ΝΕΟΤΕΡΑ ΑΝΤΙΠΗΚΤΙΚΑ. Από ις μ xλέ xς σ ην ... · 2016-10-01 · April 2012 Eur Heart J 2016 Latest 2016 ESC guidelines recommend NOACs over VKAs. April

April 2012

ΝΕΟΤΕΡΑ ΑΝΤΙΠΗΚΤΙΚΑ. Από τις μελέτες στην καθημερινή κλινική

πράξη. Η παγκόσμια εμπειρία.

Κωνσταντίνος Π. Λέτσας, MD, FESC

Β΄ Καρδιολογική ΚλινικήΕργαστήριο Επεμβατικής Ηλεκτροφυσιολογίας

Γ.Ν.Α. “ΕΥΑΓΓΕΛΙΣΜΟΣ”

2Ο ΑΡΡΥΘΜΙΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟΑΘΗΝΑ 2016

April 2012Eur Heart J 2016

Latest 2016 ESC guidelines recommend NOACs over VKAs

April 2012

R

RE-LY® provides robust data for both doses of dabigatran due to randomization into two treatment arms

*Dose selection based on individual assessment of thromboembolic and bleeding risk in patients aged 75–79 yrs or with moderate renal impairment, gastritis, oesophagitis, GERD, or other riskfactors for bleeding. RE-LY® followed a PROBE (prospective, randomized, open-label with blinded

endpoint evaluation) design. INR, international normalized ratio; R, randomization; TTR, time intherapeutic range. 1. Connolly SJ et al. N Engl J Med 2009; 2. Pradaxa®: EU SPC, 2015.

AF with ≥1 risk factor for stroke; absence of contraindications; 18 113 patients across 951 centres in 44 countries1

Dabigatran 110 mg BID

N=6015

Warfarin (INR 2.0–3.0)

N=6022INR control: mean TTR=64%


N=6076

Primary endpoint: stroke/systemic embolism

Both dabigatran arms were adequately powered to support efficacy and safety conclusions

OpenBlind dosing

The EU label recommends 150 mg BID as the standard dose of dabigatran

and 110 mg BID for patients aged ≥80 years, or on concomitant verapamil*2

April 2012

Both doses of dabigatran provide safety and efficacy benefits vs warfarin in the overall RE-LY® population

1. Connolly SJ et al. N Engl J Med 2010;

2. Connolly SJ et al. N Engl J Med 2014.

Click here to see forest plot of the key outcomes in RE-LY®

150 mg BID

Major bleeding

similar

ICH

59%

110 mg BID

ICH

70%

Major bleeding

20%

Stroke/SE

35%

CV mortality

15%

Haemorrhagic

stroke

74%

Ischaemic

stroke

24%

Stroke/SE

similar

CV mortality

similar

Haemorrhagic

stroke

69%

Ischaemic

stroke

similar

April 2012

In RE-LY®, dabigatran 150 mg BID showed both superior safety and efficacy vs warfarin in patients aged <75 years

Superior safety for dabigatran 150 mg BID vs warfarin refers to major bleeding events including ICH; *Pre-specified analysis of patients aged <75 years;6 †RRRs should be interpreted with caution for stroke/SE,

ICH and CV mortality; age–treatment interactions seen for major bleeding

1. Connolly SJ et al. N Engl J Med 2014; 2. Connolly SJ et al. N Engl J Med 2010; 3. Eikelboom JW et al. Circulation 2011; 4. Clemens A et al. Am J Cardiol 2014; 5. BI, Data on file; 6. RE-LY® trial protocol.

Stroke/SEICHMajor

bleeding

CV

mortality

Dabigatran 150 mg

vs warfarin

(<75 yrs)3–5*†

57% 37%30% 26%

Please see the MSL ‘Patients aged <75 years’ slide set for further information on this analysis

35%59%Dabigatran 150 mg

vs warfarin

(all age groups)1,215%

70%Dabigatran 110 mg

vs warfarin

(all age groups)1,220%

April 2012

Dabigatran provides superior efficacy and safety vs warfarin when used according to the EU label*

April 2012

Real-world evidence

RCTs: tightly controlled patient population

Approval

Post-approval use includes morevaried medical settings and more diverse patient populations

Differing:•Age•Race•Co-morbidities•Co-medications•Adherence

RWE clarifies whether the results observed under the tightly controlled conditions of an RCT are also observed in everyday clinical practice

1. Nallamothu BK et al. Circulation 2008

April 2012

Growing body of real-world experience from >250 000 patients confirms safety and efficacy profile of dabigatran

RE-LY®

(n>18 000)

Clinical practice (n>250000 patients)

FDA Medicare study (n>134 000)1

2 US insurance databases(n>38 000)3

US Dept of Defense database (n>25 000)2

Danish observational studies(n>21 000)4,5

1. Graham DJ et al. Circulation 2015; 2. Villines TC et al. Circulation 2014; 3. Seeger J et al. Circulation 2014; 4. Larsen TB et al. Am J Med 2014a; 5. Larsen TB et al. Am J Med 2014b; 6. Lauffenburger JC et al. J Am Heart Assoc 2015

US insurance database(n>64 000)6

April 2012

Independent FDA study of Medicare patients provides single largest body of RWE for dabigatran

>134 000 OAC-naïve dabigatran

or VKA users aged ≥65 years

>37 500patient-years’

follow-up

Propensity score-matched

16% of patients were aged ≥85 years; 16% of patients were taking dabigatran 75 mg BIDGraham DJ et al. Circulation 2015;131:157–64

April 2012

RE-LY®1–4

N>18 000WarfarinD150 BID

MEDICARE*5

N>134 000WarfarinD150 & D75 BID combined

MORTALITYISCHAEMIC

STROKEICH

MAJORBLEEDING

GIBLEEDING

MI

HR: 0.76P=0.04

HR: 0.80P=0.02

RR: 0.41P<0.001

HR: 0.34P<0.001

RR: 0.94P=0.41

HR: 0.97P=0.50

RR: 1.48P=0.001

HR: 1.28P<0.001

RR: 1.27P=0.12

HR: 0.92P=0.29

RR: 0.88P=0.051

HR: 0.86P=0.006

RCT

Real-world data

EV

EN

T R

AT

E (

% P

ER

YE

AR)

5

4

3

2

1

0

INCI

DEN

CE P

ER 1

00PE

RSO

N-

YE

AR

S

0

1

2

3

4

5

Ischaemic stroke:what does this mean for your patients?

1. Connolly SJ et al. N Engl J Med 2009;361:1139–512. Connolly SJ et al. N Engl J Med 2010;363:1875–63. Pradaxa®: EU SPC, January 20154. Connolly SJ et al. N Engl J Med 2014;371:1464–55. Graham DJ et al. Circulation 2015;131:157–64

April 2012

RE-LY®1–4


MEDICARE*5


MORTALITYISCHAEMIC

STROKEICH

MAJORBLEEDING

GIBLEEDING

MI

HR: 0.76P=0.04

HR: 0.80P=0.02

RR: 0.41P<0.001

HR: 0.34P<0.001

RR: 0.94P=0.41

HR: 0.97P=0.50

RR: 1.48P=0.001

HR: 1.28P<0.001

RR: 1.27P=0.12

HR: 0.92P=0.29

RR: 0.88P=0.051

HR: 0.86P=0.006

RCT

Real-world data

EVEN

T RA

TE (%

PER

YEA

R)

5

4

3

2

1

0

INCI

DEN

CE P

ER 1

00PE

RSO

N-

YEA

RS

0

1

2

3

4

5

Intracranial haemorrhage: what does this mean for your patients?

1. Connolly SJ et al. N Engl J Med 2009;361:1139–512. Connolly SJ et al. N Engl J Med 2010;363:1875–63. Pradaxa®: EU SPC, January 20154. Connolly SJ et al. N Engl J Med 2014;371:1464–55. Graham DJ et al. Circulation 2015;131:157–64

April 2012

RE-LY®1–4


MEDICARE*5


MORTALITYISCHAEMIC

STROKEICH

MAJORBLEEDING

GIBLEEDING

MI

HR: 0.76P=0.04

HR: 0.80P=0.02

RR: 0.41P<0.001

HR: 0.34P<0.001

RR: 0.94P=0.41

HR: 0.97P=0.50

RR: 1.48P=0.001

HR: 1.28P<0.001

RR: 1.27P=0.12

HR: 0.92P=0.29

RR: 0.88P=0.051

HR: 0.86P=0.006

RCT

Real-world data

EVEN

T RA

TE (%

PER

YEA

R)

5

4

3

2

1

0

INCI

DEN

CE P

ER 1

00PE

RSO

N-

YEA

RS

0

1

2

3

4

5

Major and GI bleeding: what does this mean for your patients?

1. Connolly SJ et al. N Engl J Med 2009; 361:1139–512. Connolly SJ et al. N Engl J Med 2010;363:1875–63. Pradaxa®: EU SPC, January 20154. Connolly SJ et al. N Engl J Med 2014; 371:1464–55. Graham DJ et al. Circulation 2015;131:157–64

April 2012

RE-LY®1–4

N>18 000

Warfarin

D150 BID

MEDICARE*5

N>134 000

Warfarin

D150 & D75 BID

combined

MORTALITYISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76P=0.04

HR: 0.80P=0.02

RR: 0.41P<0.001

HR: 0.34P<0.001

RR: 0.94P=0.41

HR: 0.97P=0.50

RR: 1.48P=0.001

HR: 1.28P<0.001

RR: 1.27P=0.12

HR: 0.92P=0.29

RR: 0.88P=0.051

HR: 0.86P=0.006

RCT

Real-world

data

EV

EN

T R

AT

E (

% P

ER

YE

AR

)

5

4

3

2

1

0

INC

IDE

NC

E P

ER

1

00

PE

RS

ON

-YE

AR

S

0

1

2

3

4

5

Myocardial infarction and mortality:what does this mean for your patients?

1. Connolly SJ et al. N Engl J Med 2009; 361:1139–512. Connolly SJ et al. N Engl J Med 2010;363:1875–63. Pradaxa®: EU SPC, January 20154. Connolly SJ et al. N Engl J Med 2014; 371:1464–55. Graham DJ et al. Circulation 2015;131:157–64

April 2012

US DoD database showed clear consistency in outcomes with data from RE-LY®

MORTALITY


DoD*5,6


EVEN

T RA

TE (%

PER

YEA

R)IN

CID

ENCE

PER

100

PERS

ON

-YE

ARS

STROKEISCHAEMIC

STROKEICH

MAJORBLEEDING

MI

HR: 0.64P<0.001

HR: 0.73P=0.03

HR: 0.76P=0.04

HR: 0.84P=0.25

RR: 0.41P<0.001

HR: 0.49P=0.004

RR: 0.94P=0.41

HR: 0.87P=0.09

RR: 1.27P=0.12

HR: 0.65P=0.02

RR: 0.88P=0.051

HR: 0.64P<0.0001

RE-LY®1–4

RCT

Real-world data

0

1

2

3

4

5

5

4

3

2

1

0

In the USA, the licensed doses for Pradaxa® are: 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF*Primary findings for dabigatran are based on analysis of both 75 mg &150 mg together without stratification by dose

1. Connolly SJ et al. N Engl J Med 2009; 2. Connolly SJ et al. N Engl J Med 2010; 3. Pradaxa®: EU SPC, January 2015; 4. Connolly SJ et al. N Engl J Med 2014; 5. Villines TC et al. Presented at AHA 2014; 6. Villines TC et al. Thromb Haemost 2015

April 2012

US Health Insurance data are consistent with RE-LY® and additional real-world data

RE-LY®1–4


US Health Insurance data*5

N>44 000WarfarinD150 & 75 BID combined

EVEN

T RA

TE (%

PER

YEA

R)IN

CID

ENCE

RA

TE P

ER 1

00PE

RSO

N-

YEA

RS

STROKEISCHAEMIC

STROKEICH

MAJORBLEEDING

MI

HR: 0.64P<0.001

HR: 0.72(0.52–1.00)

HR: 0.76P=0.04

HR: 0.82(0.57–1.18)

RR: 0.41P<0.001

HR: 0.32(0.19–0.54)

RR: 0.94P=0.41

RR: 1.27P=0.12

HR: 0.85(0.58–1.27)

HR: 0.74(0.64–0.84)

1. Connolly SJ et al. N Engl J Med 2009; 2. Connolly SJ et al. N Engl J Med 2010; 3. Pradaxa®: EU SPC, January 20154. Connolly SJ et al. N Engl J Med 2014; 5. Seeger J et al. Poster presented at AHA 2015

GIBLEEDING

HR: 0.95(0.79–1.14)

RR: 1.48P=0.001

RCT

Real-world data

5

4

3

2

1

0

0

1

2

3

4

5

In the USA, the licensed doses for Pradaxa® are: 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF*Primary findings for dabigatran are based on analysis of both 75 mg &150 mg together without stratification by dose

April 2012

Independent Danish non-interventional study assessed bleeding and MI events with dabigatran vs warfarin

Registry 1: median age 82 years (dabigatran 110 mg BID), 67 years (dabigatran 150 mg BID), 73 years (warfarin);Registry 2: median age 82 years (dabigatran 110 mg BID), 68 years (dabigatran 150 mg BID), 72 years (warfarin)1. Larsen TB et al. Am J Med 2014;127:650–6;

2. Larsen TB et al. Am J Med 2014;127:329–36.e4

>21000 OAC-naïve

dabigatran or VKA users

Mean 13.2 months’

follow-up

Matched to warfarin

users in a 2:1 ratio

>12 000 OAC-naïve

dabigatran or VKA users

Mean 16 months’ follow-up

No statistical matching

Bleeding events analysis1

MI events analysis2

April 2012

D110 vs W HR* (95% CI)

Any 0.72 (0.59–0.88)

Major 0.93 (0.74–1.16)

Fatal 0.52 (0.28–0.95)

GI 0.50 (0.27–0.94)

ICH 0.30 (0.17–0.54)

D150 vs W

Any 0.68 (0.55–0.84)

Major 0.67 (0.53–0.85)

Fatal 0.70 (0.33–1.52)

GI 1.45 (0.84–2.50)

ICH 0.33 (0.17–0.66)

Reduced risk of any bleeding and ICH with both doses of dabigatran vs warfarin

Larsen TB et al. Am J Med 2014;127:650–6

VKA-naïve stratum

0.10 5.00

Favours dabigatran Favours warfarin

0.50 1.00 2.00

April 2012

Similar incidence of MI events with both doses of dabigatran vs warfarin (VKA-naïve stratum)

D110 vs W HR* (95% CI)

Myocardial infarction 0.71 (0.47–1.07)

D150 vs W

Myocardial infarction 0.93 (0.62–1.41)

VKA-naïve stratum

0.10 5.00

Favours dabigatran Favours warfarin

0.50 1.00 2.00

Larsen TB et al. Am J Med 2014;127:329–36.e4

April 2012

Hong Kong hospital study evaluated the risk of stroke and ICH with dabigatran vs warfarin in patients with NVAF

8754 Chinese patients with

NVAF

Mean follow-up of

3.0±3.2 years

No statistical matching of

cohorts

Mean age 79.5±9.2 years; ICH, intracranial haemorrhage; NVAF, nonvalvular atrial fibrillation

Ho et al. Stroke 2015

April 2012Ho et al. Stroke 2015

Dabigatran was associated with the lowest incidence of ischaemic stroke, compared with ASA, warfarin and no therapy

Warfarin (quartiles of TTR)

HR (95% CI)

ASA 0.73 (0.67–0.81)

Q1 0.71 (0.58–0.87)

Q2 0.56 (0.45–0.69)

Q3 0.42 (0.33–0.53)

Q4 0.31 (0.23–0.40)

Dabigatran 0.20 (0.12–0.34)

0.1 1

Decreased risk of stroke Increased risk of stroke

Warfarin

(quartiles of TTR)

1.1

April 2012Ho et al. Stroke 2015

Dabigatran was associated with the lowest mortality rate compared with ASA, warfarin and no therapy

April 2012

The favourable safety profile of dabigatran has been consistently confirmed vs different comparators

Dabigatran shows similar or lower rates of major

bleeding1–5,14

Dabigatran is associated with lower rates of bleeding*

and mortality13,14

A growing number of real-world studies confirm the

favourable safety profile of dabigatran, with safety comparable to apixaban6–12,14

Results for selected analyses. *ICH, major bleeding, and major GI bleeding. References are provided in slide notes.

Dabigatran vs warfarin

Dabigatran vs apixaban

Dabigatran vs rivaroxaban

vs

vs

vs

April 2012

Patients

• New users of dabigatran, apixaban, rivaroxaban, or warfarin• N=61 678 (12 701 dabigatran, 6349 apixaban, 7192 rivaroxaban,

35 436 warfarin); only patients on standard NOAC doses were included

Safety outcomes

• Major bleeding, any bleeding (intracranial, major GI bleeding, traumatic intracranial), and all-cause mortality

Methods

• Prospective analysis of 3 Danish health registries (Aug 2011–Nov 2015)• Follow up until outcome of interest, emigration, death, or end of study

• Cox regression and inverse probability-of-treatment weighted analysis

Funding

• Obel Family Foundation

Limitations

• Only ITT analysis presented• Limited variables for adjustment

• Follow-up duration limited

for some patients• Patients included prior to

availability of apixaban

!

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Larsen et al. BMJ 2016;353:i3189

April 2012

24

Only standard doses of NOACs were compared in this study. *Inverse probability of treatment weighted and expressedas population average treatment rates per 100 years. Adjusted HR (95% CI), bold values indicate statistical significance.Limitations: ITT analysis; limited variables for adjustment; limited follow-up; patients included prior to availability of

apixaban.

Major bleeding All-cause mortality

HR 0.58 (0.47–0.71)

Dabigatran and apixaban were associated with a statistically significantly lower risk of any bleeding, major bleeding, and death compared with rivaroxaban or warfarin

HR 0.61 (0.49–0.75)

HR 1.06 (0.91–1.23)

HR 0.63 (0.48–0.82)

HR 0.65 (0.56–0.75)

HR 0.92 (0.82–1.03)

ApixabanDabigatran Rivaroxaban Warfarin ApixabanDabigatran Rivaroxaban Warfarin

Adjusted HR (95% CI) vs warfarin Adjusted HR (95% CI) vs warfarin

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Larsen et al. BMJ 2016;353:i3189

April 2012

Patients

• New users of dabigatran, rivaroxaban, or warfarin• N=22 358 (3588 dabigatran 110 mg, 5320 dabigatran 150 mg,

776 rivaroxaban 15 mg, 1629 rivaroxaban 20 mg, 11 045 warfarin)

Safety outcomes

• Any bleeding (intracranial, GI, and major bleeding), and all-cause mortality

Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care.Gorst-Rasmussen et al. Pharmacoepidemiol Drug Saf 2016; doi:10.1002/pds.4034

Methods

• Prospective analysis of three Danish health registries (1 Feb 2012– 30 Jul 2014)• Follow up until outcome of interest, emigration, death, or end of study

• Propensity-adjusted Cox regression

Funding

• Obel Family Foundation

Limitations

• Small to moderate sample size• Treatment switches and discontinuations were not taken into account

• Follow-up duration can be limited

!

April 2012

* Intracranial, bleeding, GI bleeding, and major bleeding events. D150, dabigatran 150 mg BID; D110, dabigatran 110 mg BID; R20, rivaroxaban 20 mg OD; R15, rivaroxaban 15 mg OD. Adjusted HR (95% CI), bold values indicate statistical significance. Limitations: small to moderate sample size; treatment switches and discontinuations were not

taken into account; follow-up duration can be limited.

Dabigatran showed lower bleeding and mortality than rivaroxaban

HR 1.28 (0.82–2.01)

HR 1.43 (1.13–1.81)HR 1.81 (1.25–2.62)

HR 1.52 (1.06–2.19)

Any bleeding* All-cause mortalityAdjusted HR (95% CI) Adjusted HR (95% CI)


April 2012

Dabigatran 150 mg was associated with a significantly lower rate of any bleedingand all-cause mortality vs rivaroxaban 20 mg; dabigatran 110 mg was associated

with a similar rate of bleeding and lower mortality vs rivaroxaban 15 mg

Any bleeding and all-cause death during follow-up

HR, hazard ratio. Limitations: small to moderate sample size; treatment switches and discontinuations were not taken into account; follow-up duration can be limited.

0 0,5 1 1,5 2 2,5 3

Rivaroxaban 15 mg vs dabigatran 110 mg

Rivaroxaban 20 mg vs dabigatran 150 mg

1.28 (0.82–2.01)

1.81 (1.25–2.62)

Adjusted HR (95% CI)

Any bleeding

All-cause mortality

1.43 (1.13–1.81)

1.52 (1.06–2.19)

Any bleeding

All-cause mortality

Favours rivaroxaban Favours dabigatran

HR


April 2012

Funding

• Bristol-Myers Squibb and Pfizer

Patients

• New NOAC users or switchers from warfarin to a NOAC• N=60 277 (20 963 dabigatran, 30 529 rivaroxaban, 8785 apixaban)

Safety outcomes

• Major and CRNM bleeding

Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients on apixaban, dabigatran, rivaroxaban: cohorts comprising new initiators and/or switchers from warfarin. Tepper et al. Presented at ESC 2015; Abstract 1975

CRNM, clinically relevant non-major.

Methods

• Retrospective analysis of US MarketScan Earlyview database (Jan 2013–Oct 2014)

• Follow up for 6 months until bleeding, discontinuation or switch, or end of study

• Adjusted for baseline characteristics but no propensity-score methods used

Limitations

• Abstract only• Limited variables for adjustment

• The three NOACs were launched

at different times and treatment patterns may change over time

!

April 2012

Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients on apixaban, dabigatran, rivaroxaban: cohorts comprising new initiators and/or switchers from warfarin. Tepper et al. Presented at ESC 2015; Abstract 1975

April 2012

Funding


Patients• New users of dabigatran, rivaroxaban, apixaban, or warfarin (may include switchers from

other OACs)• N=35 757 (2440 dabigatran, 6407 rivaroxaban, 2038 apixaban, 24 872 warfarin)

Safety outcomes

• Major and CRNM bleeding

CRNM, clinically relevant non-major.

Methods

• Retrospective analysis of US Humedica EHR database (Jan 2013–Jun 2014)• Follow up until OAC switch, bleeding event, last visit, or 180 days


Limitations

• Abstract only• Limited variables for adjustment

• Moderate sample size

• Only 6 months follow-up• Treatment discontinuations not

taken into account

!

Real-world bleeding risk among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, rivaroxaban and warfarin: analysis of electronic health records. Lin et al. Presented at ESC 2015

April 2012

Real-world bleeding risk among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, rivaroxaban and warfarin: analysis of electronic health records. Lin et al. Presented at ESC 2015

*Any bleed is a combination of major and clinically relevant non-major bleeding. Limitations: abstract only; may include switchers from other OACs; limited variables for adjustment; moderate sample size; only 6 months of follow-up; treatment discontinuations not taken into account.

0 30 60 90 120 150 1800

2

4

6

8

10

12

14

16

18

20

Time after index (Days)

Cu

mu

lati

ve

pro

po

rtio

n o

f

pa

tie

nts

wit

h a

ny

ble

ed

(%

) Log rank P<0.0001Rivaroxaban

Warfarin

Apixaban

Dabigatran

Kaplan–Meier analysis of any bleed during follow-up

Patients initiating treatment with dabigatran or apixaban experienced a

significantly lower risk of bleeding than those initiating treatment with warfarin

31

Curves unadjusted for differences in baseline characteristics

April 2012

Funding


Patients

• New users of dabigatran, rivaroxaban, apixaban, or warfarin (may include switchers from other OACs)

• N=4828 apixaban-dabigatran and 6721 apixaban-rivaroxaban matched patients

Safety outcomes

• Major bleeding

Methods

• Retrospective analysis of US MarketScan and Medicare supplemental databases (Jan 2012–Sep 2014)

• Follow up until bleeding, discontinuation or switch, or end of study

• Analysis based on propensity-score matched cohorts

Limitations

• Abstract only• Moderate sample size

• Limited variables used for adjustment

!

Real world comparison of major bleeding risk among non-valvular atrial fibrillation patients newly initiated on apixaban, warfarin, dabigatran, or rivaroxaban: a 1:1 propensity-score matched analysis. Lip et al. Presented at ACC 2016; Abstract 1268-34

April 2012

Real world comparison of major bleeding risk among non-valvular atrial fibrillation patients newly initiated on apixaban, warfarin, dabigatran, or rivaroxaban: a 1:1 propensity-score matched analysis. Lip et al. Presented at ACC 2016; Abstract 1268-34

HR, hazard ratio. Bold values indicate statistical significance. Limitations: abstract only; may include switchers from otherOACs; moderate sample size; limited variables used for adjustment.

Major bleeding during follow-up

Dabigatran was associated with a similar rate of major bleeding vs apixaban

HR 2.05 (1.50–2.79)

Apixaban(n=4828)

HR 2.06 (1.50–2.84)

Dabigatran(n=4828)

Apixaban(n=6721)

Rivaroxaban(n=6721)

Apixaban(n=6441)

Warfarin(n=6441)

HR 1.25 (0.84–1.87)

Propensity-score-matched HR (95% CI)

April 2012

Funding


Safety outcomes

• Bleeding-related and all-cause hospitalization

Methods

• Retrospective analysis of US Premier Hospital database (Jan 2012–March 2014) and Cerner Health Facts Hospital database (Jan 2012–Aug 2014)


PatientsPremier Hospital database• N=74 730 (32 838 dabigatran,

37 754 rivaroxaban, 4138 apixaban)

Cerner Health Facts Hospital database

• N=14 201 (5753 dabigatran, 6635 rivaroxaban, 1813 apixaban)

Limitations

• OAC-experienced patients• Limited variables for adjustment

• Moderate sample size

• Only 1 month of follow-up• Patients included prior to

availability of apixaban

!

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants. Deitelzweig et al. Curr Med Res Opin 2016;32:573–82

April 2012

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants. Deitelzweig et al. Curr Med Res Opin 2016;32:573–82

*Frequency data not reported for the Cerner Health Facts database. OR, odds ratio. Limitations: includes OAC-experienced patients; limited variables used for adjustment; moderate sample size; 1 month of follow-up; patients included prior to availability of apixaban.

OR 1.2 (0.9–1.6); P=0.16

OR 1.1 (1.0–1.2); P=0.21

Dabigatran was associated with a similar risk of bleeding-related

or all-cause readmission compared with apixaban

ORs (95% CI) adjusted for baseline characteristics

Bleeding-related readmissions All cause readmissions

Hospital readmissions in the Premier Hospital database*

Dabigatran

Apixaban

April 2012

Funding


Safety outcomes

• All-cause and major bleeding-related hospitalization and length of stay

Methods

• Retrospective analysis of US Truven MarketScan and Medicare supplemental databases (Jan 2012–Dec 2013)


• Follow up until admission, discontinuation or switch, or end of study

Patients

• New users of dabigatran, rivaroxaban, apixaban, or warfarin (may include switchers from another OAC)

• N=29 338 (4173 dabigatran, 10 050 rivaroxaban, 2402 apixaban, 12 713

warfarin)

Limitations

• Abstract only• Moderate sample size

!

What do real world data say about safety and resource use of oral anticoagulants? Early analysis of newly anticoagulated non-valvular atrial fibrillation patients using either apixaban, dabigatran, rivaroxaban or warfarin. Pan et al. Presented at ACC 2016; Abstract 1268-361

April 2012

What do real world data say about safety and resource use of oral anticoagulants? Early analysis of newly anticoagulated non-valvular atrial fibrillation patients using either apixaban, dabigatran, rivaroxaban or warfarin. Pan et al. Presented at ACC 2016; Abstract 1268-361

HR, hazard ratio. Bold values indicate statistical significance. Limitations: abstract only; may include switchers from otherOACs; moderate sample size.

Major bleeding-related hospitalization during follow-up

Dabigatran was associated with a similar rate of major bleeding

and hospital length of stay vs apixaban

HRs (95% CI) vs apixaban

HR 2.06 (1.19–3.57)

HR 1.18 (1.04–3.11)

HR 1.65 (0.90–3.00)

April 2012

What can we expect in the field of DOACs ?

April 2012Boehringer Ingelheim Clinical Trial Protocol, Trial No. 1160.204

RE-CIRCUIT™: robust data on the use of dabigatran in patients undergoing catheter ablation

Randomization(Month −1)

Warfarin (INR 2.0–3.0)


Day 0 (Ablation)

Target n=362 patients per arm (total N=724 patients)

Patients with paroxysmal or

persistent NVAFscheduled for catheter ablation, eligible for dabigatran 150 mg

BID according to local label

Pre-ablation4–8 weeks

Post-ablation60 days

Screening0–2 weeks Follow-up

Day 60(End of treatment)

Pr imaryendpoint:

ISTH majorbleeding

April 2012

Even the low dose dabigatran regimen displays an excellent profile in left atrial ablation procedures

April 2012

DAPT, dual antiplatelet therapy

1. Lip GY et al. Thromb Haemost 2010;103:13–28; 2. Schlitt A et al. Catheter Cardiovasc Interv 2013;82:E864–704; 3. Ruiz-Nodar JM et al. J Am Coll Cardiol 2008;51:818–25; 4. Nikolsky E et al. Am J Cardiol 2012;109:831–8;5. Lamberts M et al. J Am Coll Cardiol 2013;62:981–9; 6. Dewilde WJ et al. Lancet 2013;381:1107–15

RE-DUAL PCI™: There is a need for robust data on antithrombotic strategy for patients with AF undergoing PCI

PCI in patient with AF:expert consensus =

triple therapy1

Stroke prevention in

AF = OAC

Thrombosis prevention in

PCI = DAPT

~30% of AF patients at risk of stroke have coexisting CAD and

may require PCI:

BUT: how to balance benefit–risk with double vs triple

antithrombotic therapy?4–6

Additional data will help to optimize antithrombotic strategy

High risk of ischaemic CV events and bleeding1–3

April 2012

Antithrombotic therapy after an acute coronary syndrome in AF patients requiring anticoagulation

2016 ESC Guidelines for the management of atrial

fibrillation developed in collaboration with EACTS

April 2012

Antithrombotic therapy after elective percutaneous intervention in AF patients requiring anticoagulation

2016 ESC Guidelines for the management of atrial

fibrillation developed in collaboration with EACTS

April 2012

*Warfarin arm: 1 month after bare metal stent or 3 months after drug-eluting stent

Adapted from Cannon C. AHA 2013 and Boehringer Ingelheim data on file

RE-DUAL PCI™: two new approaches to improving care for patients with AF undergoing PCI

Dual primary endpoints: death, MI, stroke/SE and major bleeding

Patients with AF undergoing PCI (n=8520)

R

Dabigatran 150 mg BID + clopidogrel/ticagrelor

Screening

0–72 hours after PCI

Dabigatran 110 mg BID + clopidogrel/ticagrelor

Warfarin (INR 2.0–3.0) + clopidogrel/ticagrelor*

n=2840 patients per arm

Minimum treatment duration: 6 months

April 20121. Andersen K et al. Stroke 2009;40:2068–72; 2. Adams HP et al. Stroke 1993;24:35–41; 3. Hart RG et al. Lancet Neurol 2014;13:429–38

RE-SPECT ESUS™: There is currently limited data to guide preventative treatment after embolic strokes of undetermined source

92% of all strokes are ischaemic1,2

25% are cryptogenic2,3

If clearly specified diagnostic criteria are

fulfilled

ESUS3

A subgroup of these strokes are due to thromboembolism

~300 000 incident cases/year in North America and Europe3

Standard of care:Antiplatelets

Clinical data limited

April 2012

*All patients receive dabigatran 150 mg BID, unless ≥75 years or CrCl 30–50 mL/min. These patients receive dabigatran 110 mg BID; †0 days–6 months in patients aged >60 years with additional risk factors

Adapted from Boehringer Ingelheim press release 19 November 2013; available at: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/19_november_2013_dabigatranetexilate1.html ; accessed November 2014

RE-SPECT ESUS™: efficacy and safety of dabigatran for secondary stroke prevention after ESUS

Primary endpoints: stroke & SE // major bleeding

30-dayfollow-up0 days–3 months† 0.5–3 years

‘Diagnostic pathway’:

Assess with MRI/CTto rule out lacunae; vascular imagingand ≥24-hour rhythm monitoring to ruleout AF

Patients with ESUS(estimated n=6000) n=3000

n=3000

Dabigatran (150 or 110 mg BID)*

ASA (100 mg OD)

Placebo (matching dabigatran)

Placebo (matching ASA)

End of treatment

R

http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/19_november_2013_dabigatranetexilate1.html

April 2012Huisman et al. Am Heart J 2014; Huisman et al. Am J Med 2015

GLORIA™-AF: observation registry programme with a unique study design

up to 56 000 patients Up to 2200 sites up to 50 countries

All patients

Phase IIICross-sectional and comparative analysis

Patients on dabigatran etexilate

Phase IICross-sectional, cohort, andcase-control analysis

Phase ICross-sectional analysis

Patients with newly diagnosed AF at risk of stroke (CHA2DS2-VASc score ≥1)

May 2011–Jan 2013

April 2012Huisman et al. ESC 2015

GLORIA™-AF Phase II (Europe): clear shift away from VKAs and ASA following introduction of the NOACs

Phase I(n=291)

Phase II(n=7108)

VKA 64% 38%

ASA 25% 5%

None 9% 4%

NOAC 0 52%

April 2012

Thank you very much for your attention

Bad Krozingen, 2008

April 2012

Thank you very much for your attention !!!!!!

Bad Krozingen, 2008

Documents

ΝΕΟΤΕΡΑ ΑΝΤΙΠΗΚΤΙΚΑ. Από ις μ xλέ xς σ ην ... · 2016-10-01 · April 2012 Eur Heart J 2016 Latest 2016 ESC guidelines recommend NOACs over VKAs. April