Dopo i grandi trial sui NAO:
studi post-marketing,registri e dati dal
mondo reale
Dr. Claudio Fresco
Responsabile Scientifico Dipartimento Scienze
Cardiopolmonari, AOUD
Presidente Eletto, ATBV
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Disclosures
• 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
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Ingelheim
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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Concludendo
1. 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
68%
Eligible
CHADS
74%
Apixaban
65%
72%
Rivaroxaban
51%
56%
Dabigatran
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*
Thromb Haemost 2012; 107: 584–589
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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 Teorico
Net Clinical benefit
Thromb Haemost 2012; 107: 584–589
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Il Mondo Reale…
DABIGATRAN
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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
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
22
SPAF
Safety and efficacy of dabigatran are maintained
long-term in the RELY-ABLE® extended follow-up trial
Rates of major bleeding remained
consistent over 6.7 years of follow-up
Dabigatran 150 mg BID
Cumulative risk
0.25
0.20
0.15
Stroke/SE remained low
Dabigatran 110 mg BID
0.25
D150: 3.34%/yr
D110: 2.76%/yr
HR: 1.22; 95% CI: 1.08–1.37
0.20
0.15
0.10
0.10
0.05
0.05
0.0
0.0
0
1
2
3
4
D150: 1.25%/yr
D110: 1.54%/yr
HR: 0.81; 95% CI: 0.68–0.96
5
6
0
1
2
3
4
5
6
Time from randomization (years)
Time from randomization (years)
No at risk:
D110
6015
5616
4075
2658
2085
903
158
6015
5706
4190
2737
2147
929
157
D150
6076
5622
4130
2638
2077
910
146
6076
5774
4276
2753
2181
953
149
Connolly S et al. Circulation 2013;128:237–43; Ezekowitz M. AHA 2013; abstr 10684
23
‘EU label’ analysis assessed outcomes when dabigatran
was used according to EU label recommendations
Full RE-LY® population
(n=18 113)
Patients fully
randomized:
Post-hoc analysis of patients’ baseline
characteristics
D150
D110
recommended
recommended
population (71.4%)*
population (28.6%)*
Received D110
(under-treated)
n=4307
Received D110
(recommended)
n=1708
n=6076
Received D150
(recommended)
n=4296
Received D150
(over-treated)
n=1780
Warfarin
n=6022
Received
warfarin
n=4324
Received
warfarin
n=1698
D110
n=6015
D150
<80 years and
HAS-BLED <3
OR verapamil
SPAF
Post-hoc pooled population
‘EU label simulated dabigatran’
vs warfarin
Dabigatran
recommended
dose
Warfarin
≥80 years OR
HAS-BLED ≥3
OR verapamil
*Percentages expressed as proportion of total RE-LY® population
Lip GY et al. Thromb Haemost 2014;111:933–42
24
‘EU label-compliant’ dabigatran treatment provides a
meaningful and clinically relevant benefit over warfarin
Source
SPAF
HR vs warfarin
Efficacy endpoints (ITT)
Primary: stroke/SE
Ischaemic stroke
Haemorrhagic stroke
Death
Vascular death
MI
Safety endpoints (safety set)
MBE
0.74 (0.60–0.91)
0.91 (0.72–1.15)
0.22 (0.11–0.44)
0.86 (0.75–0.98)
0.80 (0.68–0.95)
1.14 (0.83–1.55)
0.85 (0.73–0.98)
Life-threatening MBE
ICH
GI MBE
Any bleeds
0.72 (0.58–0.91)
0.28 (0.17–0.45)
1.23 (0.96–1.59)
0.86 (0.81–0.92)
0.1
1
Favours dabigatran
1.6
Favours warfarin
Stroke/SE
Major bleed
Mortality
RR (95% CI)
RR (95% CI)
RR (95% CI)
0.74
(0.60–0.91)
0.85
(0.73–0.98)
0.86
(0.75–0.98)
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 event
Lip GY et al. Thromb Haemost 2014;111:933–42
25
Independent FDA study of Medicare patients analysed
outcomes in >134 000 new users of dabigatran or warfarin
• 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
Study period
2010
2011
2012
• >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
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
26
Independent FDA Medicare analysis findings support favourable
benefit–risk profile of dabigatran shown in RE-LY®*
HR: 0.97
P=0.50
Incidence rate per
100 person-years
Medicare1
Warfarin
5
4
3
2
Dabigatran 150 mg & 75 mg BID
combined
HR: 0.80
P=0.02
HR: 0.86
P=0.006
HR: 1.28
P<0.001
HR: 0.92
P=0.29
HR: 0.34
P<0.001
1
0
4
Event rate
(% per year)
RE-LY®2–5
5
Warfarin
Dabigatran 150 mg BID
3
2
RR: 0.76
P=0.04
1
RR: 0.88
P=0.05
RR: 0.94
P=0.41
RR: 1.48
P=0.001
RR: 0.41
P<0.001
RR: 1.27
P=0.12
0
Ischaemic stroke
ICH
Major bleeding
GI bleeding
MI
Mortality
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
27
Favourable benefit–risk profile of dabigatran supported by
real-world evidence: US Department of Defense database
HR (95% CI)
• Observational study
(Oct 2010 to Jul 2012)
• US DoD database
Stroke
0.73 (0.55–0.97)
Ischaemic stroke
0.84 (0.62–1.13)
Haemorrhagic
stroke
0.32 (0.14–0.73)
Major bleeding
• >25 000 new users of
dabigatran or warfarin
available for matching
• All NVAF patients
• Aged 18–89 years at
index date
0.87 (0.74–1.02)
Major ICH
0.49 (0.30–0.79)
Major GI bleeding
1.13 (0.94–1.37)
MI
0.65 (0.45–0.95)
Death
0.64 (0.55–0.74)
0.0
0.5
1.0
Favours dabigatran
Pradaxa®
Pradaxa®
Pradaxa®
In the USA, the licensed doses for
are:
150 mg BID and
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
1.5
2.0
Favours warfarin
75 mg BID for the prevention
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Favourable benefit–risk profile of dabigatran supported by
real-world evidence: independent Danish registry
VKA-naïve stratum
• Observational cohort study
(Aug 2011 to May 2013)
• Nationwide Danish registries
• 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
D110
vs W
D150
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)
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)
0.10
0.50 1.00 2.00 5.00
Favours dabigatran Favours warfarin
*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
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Il Mondo Reale…
RIVAROXABAN
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Il Mondo Reale…
RIVAROXABAN
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Major
Bleeds
Rocket AF
Dresden
Registry
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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Apixaban
Terzo 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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Conclusioni
1. 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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