Scacco all’ictus!
Dabigatran ed il ruolo del neurologo nelle
strategie di cura e prevenzione dell’ictus
cerebrale cardioembolico
Francesca Romana Pezzella, MD, PhD, BSc
Stroke Unit AO S Camillo Forlanini
• Worldwide, 16 million people suffer a stroke each year
• Italy: 200.000 stroke/year
• 0.27% of gross domestic product was spent on stroke by national health
systems
• stroke care accounted for ∼3% of total health care expenditures
• 27 EU countries, total annual cost of stroke is estimated at €27 billion:
– €18.5 billion (68.5%) for direct cost
– €8.5 billion (31.5%) for indirect costs
• €11.1 billion is calculated for the value of informal care
• Indirect and informal care costs are related to mortality, morbidity and
functional impairment
(Stroke.2006;37:263-266.)
stroke, just one disease?
Sopravvivenza dopo primo episodio di ictus in base
al sottotipo
Lac=339
At=435
Card=224
p=<0.0001
Giorni di follow up
Giorni di follow up
De Jong et al J Clin Epidemiol 2003
De Jong et al J Clin Epidemiol 2003
AF associated with increased risk of recurrent stroke
Recurrent stroke after ischaemic stroke
10
Cumulative probability
of recurrence (%)
8
Patients with AF
6
Patients
without AF
4
P=0.0398
2
0
0
2
4
6
8
10
12
Months after first stroke
6
Marini C et al. Stroke 2005;36:1115–9
Paciaroni et al, Stroke 2008
prevalence of atrial fibrillation in relation to CHADS-VASC score BEFORE stroke onset;
CHADS-VASC counts 2 points for prevoius stroke/TIA, age> 75 aa; 1 point for female sex,
age 65to 74, heart failure, hypertension diabetes, vascular disease.
AF and cardioembolic stroke
1549 PATIENT WITH ISCHEMIC STROKE
Age (yrs)
75.8±12.8
Known AF (%)
15.8
52.1% no treatment
34.9% antiplatelet agents
13% anticoagulants
Only 10.1% adequately treated
New diagnosis of AF (%)
4.9
Paciaroni & Agnelli, JTH 2005
Warfarin purchase within 3 months after ischemic stroke among patients with atrial
fibrillation in relation to risk for new ischemic stroke expressed as CHA2DS2-VASc score at
discharge.
Leif Friberg et al. Stroke. 2014;45:2599-2605
Copyright © American Heart Association, Inc. All rights reserved.
the stroke “cold” case:
atrial fibrillation and stroke victims
✎Atrial fibrillation (AF) is the most common cardiac arrhythmia
(1,5%-2%)
✎Over 6 million Europeans are affected, by 2050 12 milions are expected to be AF victims as
the population ages
✎AF confers a 5-fold risk of stroke, and one in five of all strokes is attributed to AF
✎Ischaemic strokes in association with AF are often fatal, survivors are left more disabled
and more likely to suffer a recurrence than patients with other causes of stroke
✎The risk of death from AF-related stroke is doubled and the cost of care is increased 1.5-fold
✎PREFER (9/2014): 80% patients with OAC: 12,5 NOAC, 67% VKA
20% receive aspirin or no treatment at all!!!
✎EORP-AF (7/2014): 7,7 NOAC; 72,2 5 VKA








Increasing use of warfarin – increasing rates
of anticoagulant-related ICH
1988
1993–1994
1999
All ischaemic
stroke
N/A
140.0
(133.2–146.8)
142.6
(135.8–149.3)
Cardioembolic
ischaemic stroke
N/A
31.1
(27.9–34.3)
30.4
(27.3–33.5)
Cardioembolic
ischaemic stroke
due to AF
N/A
22.0
(19.3–24.7)
20.6
(18.1–23.2)
16.5
(14.1–18.9)
22.1
(19.4–24.8)
24.6
(21.8–27.4)
0.8
(0.3–1.3)
1.9
(1.1–2.7)
4.4
(3.2–5.5)
All ICH
Anticoagulantassociated ICH
Annual incidence rates for intracerebral haemorrhage (ICH) and ischaemic stroke in the Greater
Cincinnati/Northern Kentucky area: age-, sex- and race-adjusted to the 2000 US population,
expressed per 100,000 persons.
Parentheses indicate 95% confidence intervals
Flaherty et al. Neurology 2007;68:116-121
Figura tratta da rif. 2
Tasso di incidenza di emorragie, % per persona/anno
DATI DI REAL LIFE ONTARIO – CANADA: In questo ampio
studio su pazienti anziani con fibrillazione atriale si osserva
una più alta incidenza di emorragie nei primi 30 giorni di
terapia con Warfarin e che circa 1 paziente su 5,
ospedalizzato per emorragia, è morto in ospedale o poco dopo
la dimissione2.
Mesi (finestra temporale di 30 giorni)
Nei pazienti anziani ( ≥ 66 anni), con fibrillazione atriale, il tasso di incidenza delle visite in ospedale per emorragia incrementa nell’arco dei
30 giorni dopo l'inizio della terapia con warfarin. I tassi sono stratificati in base al punteggio CHADS2 all'inizio del trattamento
1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9; 2. Gomes T et al. CMAJ. 2013;185:E121–E127
DATI DI REAL LIFE ONTARIO – CANADA: in pazienti
anziani con fibrillazione atriale che iniziavano il
trattamento con warfarin, il tasso di ictus ischemico era
significativamente più elevato durante il primo mese di
trattamento2
Figura tratta da rif. 2
Tasso di incidenza, % per persona/anno
Incidenza di ictus ischemico tra i pazienti con fibrillazione atriale, naive al warfarin2
Mesi (finestra temporale di 30 giorni)
1 Eikelboom JW et al. J Thromb Haemost 2010;8:1438-9;; 2. Tung Stroke. 2015;46:00-00
• anticoagulante più
efficace nel ridurre
il rischio di ictus
cerebrale
• anticoagulante più
sicuro
• più “facile” per i
pazienti
• risultati dei trial=
risultati del mondo
reale
N Engl J Med 2009;361(12):1139-51
New Anticoagulant Therapies Compared to
Warfarin: Stroke or Systemic Embolism
Study Drug Better
Warfarin Better
Dabigatran 150 mg BID1
HR 0.65 (95% CI, 0.52 to 0.81)
Dabigatran 110 mg BID1
HR 0.90 (95% CI, 0.74 to 1.10)
Rivaroxaban 20 mg QD2
HR 0.88 (95% CI, 0.74 to 1.03)
Apixaban 5 mg BID3
HR 0.79 (95% CI, 0.66 to 0.95)
Edoxaban 60 mg QD4
HR 0.87 (95% CI, 0.73 to 1.04)
HR 1.13 (95% CI, 0.96 to 1.34)
Edoxaban 30 mg QD4
0.5
1
Hazard Ratio
1.Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.
2.Patel MR et al. N Engl J Med. 2011;365:883-891.
3.Granger CB et al. N Engl J Med. 2011;365:981-992.
4.Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907
1.5
New Anticoagulant Therapies Compared to
Warfarin: Intracranial Hemorrhage
Study Drug Better
Warfarin Better
Dabigatran 150 mg BID1
HR 0.41 (95% CI, 0.28 to 0.60)
Dabigatran 110 mg BID1
HR 0.30 (95% CI, 0.19 to 0.45)
Rivaroxaban 20 mg QD2
HR 0.67(95% CI, 0.47 to 0.93)
Apixaban 5 mg BID3
HR 0.42 (95% CI, 0.30 to 0.58)
Edoxaban 60 mg QD4
HR 0.47 (95% CI, 0.34 to 0.63)
Edoxaban 30 mg QD4
HR 0.30 (95% CI, 0.21 to 0.43)
0
0.5
1.0
Hazard Ratio
1.Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.
2.Patel MR et al. N Engl J Med. 2011;365:883-891.
3.Granger CB et al. N Engl J Med. 2011;365:981-992.
4.Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907
1.5
2.0
New Anticoagulant Therapies Compared to
Warfarin: Major Bleeding
Study Drug Better
Warfarin Better
Dabigatran 150 mg BID1
HR 0.93 (95% CI, 0.81 to 1.07)
Dabigatran 110 mg BID1
HR 0.80 (95% CI, 0.70 to 0.93)
Rivaroxaban 20 mg QD2
HR 1.04 (95% CI, 0.90 to 1.20)
Apixaban 5 mg BID3
HR 0.69 (95% CI, 0.60 to 0.80)
Edoxaban 60 mg QD4
HR 0.80 (95% CI, 0.71 to 0.91)
Edoxaban 30 mg QD4
HR 0.47 (95% CI, 0.41 to 0.55)
0.5
1
Hazard Ratio
1.Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.
2.Patel MR et al. N Engl J Med. 2011;365:883-891.
3.Granger CB et al. N Engl J Med. 2011;365:981-992.
21 RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907
4.Giugliano
1.5
Circulation 2013;128:237-43
Stroke and ischaemic events: RELY-ABLE®
D 150 mg D110 mg
Event
HR
95% CI
(%/yr)
(%/yr)
Stroke or SEE
1.46
1.60
0.91
0.69–1.20
All stroke
1.24
1.38
0.89
0.66–1.21
Ischaemic
1.15
1.24
0.92
0.67–1.27
Haemorrhagic
0.13
0.14
0.89
0.34–2.30
Myocardial infarction
0.69
0.72
0.96
0.63–1.45
Pulmonary embolism
0.13
0.11
1.14
0.41–3.15
5851 patients followed for mean of 2.3 years
D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio
Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Doubleblind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.&nbsp; Presented on 7
November 2012 at the American Heart Association Scientific Sessions 2012.
Bleeding events: RELY-ABLE®
RELY-ABLE® only
D150 mg
(%/yr)
D110 mg
(%/yr)
HR
95% CI
3.74
2.99
1.26
1.04–1.53
Life-threatening
1.79
1.57
1.14
0.87–1.49
GI
1.54
1.56
0.99
0.75–1.31
Intra-cranial
0.33
0.25
1.31
0.68–2.51
Extra-cranial
3.43
2.82
1.23
1.01–1.49
Fatal
0.24
0.25
0.94
0.46–1.89
9.70
8.19
1.21
1.07–1.36
Event
Major bleeding
Minor bleeding
5851 patients followed for mean of 2.3 years
D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio
Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Doubleblind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.&nbsp; Presented on 7
November 2012 at the American Heart Association Scientific Sessions 2012.
NOACs Drug Interaction
according to Type of Metabolism
Pengo et al. New oral anticoagulants Thrombosis and Haemostasis 106.5/2011
VKA therapy , apixaban, and dabigatran (1 B) are all indicated for the
prevention of recurrent stroke in patients with nonvalvular AF, whether
paroxysmal or permanent. (Class I; Level of Evidence A)
Rivaroxaban is reasonable for the prevention of recurrent stroke in patients with
nonvalvular AF (Class IIa; Level of Evidence B).
“… we found a surprisingly good adherence; overall 88% of the patients had adequate
adherence, without any difference by sex, age or previous participation in the clinical
trials …”
Gorst-Rasmussen A et al. J Thromb Haemost 2015
Conclusions
More than 75% of patients were showed > 80% adherence to medication
regimens during the first year. Patients with higher morbidity, including
patients with a higher risk of stroke or bleeding, exhibited better adherence.
63%
39%
Maggior frequenza di interruzioni nei pazienti con basso rischio tromboembolico
Circ Cardiovasc Qual Outcomes 2013;6(5):567-74
Real World Data
• Mini Sentinel Registry (FDA)
• Ampio registro del mondo reale Danese
• Medicare (FDA)
La FDA ha richiesto il “Mini Sentinel”:
studio di sicurezza, focalizzato sulla reale incidenza
di sanguinamenti GI ed intracranici
in nuovi pazienti in terapia con Pradaxa rispetto a Warfarin
Baseline Characteristics
J Am Coll Cardiol 2013;61:2264-73
Primary Outcome Measures: Efficacy
Favors
Dabi 110 mg
Favors
Dabi 150 mg
J Am Coll Cardiol 2013;61:2264-73
Primary Outcome Measures: Safety
Favors
Dabi 110 mg
Favors
Dabi 150 mg
J Am Coll Cardiol 2013;61:2264-73
(Circulation.2015;131:157-164.)
Independent FDA Medicare analysis findings are
consistent with findings from RE-LY®
Medicare1 >134 000 patients
0.86
1.28
0.92
0.88
0.80
0.34
RE-LY®2–4 >18 000 patients
1.48
1.27
0.75
0.41
Independent FDA analysis confirmed the favourable benefit–risk profile of dabigatran
in clinical practice
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
Numbers on bars denote HRs vs warfarin. D75 = dabigatran 75 mg; D150 = dabigatran 150 mg
1. Available at http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm; accessed September 2014; 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
39
Ann Emerg Med. 2013 Apr;61(4):475-9. doi: 10.1016/j.annemergmed.2013.02.008.
Hemorrhagic complications in emergency department patients who are
receiving dabigatran compared with warfarin.
Berger R1, Salhanick SD, Chase M, Ganetsky M.
Author information
Abstract
STUDY OBJECTIVE: Dabigatran is a reversible direct thrombin inhibitor recently approved for
stroke prevention in patients with atrial fibrillation. An increasing number of patients receiving
dabigatran present to the emergency department (ED) with bleeding complications. Unlike
vitamin K antagonists, there are no accepted reversal agents for dabigatran and the data on
course and management of bleeding complications are limited. The study objective is to describe
the course of bleeding complications in patients admitted through the ED who are prescribed
dabigatran in comparison with warfarin therapy.
<<
>>
METHODS: This was a prospective observational study of ED patients under treatment with
dabigatran or warfarin who were admitted with bleeding complications during a 6-month period.
Patient demographics, laboratory results, bleeding site, interventions, and outcomes are reported
RESULTS: There were 15 and 123 patients admitted with dabigatran and warfarin-induced
bleeding complications, respectively. Of the warfarin patients, 25 charts were randomly chosen fo
extraction. Patients with dabigatran-induced bleeding had a shorter length of stay (3.5 versus 6.
days) and were older (77 versus 70 years). Patients receiving dabigatran were more likely to
have gastrointestinal bleeding (80% versus 48%) and less likely to have intracranial bleeding (0%
Ann Emerg Med 2013;61(4):475-79
versus 32%) than those receiving warfarin. Of patients with dabigatran-induced bleeding, 53%
Circulation 2013;128:2325-32
ESC 2012 : Insufficienza Renale
Real World Data confirm the results of Dabigatran RCTs :
 reduced risk of ischemic stroke
 reduced risk of intracranial hemorrhage
 reduced risk of death
compared with Warfarin.
World Stroke Organization Global Stroke Services Guidelines and Action Plan
Lindsay P et al, IJS 2014