Congresso Interregionale
A.R.C.A. del Nord
NAO: vi sono reali
vantaggi rispetto al
Warfarin?
Dott. Sergio Agosti
Dirigente Medico
SOC Cardiologia
Ospedale Novi Ligure
Genova,
23-24 Ottobre 2015
Assume that NAOs have been on the market for 5 year
➢A new drug comes to the market. Compared to NAOs, the new drug has:
- cheaper
- antidote
- requirement for monthly monitoring to adjust dose
- many food and drug interactions
- 25% increased relative risk of stroke/systemic embolism
- nearly 50% increased relative risk of major bleeding
- approx. 2.5 times the rate of ICH
- 10% increased relative risk of mortality
➢Would Warfarin be approved by regulatory authorities now?
A new era of anticoagulation?
A new era of anticoagulation?
Diener H-C et al. Int J of Stroke: Vol 7, February 2012, 139–141
Lancet, published online December 4, 2013
STROKE OR SYSTEMIC EMBOLISM
NNT 173
Ruff CT, Lancet, December 4, 2013
MAJOR BLEEDING
Ruff CT, Lancet, December 4, 2013
EFFICACY AD SAFETY
SECONDARY ENDPOINTS
ICH NNT 141
Ruff CT, Lancet, December 4, 2013
Haemorrhagic stroke
Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel
Caldeira et al. J Neurol 2014
Haemorrhagic stroke (TF receptor)
Mackmann, Anesth Analg. 2009 May; 108(5):1447-52
The role of tissue factor and factor VIIa in hemostasis.
Antidoto
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm
In which patients
 Elderly patients
 Patients with renal insufficiency
 Patients with valvular atrial fibrillation
NOA in Elderly patients
Risk of non prescription of OAC by age
NAO vs Warfarin nei pazienti > 75 anni
MAJOR BLEEDING
J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults:
evidence from a meta-analysis of randomized trials. Sardar P, Lip G.
NAO vs Warfarin nei pazienti > 75 anni
STROKE OR SE
J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults:
evidence from a meta-analysis of randomized trials. Sardar P, Lip G.
NOA in patients with renal
insufficiency
Chronic kindney disease is common among AF patients
Kooiman et al. J Thromb Haemost 2011;9:1652–3
Chronic kindney disease increases the risk of stroke, bleeding, and
all-cause death in AF patients
Olesen et al. N Engl J Med 2012;367:625–35.
Xa inhibitors are eliminated from the body
via multiple routes
NAO vs Warfarin nei pazienti con IR moderata
MAJOR BLEEDING
Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials.
Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.
NAO vs Warfarin nei pazienti con IR moderata
STROKE OR SE
Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials.
Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.
Raccomandazioni dell’ESC nei pazienti con IR
Raccomandazioni dell’EHRA
nei pazienti con IR (2015)
Cambiamento della GFR in pt con D110, D150 o Warfarin
0
*p< 0.005 vs warfarin
Change from Baseline
-1
-2
*
*
-3
DE 110mg bid
DE 150mg bid
Warfarin
*
-4
0
3
6
9
12
15
18
21
24
27
30
Months
Available
patients
DE 110mg bid
DE 150mg bid
Warfarin
3 months
6 months
12 months
24 months
30 months
5130
5171
5243
5000
5005
5146
4686
4696
4895
3368
3434
3519
1672
1685
1703
Michael Böhm, ESC 2014, Barcelona, 30 Aug - 3 Sep 2014
Backgroun: Vitamin K-Antagonists Induce Vascular Damage
Price et al,
Arterioscler Thromb Vasc Biol 18 (1998): 1400-1407
Schurgers et al,
Blood 109 (2007): 2823-2831
Brodsky et al,
Kidney Int 109 (2011): 181-189
Krüger et al,
Arterioscler Thromb Vasc Biol 33 (2013): 2618-2624
NOA in patients with valvular
atrial fibrillation
Definition of non valvular atrial fibrillation (NVAF)
Updated EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with NVAF:
Heidbuchel, August 31, 2015
NAO in numeri….
• 180000 pz nei trials
• 6200 articoli - studi clinici (PUBMED)
• Almeno 300000 pz nei registri
• Oltre 18 milioni di pz trattati nel mondo
Real world data
Due importanti problemi
nell’interpretazione dei dati
provenienti dal mondo reale (registri e studi
osservazionali)
• Selection bias
• Prescrizione inappropriata
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Medicare analysis: results
Incidence rate per 1000 personyears
Adjusted HR
(95% CI)
Dabigatran
Warfarin
Ischaemic stroke
11.3
13.9
0.80 (0.67-0.96)
Intracranial haemorrhage
3.3
9.6
0.34 (0.26-0.46)
Major gastrointestinal
bleeding
34.2
26.5
1.28 (1.14-1.44)
Acute myocardial infarction
15.7
16.9
0.92 (0.78-1.08)
Mortality
32.6
37.8
0.86 (0.77-0.96)
Dabigatran was associated with a lower risk of ischaemic stroke, intracranial
haemorrhage and death than warfarin.
Risk of MI was similar for dabigatran and warfarin.
Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg
together without stratification by dose. Warfarin is the reference group. CI = confidence
interval; HR = hazard ratio; MI = myocardial infarction;
Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)
Global Registry on Long-Term Oral
Antithrombotic Treatment in AF Patients
• Collection of data on dabigatran in countries/regions and globally
• Increase knowledge on AF patients, treatment patterns, and outcome events
in a real-world setting
• Involvement of up to 2200 physicians worldwide: GPs, cardiologists,
neurologists, internists, geriatricians, etc – hospital based or private practice
up to
56 000
patients
2200
sites
up to
50 countries
Comparison of Main Outcomes:
XANTUS versus ROCKET AF
CHADS2
Prior stroke#
ROCKET AF1
3.5
55%
XANTUS2
2.0
19%
#Includes
1.
prior stroke, SE or TIA; *Events per 100 patient-years
Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
Major Bleeding Rates with Rivaroxaban:
Low and consistent in clinical trial and real life setting
Data on more than 54.000 rivaroxaban treated patients
Dresden NOAC Registry2
US DoD PMSS3
XANTUS4
mean CHADS2-Score 3.5
mean CHADS2-Score 2.4#
mean CHADS2-Score 2.25
mean CHADS2-Score 2.1
Event rate (%/year)
ROCKET AF1
n=7,111
n=1,200
n=39,052
3,6
3.1
2.9
n=6,784
2.
9
2.1
*Major bleeding definitions according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding)
**Major bleeding was defined by the Cunningham algorithm 3
#55th ASH Meeting 2013, Oral presentation, Abstract 213, https://ash.confex.com/ash/2013/webprogram/Paper58333.html
1. Patel MR et al. N Engl J Med 2011; 365(10):883–891; 2. Beyer—Westendorf et al. Blood 2014;124(6); 955-962; 3. Peacok ESC 2015; 4. Camm
et al Eur Heart J 2015; 5. Tamayo et al. Clin Cardiol 2015
Conclusions
• The efficacy and major bleeding results of
NOA vs. warfarin were consistent
• NOA have benefits over warfarin that are
maintained irrespective of age
• NOA have benefits over warfarin that are
maintained irrespective of renal function
• NOA real world data are consistent
GRAZIE PER L’ATTENZIONE
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