Congresso Interregionale A.R.C.A. del Nord

Genova, 23-24 Ottobre 2015

Dott. Sergio AgostiDirigente MedicoSOC Cardiologia Ospedale Novi Ligure

NAO: vi sono reali vantaggi rispetto al Warfarin?

➢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?

Assume that NAOs have been on the market for 5 year

A new era of anticoagulation?

Diener H-C et al. Int J of Stroke: Vol 7, February 2012, 139–141

A new era of anticoagulation?

WOULD WARFARIN BE

APPROVED TODAY?

Lancet, published online December 4, 2013

STROKE OR SYSTEMIC EMBOLISM

Ruff CT, Lancet, December 4, 2013

NNT 173

MAJOR BLEEDING

Ruff CT, Lancet, December 4, 2013

EFFICACY AD SAFETYSECONDARY ENDPOINTS

ICH NNT 141

Ruff CT, Lancet, December 4, 2013

Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014

Haemorrhagic stroke

Mackmann, Anesth Analg. 2009 May; 108(5):1447-52The role of tissue factor and factor VIIa in hemostasis.

Haemorrhagic stroke (TF receptor)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm

Antidoto

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 anniMAJOR 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 anniSTROKE 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 moderataMAJOR 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 moderataSTROKE 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

-1

-2

-3

-4

Chan

ge fr

om B

asel

ine

30 6 9 12 15 18 21 3024 27

Months

DE 110mg bid DE 150mg bid Warfarin*

*p< 0.005 vs warfarin

**

Available patients

3 months 6 months 12 months 24 months 30 months

DE 110mg bid 5130 5000 4686 3368 1672DE 150mg bid 5171 5005 4696 3434 1685Warfarin 5243 5146 4895 3519 1703

Michael Böhm, ESC 2014, Barcelona, 30 Aug - 3 Sep 2014

Schurgers et al,Blood 109 (2007): 2823-2831

Brodsky et al,Kidney Int 109 (2011): 181-189

Price et al,Arterioscler Thromb Vasc Biol 18 (1998): 1400-1407

Krüger et al,Arterioscler Thromb Vasc Biol 33 (2013): 2618-2624

Backgroun: Vitamin K-Antagonists Induce Vascular Damage

NOA in patients with valvular atrial fibrillation

Updated EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with NVAF: Heidbuchel, August 31, 2015

Definition of non valvular atrial fibrillation (NVAF)

NAO in numeri….

• 180000 pz nei trials

• Oltre 18 milioni di pz trattati nel mondo

• 6200 articoli - studi clinici (PUBMED)

• Almeno 300000 pz nei registri

Real world data

Due importanti problemi nell’interpretazione dei dati

provenienti dal mondo reale (registri e studi osservazionali)

• Selection bias

• Prescrizione inappropriata

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)

Incidence rate per 1000 person-years 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.

Medicare analysis: resultsMedicare analysis: results

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)

Incidence rate per 1000 person-years 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.

Medicare analysis: resultsMedicare analysis: results

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)

Incidence rate per 1000 person-years 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.

Medicare analysis: resultsMedicare analysis: results

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)

Incidence rate per 1000 person-years 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.

Medicare analysis: resultsMedicare analysis: results

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 prior stroke, SE or TIA; *Events per 100 patient-years

1. 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

ROCKET AF1 mean CHADS2-Score 3.5

n=7,111

Eve

nt r

ate

(%/y

ear

)

*Major bleeding definitions according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding)**Major bleeding was defined by the Cunningham algorithm3

#55th ASH Meeting 2013, Oral presentation, Abstract 213, https://ash.confex.com/ash/2013/webprogram/Paper58333.html1. 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

n=1,200

Major Bleeding Rates with Rivaroxaban:Low and consistent in clinical trial and real life setting

Dresden NOAC Registry2

mean CHADS2-Score 2.4#

US DoD PMSS3

mean CHADS2-Score 2.25

n=39,052

2.9

3,6

2.93.1

XANTUS4

mean CHADS2-Score 2.1

n=6,784

2.1

Data on more than 54.000 rivaroxaban treated patients

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

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