran 110 mg

1.15 1.071.08 (0.85-

1.38)

Rivaroxaban 2.00 1.241.61 (1.30-

1.99)

Apixaban 0.76 0.860.89 (0.70–

1.15)


0 1 2.0


Novel agents: Intracranial bleeding vs warfarin



Intracranial bleeding vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

0.32 0.760.41 (0.28-

0.60)

Dabigatran 110 mg

0.23 0.760.30 (0.19-

0.45)

Rivaroxaban 0.5 0.70.67 (0.47-

0.93)

Apixaban 0.33 0.800.42 (0.30-

0.58)

Favours novel orals Favours warfarin0 1 2.

0


Novel agents: Any bleeding vs warfarin


0.5 1



Any bleeding vs warfarin

%/yrWarfari

n

%/yr

HR

(95% CI)

Dabigatran 150 mg

16.56 18.370.91 (0.85-

0.96)

Dabigatran 110 mg

14.74 18.370.78 (0.73-

0.83)

Rivaroxaban* 14.9 14.51.03 (0.96-

1.11)

Apixaban 18.1 25.80.71 (0.68-

0.75)

1.5* major and non-major clinically relevant bleeding (excludes minimal bleeding)


Novel AgentsPrescriber guides and adverse event reporting


• An educational pack has been developed to support the prescribing of dabigatran etexilate for stroke prevention in nonvalvular atrial fibrillation

• Go to www.pradaxa.co.uk where you will be able to download the Pradaxa® Educational Pack

• The pack contains:– Prescriber guide

– Summaries of Product Characteristics (SPC)

– Patient alert card

• To order a copy, call the Pradaxa® information line on 0845 601 7880

• Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (Freephone)

Dabigatran etexilate – educational pack and prescriber guide and adverse event reporting

30Summary of Product Characteristics for dabigatran etexilate (Pradaxa®) can be found at:Pradaxa 150 mg: http://www.medicines.org.uk/EMC/medicine/24839/SPCPradaxa 110 mg: http://www.medicines.org.uk/EMC/medicine/20760/SPC


• A prescriber guide has been developed to support the prescribing of rivaroxaban for stroke prevention in nonvalvular atrial fibrillation

• Go to www.xarelto.co.uk to download the following: – Prescriber guide



• Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard

• Adverse events should be also be reported to Bayer plc, on tel: 01635 563500, fax: 01635 563703, email: [email protected]

Rivaroxaban – prescriber guide and adverse event reporting

31Summary of Product Characteristics for rivaroxaban (Xarelto® ) can be found at: Xarelto 20 mg: http://www.medicines.org.uk/EMC/medicine/25586/SPCXarelto 15 mg: http://www.medicines.org.uk/EMC/medicine/25592/SPC


• A prescriber guide has been developed to support the prescribing of apixaban for stroke prevention in nonvalvular atrial fibrillation

• Go to www.eliquis.co.uk to download the following: – Prescriber guide



• Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard

• Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd, Medical Information on 0800 731 1736, email: [email protected]

Apixaban – prescriber guide and adverse event reporting

32Summary of Product Characteristics for apixaban (Eliquis® ) can be found at: Eliquis 5.0 mg: http://www.medicines.org.uk/EMC/medicine/27220/SPCEliquis 2.5 mg: http://www.medicines.org.uk/EMC/medicine/24988/SPC

Documents

UK/CVS-121035(1) | February 2013 Emerging technologies for stroke prevention in atrial fibrillation UK/CVS-121035(1) | Date of preparation: February 2013