Criteri di scelta per una terapia anticoagulante

Criteri di scelta per una terapia
anticoagulante
Walter Ageno
Degenza Breve Internistica e Centro Trombosi
Dipartimento di Medicina Clinica e Sperimentale
Università dell’Insubria
Varese
Conflitti di interesse
• Supporto alla ricerca: Bayer Healthcare, Boehringer
Ingelheim
• Advisory Boards: Bayer Healthcare, Boehringer
Ingelheim, Daiichi Sankyo, BMS-Pfizer, Italfarmaco, ONO
• Fees per letture a congressi: Bayer Healthcare,
Boehringer Ingelheim, Daiichi Sankyo, BMS-Pfizer, Stago
Camm AJ et al. Eur Heart J 2012 doi:10.1093/eurheartj/ehs253
Event rates in patients with a
CHA2DS2-VASc score of 1
The low annual event rates call into question the need for or use of oral
anticoagulation therapy in low-risk patients
Risk of stroke or stroke/TIA/SE
CHA2DS2-VASc score
Events rate per 100 person-yrs
1 (all)
1 (men)
1 (women)
0.5 – 0.9
0.5 – 0.7
0.1 – 0.2
1. 140,420 untreated patients from the Swedish National Patient Register (2005–2010). Friberg L, et al. J Am Coll Cardiol 2015;65:225-32.
ESC recommendations based on
CHA2DS2-VASc score
RISK GOUPS
And Guideline Recommendations
CHA2DS2-VASc
score
Men
Women
Do not anticoagulate (ESC)
0
1
Consider anticoagulation (ESC 2012)
1
-
Consider anticoagulation (ESC 2016)
1
2
Consider / not recommend anticoagulation (ESC 2016)
-
2
Recommend anticoagulation (ESC 2012)
≥2
≥2
Recommend anticoagulation (ESC 2016)
≥2
≥3
Direct Oral Anticoagulants 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)
Edoxaban 30 mg QD4
HR 1.13 (95% CI, 0.96 to 1.34)
0.5
1
Hazard Ratio
1.
2.
3.
4.
Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.
Patel MR et al. N Engl J Med. 2011;365:883-891.
Granger CB et al. N Engl J Med. 2011;365:981-992.
Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907
1.5
VKAs versus novel OACs:
organ-specific patterns of bleeding
Meta-analysis: ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF
Relative risk difference (%) (95% CI)
Intracranial bleeding
Other major bleeding
Gastrointestinal bleeding
–100
–50
Favours novel OAC
84,540 patients and 4781 bleeding events
Vanassche et al, 2014
0
50
Favours warfarin
100
Criteri di scelta per la terapia
anticoagulante
• Anticoagulanti orali diretti
– Nei pazienti mai trattati (soprattutto anziani?)
– nei pazienti in terapia dicumarolica con controllo INR
inadeguato (salvo pazienti con chiari problemi di
aderenza)
• AVK
– Nei pazienti con controindicazioni specifiche ad AOD
(incluse stenosi valvolare mitralica, protesi valvolari,
insufficienza renale stadio IV, insufficienza epatica)
– Nei pazienti con recente/pregressa emorragia
digestiva (?)
– Nei pazienti in terapia dicumarolica ben condotta
(salvo richiesta del paziente?)
Evolution in baseline treatment for patients
enrolled in sequential cohorts of GARFIELD-AF
VKA±AP
FXA/DTI±AP
AP
None
Proportion of patients on treatment, %
100
80
60
13,8
4,2
26,3
37,2
43,1
40
71.8%
57.4%
20
0
Cohort 1
2010–2011
Cohort 2
2011–2013
Cohort 3
2013–2014
Cohorts 1–5, N=51,270
Cohort 4
2014–2015
Cohort 5
2015–2016
How are low and high risk AF patients
managed in practice?
•
Contrary to international guideline recommendations,
– 28% high-risk patients (CHA2DS2-VASc ≥2) are not anticoagulated
– 51% of very low-risk patients (CHA2DS2-VASc 0) are anticoagulated
CHA2DS2-VASc
0
1
≥2
Proportion of patients, %
100
90
NOAC ± AP
80
VKA ± AP
70
60
50
40
30
20
10
0
(n=352)
(n=1336)
Camm AJ et al. Heart 2016 (in press)
(n=9027)
“Real world” comparison between DOACs
and VKAs: US healthcare databases
HR: 0.89
(0.63–1.26), P=NS
5
4
3
2,69
3,06
2
1
0
6
HR: 0.49
(0.35–0.67), P<0.05
5
4,60
4
3
2,29
2
1
0
Major bleeding
Rivaroxaban vs
Warfarin
Rate/100 patient-years
Rate/100 patient-years
6
Apixaban vs
Warfarin
Rate/100 patient-years
Dabigatran vs
6
5
Warfarin
HR: 0.98
(0.83–1.16), P=NS
4,61
4,78
4
3
2
1
0
Major bleeding
Major bleeding
Propensity-score-matched HR (95% CI). Baseline patient characteristics differ between the matched cohorts; no indirect
comparison of NOACs can be made. Bold values indicate statistical significance. Limitations: abstract only; moderate sample size;
11
limited variables used for adjustment. Lip GY et al. ACC 2016
Efficacy: propensity-matched medication comparison
Event Rate per 100 person-years
Hazard Ratio (95% CI) p value
Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725
Safety: propensity-matched medication comparison
Event Rate per 100 person-years
Hazard Ratio (95% CI) p value
Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725
Real-World Evidence
• Real-world evidence is a broad term for many
different study designs, including, in order of
strength of evidence:
– Retrospective clinical studies (including case/case
series studies)
– Claims database analyses
– Prospective registries
– Phase IV non-interventional studies
Strength of
evidence
Low
High
Design of GLORIA-AF
Baseline Visit
Baseline Visit
Baseline Visit
3M
6M
1YR
2YR
Patients on dabigatran
Phase I
Cross-sectional
analysis
Phase II
Cross-sectional and
dabigatran follow-up
Status: Ended
January 2013
Status: Currently ongoing
(Europe, Asia, North America,
Latin America, Africa/Middle
East)
Before approval of
dabigatran, the first
available NOAC
After approval of dabigatran
Huisman MV, et al. Am Heart J. 2014;167:329–334
NOAC, non-Vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist
6M
1YR
2YR
3YR
All patients
Phase III
Cross-sectional and
comparative analyses
Status: Currently ongoing
(Europe, Asia, North America, Latin
America)
When baseline characteristics of patients
receiving dabigatran and VKA are comparable
XANTUS: Study Objective and Design
•
To collect real world data on adverse events in patients with NVAF treated with
rivaroxaban to determine the safety profile of rivaroxaban across the broad range
of patient risk profiles encountered in routine clinical practice
– Primary outcomes: major bleeding (ISTH definition), all-cause mortality,
any other adverse events
N=6,784
Population:
Adult patients with NVAF
receiving rivaroxaban for
stroke/non-CNS SE prevention
Rivaroxaban;
treatment
duration and
dose at
physician’s
discretion
Data collection at initial
visit, hospital discharge
(if applicable) and quarterly*
1 year
Prospective, single-arm, observational, non-interventional phase IV study
Statistical analyses were descriptive and exploratory in nature
*1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425–434; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
Final visit:
1 year#
RCP: dosi raccomandate per età e
funzionalità renale
Caratteristiche
Insufficienza renale lieve
(CrCl 50–80 mL/min)
Apixaban1
Dabigatran2
Rivaroxaban3
Edoxaban4
5 mg BID
150 mg BID
20 mg OD
60 mg OD
Insufficienza renale
moderata
(CrCl: 30–50 mL/min)
5 mg BID
Pazienti con insufficienza renale moderata:
la dose di dabigatran (300 mg o 220 mg)
dovrebbe essere selezionata sulla base del
rischio tromboembolico ed emorragico
Ridurre a 15 mg
OD
Ridurre a 30 mg
OD
Insufficienza renale severa
(CrCl: 15–29 mL/min)
Ridurre la
dose a 2,5 mg
BID
Ridurre a 15 mg
OD
Ridurre a 30 mg
OD
Insufficienza renale
con CrCl: <15 mL/min
Non
raccomandato
Non raccomandato
Non raccomandato
Pazienti 75–80 anni: la dose giornaliera di
dabigatran (300 mg o 220 mg) dovrebbe
essere selezionata sulla base del rischio
tromboembolico ed emorragico
20 mg OD
60 mg OD
Ridurre a 110 mg BID per l’aumentato
rischio di sanguinamento in questa
popolazione
20 mg OD
60 mg OD
Età 75–80 anni
Età >80 anni
1. Apixaban SmPC 2014
2. Dabigatran SmPC 2013
3. Rivaroxaban SmPC 2013
2. 4. Edoxaban SmPc, 2016
5 mg BID
5 mg BID
Controindicato
Controindicato
Dabigatran 110 mg BID is used more widely
in clinical practice
RE-LY®1
Prescription data2,3
150 mg BID
50%
(n=6076)
50%
(n=6015)
40%
110 mg BID
75 mg BID*
58%
2%
(All indications; IMS data June 2014–June 2015)
1. Connolly et al. N Engl J Med 2009; 2. BI, Data on file: DBG 15–04; 3. IMS Information Solutions UK Ltd. Patient data, June 2015
18
Apixaban 2.5 mg dose is used more widely
in clinical practice
Prescription data2
ARISTOTLE1
Number of patients
10000
8692
5 mg
95%
8000
95%
6000
4000
2.5 mg
59%
2.5 mg
41%
5%
2000
0
5 mg
428
5 mg BID
2.5 mg BID
(All indications; IMS data June 2014–June 2015)
*Dose reduction to 2.5 mg BID if ≥2 criteria: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol /L).
1. Granger et al. N Engl J Med 2011; 2. IMS Information Solutions UK Ltd. Patient data, June 2015; 3. Halvorsen et al. Eur Heart J
2014
19
Conclusioni
• La prima scelta riguarda l’opportunità di
anticoagulare
• La seconda scelta riguarda il farmaco,
ricordando che non dovrebbe esserci più
posto per l’ASA
• Gli anticoagulanti orali diretti offrono
vantaggi per i pazienti che iniziano la terapia
• Esiste probabilmente il farmaco (e il
dosaggio) giusto per il singolo paziente, ma
dobbiamo imparare di più