Dopo i grandi trial sui NAO: studi post-marketing,registri e dati dal

mondo reale

Dr. Claudio FrescoResponsabile Scientifico Dipartimento Scienze

Cardiopolmonari, AOUDPresidente Eletto, ATBV

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• Relatore a congressi sponsorizzati da Boehringer Ingelheim, Bayer, Pfizer, BMS, Daiichi Sankyo

• Responsabile Scientifico del sito www.pantareionline.it, supportato da un grant incondizionato di Boehringer Ingelheim

Disclosures

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I trials ci sono stati presentati bene??

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Primary Efficacy Outcome:Stroke and Systemic Embolism

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Haemorrhagic Stroke

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Dove sta il problema?

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Haemorrhagic Stroke

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Non haemorragic stroke

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Systemic Embolism

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Major Bleeding

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Major Gastrointestinal Bleeding

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Concludendo1. Dabigratran 150 mg bid is more effective in preventing SSE than W

without significantly increasing MB.2. Dabigatran 110 mg bid is non-inferior to warfarin for the prevention

of SSE and causes less MB.3. Rivaroxaban is non-inferior to W for the prevention of SSE without

significantly increasing MB.4. Apixaban is superior to W in preventing SSE, reducing bleeding and

mortality.5. Edoxaban 60 mg is non-inferior to W for the prevention of SSE,

reduces the risk of MB and CV death.6. Edoxaban 30 mg is non-inferior to W for the prevention of SSE,

reduces the risk of MB and CV death.

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I pazienti dei trials sono gli stessi che vediamo ogni giorno?

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Lee S et al. BMJ Open 2012;

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• The source population for this research, that is, the General Practice Research Database (GPRD) is the largest primary care database in the world.

• 83.898 patients included in the analysis

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Drug Eligible ChadsVasc

Eligible CHADS

Dabigatran 68% 74%

Apixaban 65% 72%

Rivaroxaban 51% 56%

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Thromb Haemost 2012; 107: 584–589

*Gli effetti attesi

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Approccio Teorico:Stroke Ischemico

Thromb Haemost 2012; 107: 584–589

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Approccio Teorico:ICH

Thromb Haemost 2012; 107: 584–589

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Approccio TeoricoNet Clinical benefit

Thromb Haemost 2012; 107: 584–589

Il Mondo Reale…

DABIGATRAN

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In the USA, the licensed doses for Pradaxa® are: Pradaxa® 150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF. Pradaxa® 110 mg BID is indicated for certain patients in Europe, and was shown to be as effective as warfarin in preventing stroke or systemic embolism.

1. Available at www.fda.gov/Drugs/DrugSafety/ucm396470.htm; accessed September 2014; 2. Villines TC et al. AHA 2014; 3. Seeger JD et al. AHA 2014; 4. Larsen TB et al. Am J Med 2014;127:650–6.e5; 5. Larsen TB et al. Am J Med 2014;127:329–36.e4

Real-world evidence from >200 000 patients is largely consistent with the results from RE-LY®

Positive safety and efficacy profile of dabigatran vs warfarin confirmed in:

FDA study of >134 000 US Medicare patients1

>25 000 pts from US Department of Defense database2

>38 000 pts from two large US health insurance databases3

>20 000 pts from independent Danish observational studies4,5

22

Connolly S et al. Circulation 2013;128:237–43; Ezekowitz M. AHA 2013; abstr 10684

Safety and efficacy of dabigatran are maintained long-term in the RELY-ABLE® extended follow-up trial

No at risk:

D110 6015 5616 4075 2658 2085 903 158

D150 6076 5622 4130 2638 2077 910 146

Dabigatran 150 mg BID

0.25

0.20

0.15

0.05

0.10

0.00 1 2 3 4 5 6

Time from randomization (years)

Dabigatran 110 mg BID

D150: 3.34%/yrD110: 2.76%/yrHR: 1.22; 95% CI: 1.08–1.37

Cum

ulat

ive

risk

0.25

0.20

0.15

0.05

0.10

0.00 1 2 3 4 5 6

Time from randomization (years)

D150: 1.25%/yrD110: 1.54%/yrHR: 0.81; 95% CI: 0.68–0.96

6015

5706 4190 2737 2147 929 157

6076

5774 4276 2753 2181 953 149

Rates of major bleeding remained consistent over 6.7 years of follow-up

Stroke/SE remained low

SPAF

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Received D150(over-treated)

n=1780

Received D110(recommended)

n=1708

*Percentages expressed as proportion of total RE-LY® population Lip GY et al. Thromb Haemost 2014;111:933–42

‘EU label’ analysis assessed outcomes when dabigatran was used according to EU label recommendations

Patients fully randomized:

D150recommended

population (71.4%)*

D110recommended

population (28.6%)*‘EU label simulated dabigatran’

vs warfarin

D110n=6015

D150n=6076

Warfarinn=6022

Received D110(under-treated)

n=4307

Received D150(recommended)

n=4296

Received warfarinn=4324

Dabigatranrecommended

dose

Warfarin

≥80 years ORHAS-BLED ≥3OR verapamil

<80 years andHAS-BLED <3OR verapamil

Received warfarinn=1698

SPAF

Full RE-LY® population (n=18 113)

Post-hoc pooled populationPost-hoc analysis of patients’ baseline characteristics

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Data from EU label simulated dabigatran treatment analysis. Patients received dabigatran 150 mg BID or 110 mg BID according to EU label recommendations

ITT, intention to treat; MBE, major bleeding eventLip GY et al. Thromb Haemost 2014;111:933–42

‘EU label-compliant’ dabigatran treatment provides a meaningful and clinically relevant benefit over warfarin

Source HR vs warfarin

Efficacy endpoints (ITT)

Primary: stroke/SE 0.74 (0.60–0.91)

Ischaemic stroke 0.91 (0.72–1.15)

Haemorrhagic stroke 0.22 (0.11–0.44)

Death 0.86 (0.75–0.98)

Vascular death 0.80 (0.68–0.95)

MI 1.14 (0.83–1.55)

Safety endpoints (safety set)

MBE 0.85 (0.73–0.98)

Life-threatening MBE 0.72 (0.58–0.91)

ICH 0.28 (0.17–0.45)

GI MBE 1.23 (0.96–1.59)

Any bleeds 0.86 (0.81–0.92)Favours dabigatran Favours warfarin

0.1 1.61

Stroke/SERR (95% CI)

0.74(0.60–0.91)

Major bleedRR (95% CI)

0.85(0.73–0.98)

MortalityRR (95% CI)

0.86(0.75–0.98)

SPAF

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In the USA, the licensed doses for Pradaxa® are: Pradaxa® 150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF

Graham DJ et al. Circulation 2015;131:157-64

Independent FDA study of Medicare patients analysed outcomes in >134

000 new users of dabigatran or warfarin

• >134 000 new users (OAC treatment-naïve) of dabigatran or warfarin

• All recently diagnosed with AF• All aged ≥65 years• 37 500 person-years of follow-up• Adjustments were made for

confounding variables

• Observational cohort study • US Medicare database• Comparison of ischaemic stroke,

ICH, major GI bleeding, acute MI, and mortality rates using insurance-claim and administrative data

2010 2011 2012

Study period

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In the USA, the licensed doses for Pradaxa® are: Pradaxa® 150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF. Pradaxa® 110 mg BID is indicated for certain patients in Europe, and was shown to be as effective as warfarin in preventing stroke or systemic embolism. RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) study *Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Numbers above bars denote HRs vs warfarin. 1. Graham DJ et al. Circulation 2015;131:157-64; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–6; 4. Pradaxa®: EU SPC, 2014; 5. Connolly SJ et al. N Engl J Med 2014; 371:1464–5

Independent FDA Medicare analysis findings support favourable benefit–risk profile of dabigatran shown in RE-LY®*

0

1

2

3

4

5Warfarin

Dabigatran 150 mg & 75 mg BID combined

Inci

de

nce

ra

te p

er

10

0 p

ers

on

-ye

ars

HR: 0.86P=0.006HR: 1.28

P<0.001

HR: 0.80P=0.02

HR: 0.92P=0.29HR: 0.34

P<0.001

HR: 0.97P=0.50

Med

icar

e1

Ischaemic stroke

ICH Major bleeding GI bleeding MI Mortality0

1

2

3

4

5Warfarin

Dabigatran 150 mg BID

Eve

nt r

ate

(% p

er

yea

r)

RR: 0.88P=0.05

RR: 1.48P=0.001 RR: 1.27

P=0.12

RR: 0.76P=0.04 RR: 0.41

P<0.001

RR: 0.94P=0.41

RE

-LY

®2–

5

27

In the USA, the licensed doses for Pradaxa® are: Pradaxa® 150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF

Comparison groups (each n=12 793) established using propensity score matching

Villines TC et al. AHA 2014

Favourable benefit–risk profile of dabigatran supported by real-world evidence: US Department of Defense database

• >25 000 new users of dabigatran or warfarin available for matching

• All NVAF patients

• Aged 18–89 years at index date

• Observational study (Oct 2010 to Jul 2012)

• US DoD database

0.5 1.0 1.50.0 2.0

Stroke

Ischaemic stroke

Haemorrhagicstroke

Major ICH

MI

Major bleeding

Major GI bleeding

Death

0.73 (0.55–0.97)

0.84 (0.62–1.13)

0.32 (0.14–0.73)

0.49 (0.30–0.79)

0.65 (0.45–0.95)

0.87 (0.74–1.02)

1.13 (0.94–1.37)

0.64 (0.55–0.74)

HR (95% CI)

Favours dabigatran Favours warfarin

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*Adjusted HR: age, components of CHA2DS2-VASc, HAS-BLED, months since August 2011, time since initiation of VKA therapy; W, warfarin

Larsen TB et al. Am J Med 2014;127:650–6.e5

Favourable benefit–risk profile of dabigatran supported by real-world evidence: independent Danish registry

• 11 315 first-time dabigatran users (7063 VKA-naïve) vs 22 630 matched warfarin users

• VKA-naïve = ≥2 years since last warfarin purchase

• All AF patients

• Observational cohort study (Aug 2011 to May 2013)

• Nationwide Danish registries

VKA-naïve stratum

D110vs W

D150vs W

0.72 (0.59–0.88)

0.93 (0.74–1.16)

0.52 (0.28–0.95)

0.50 (0.27–0.94)

0.30 (0.17–0.54)

Favours dabigatran Favours warfarin

0.68 (0.55–0.84)

0.67 (0.53–0.85)

0.70 (0.33–1.52)

1.45 (0.84–2.50)

0.33 (0.17–0.66)

Any

Major

Fatal

GI

ICH

Any

Major

Fatal

GI

ICH

0.10 0.50 1.00 2.00 5.00

HR* (95% CI)

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Il Mondo Reale…

RIVAROXABAN

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Il Mondo Reale…RIVAROXABAN

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Rocket AF Dresden Registry

Major Bleeds

3.6 3.1

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Current Medical Research & Opinion 2014, 1–9

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Il Mondo Reale…

Apixaban

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ApixabanTerzo NOAC, approvato da meno tempo rispetto a dabigatran e rivaroxaban. Non ci sono motivi per pensare che nel mondo reale debba comportarsi in modo diverso rispetto agli altri due NOAC

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Conclusioni1. Contrariamente a quello che solitamente succede,

dove i risultati dei trials sono in parte mitigati dalle analisi dei registri, nel caso dei NOAC i registri confermano e anche amplificano i benefici osservati negli studi registrativi

2. Non dobbiamo quindi aver paura di utilizzare questi farmaci, perché a lungo termine i benefici saranno evidenti

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