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(A) and major bleeding

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(A) and major bleeding
Gli anticoagulanti diretti nel mondo reale
Il neurologo: Efficacia e sicurezza
Antonio Carolei* e Cindy Tiseo
Clinica Neurologica e Stroke Unit Avezzano - Sulmona
Università degli Studi dell’Aquila
*Presidente Italian Stroke Organization
Roma, 15 febbraio 2016
Natural history of AF
J Am Heart Assoc 2016;5:e002984 doi: 10.1161/JAHA.115.002984
…despite a great unmet need for safer antiarrhythmic drugs,
developments in this field are expected to be much slower
Two potential antiarrhythmic drugs are forecast to enter the
market within the next decade. Both drugs candidates are
expected to launch late in the forecast period and will not
reach peak sales until after 2023
The low level of activity in the pipeline is expected to continue
due to the high risk involved in developing antiarrhythmic
drugs
VKAs vs NOACs
Decision tree for antithrombotic therapy
in patients with nvAF
Antithrombotic
therapy
Eur Heart J 2012;33:2719-2747 & Europace 2015;17:1467-507
Why should we care about any real world
data versus clinical trial?
Efficacy (Clinical trial data)
Effectiveness (Real-world data)
 Does it work under ideal
circumstances?
 Controlled clinical trial
environment
 Geared to get FDA approval
 Fixed regimen with highly
motivated patients
 Compliance usually high
 External validity - low to medium
 Does it work under usual
circumstances?
 Real world clinical practice
 Drug performance in the real
world
 Flexible regimen with your regular
day to day clinic patient
 Low to high compliance
 External validity - medium to high
Favourable risk-benefit profile
Lancet 2014;383:955-962
Efficacy of NOAC in the SPAF Trials
Ischemic stroke or Systemic embolism
RRR 19%
Major bleeding
RRR 14%
Lancet 2014;383:955-962
*
Efficacy of NOAC in the SPAF Trials
Secondary efficacy and safety outcomes
Ischemic vs hemorrhagic stroke
RRR 8%
RRR 51%
RRR 52%
Lancet 2014;383:955-962
*
*
Stroke or SE
Major bleeding
Compared
OR for all-cause
with standard
stroke oradjusted
systemicdose
embolism
VKA, (A)
newand
oralmajor
anticoagulants
bleeding (B)
were
in
associated
Bayesian network
with modest
meta-analysis
reductions
versus
in standard
the absolute
adjusted
riskdose
of stroke
VKA. CrI,
andcredible
major
bleeding.
interval; VKA, vitamin K antagonist. BMJ Open 2014;4:e004301
What do these meta-analyses tell us?
Overall the results appear reassuring for the NOACs
NOACs are associated with significant reduction in major bleeding,
fatal bleeding, intracranial bleeding, clinically relevant non-major
bleeding and total bleeding
However, results should be interpreted in the context that these
analyses included patients that participated in major randomized
trials where the environment was more controlled
They may not reflect the “true” incidence of bleeding in the real day
to day clinical practice world
The EURObservational Research Programme Atrial Fibrillation
(EORP-AF) Pilot Registry has provided systematic collection of
contemporary data regarding the management and treatment of
AF by cardiologists in ESC member countries
Oral anticoagulant use has increased, but novel OAC use was still
low (8%). Compliance with the treatment guidelines for patients
with the lowest and higher stroke risk scores remains suboptimal
Europace 2014:16,308-319
Between
February 2012 and March 2013
Europace 2014:16,308-319
*
J Am Coll Cardiol 2013 ;61:2264-73
Major bleedings
Warfarin vs Apixaban
MARKETSCAN REAL-WORLD
Studio ARISTOTLE
HR=0.69 (95% CI: 0.60–0.80)
HR=0.52 (95% CI: 0.30–0.89)
RRR 31%
RRR 48%
3.09
2.13
N=9052
N=9088
Incidenza dell’evento
(%/anno)
4.66
N Engl J Med 2011;365:981-92 & Lip ESC 2015
2.35
N=12,713
N=2402
Major bleedings
Warfarin vs Apixaban - Rivaroxaban - Dabigatran
RRR 48%
Lip ESC 2015
RRR 12%
XANTUS vs ROCKET-AF
Eur Heart J 2015 [Epub ahead of print]
Comparison of Major Bleeding, Stroke and Associated Medical Costs among
Treatment-naïve Non-valvular Atrial Fibrillation Patients Initiating Apixaban,
Dabigatran, Rivaroxaban or Warfarin within One Year of Treatment Initiation
Major bleedings
Adjusted HR: 0.87; 95% CI: 0.74 – 1.03
P = 0.109
Adjusted HR: 0.71, RRR 29%; 95% CI: 0.62– 0.82
P < 0.001
*
Adjusted HR: 0.71, RRR 29%; 95% CI: 0.62 – 0.80
P < 0.001
Favours Apixaban
Favours comparator
Adjusted HR
*ARISTOTLE: HR=0.69 (95% CI 0.60–0.80)
RRR 31%, P< 0.001 for superiority
Comparison of Major Bleeding, Stroke and Associated Medical Costs among
Treatment-naïve Non-valvular Atrial Fibrillation Patients Initiating Apixaban,
Dabigatran, Rivaroxaban or Warfarin within One Year of Treatment Initiation
Stroke and SE
Adjusted HR: 0.91; 95% CI: 0.81 – 1.02
P = 0.120
Adjusted HR: 0.94; 95% CI: 0.86 – 1.04
P = 0.215
*
Adjusted HR: 0.74, RRR 26%; 95% CI: 0.68 – 0.81
P <0.001 *
Favours Apixaban
Favours comparator
Adjusted HR
*ARISTOTLE: HR 0.79 (95% CI: 0.66-0.95)
RRR 21%, P=0.01 for superiority
Circ Cardiovasc Qual Outcomes 2016;DOI: 10.1161/CIRCOUTCOMES.115.002369
Circ Cardiovasc Qual Outcomes 2016;DOI: 10.1161/CIRCOUTCOMES.115.002369
Conclusions
Registries and trials are complementary
Randomized clinical trials determine the efficacy and safety
compared with VKA
Registries test how these drugs work in the real world
Some patients are overtreated and do not need
anticoagulation (patients at very low risk for stroke)
Other patients at high risk for stroke do not receive the
treatment they need
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