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

Risk of stroke or stroke/TIA/SE

CHA2DS2-VASc score 1 (all) 1 (men) 1 (women)

Events rate per 100 person-yrs 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.

The low annual event rates call into question the need for or use of oral anticoagulation therapy in low-risk patients

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

0.5 1

HR 0.65 (95% CI, 0.52 to 0.81)

HR 0.90 (95% CI, 0.74 to 1.10)

HR 0.88 (95% CI, 0.74 to 1.03)

HR 0.79 (95% CI, 0.66 to 0.95)

Hazard Ratio

Study Drug Better Warfarin Better

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

Dabigatran 150 mg BID1

Dabigatran 110 mg BID1

Rivaroxaban 20 mg QD2

Apixaban 5 mg BID3

Edoxaban 60 mg QD4

Edoxaban 30 mg QD4

1.5

HR 1.13 (95% CI, 0.96 to 1.34)

HR 0.87 (95% CI, 0.73 to 1.04)

Meta-analysis: ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF

VKAs versus novel OACs: organ-specific patterns of bleeding

Relative risk difference (%) (95% CI)

Intracranial bleeding

Other major bleeding

Gastrointestinal bleeding

Vanassche et al, 2014

Favours novel OAC Favours warfarin –100 –50 0 50 100

84,540 patients and 4781 bleeding events

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

4,2 13,8 26,3 37,2 43,1

0

20

40

60

80

100

Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5

Prop

ortio

n of

pat

ient

s on

trea

tmen

t, %

VKA±AP FXA/DTI±AP AP None

57.4% 71.8%

2010–2011 2011–2013 2013–2014 2014–2015 2015–2016

Cohorts 1–5, N=51,270

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

0 1 ≥2 CHA2DS2-VASc

0

10

20

30

40

50

60

70

80

90

100

(n=352) (n=1336) (n=9027)

Prop

ortio

n of

pat

ient

s, %

– 51% of very low-risk patients (CHA2DS2-VASc 0) are anticoagulated

VKA ± AP

NOAC ± AP

Camm AJ et al. Heart 2016 (in press)

“Real world” comparison between DOACs and VKAs: US healthcare databases

11

2,69 3,06

0

1

2

3

4

5

6

Major bleeding

Rate

/100

pat

ient

-yea

rs

2,29

4,60

0

1

2

3

4

5

6

Major bleeding

Rate

/100

pat

ient

-yea

rs

4,61 4,78

0

1

2

3

4

5

6

Major bleeding

Rate

/100

pat

ient

-yea

rs HR: 0.89

(0.63–1.26), P=NS HR: 0.49

(0.35–0.67), P<0.05 HR: 0.98

(0.83–1.16), P=NS

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; limited variables used for adjustment. Lip GY et al. ACC 2016

Dabigatran vs Warfarin Apixaban vs Warfarin Rivaroxaban vs Warfarin

Efficacy: propensity-matched medication comparison

Event Rate per 100 person-years

Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725

Hazard Ratio (95% CI) p value

Safety: propensity-matched medication comparison

Xiaoxi Yao et al. J Am Heart Assoc. 2016;5:e003725 - doi: 10.1161/JAHA.116.003725

Event Rate per 100 person-years

Hazard Ratio (95% CI) p value

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

Low

High

Strength of evidence

Design of GLORIA-AF

When baseline characteristics of patients receiving dabigatran and VKA are comparable

Before approval of dabigatran, the first

available NOAC After approval of dabigatran

Patients on dabigatran

Baseline Visit

Phase I Cross-sectional analysis

All patients

Phase II Cross-sectional and dabigatran follow-up

Phase III Cross-sectional and comparative analyses

Baseline Visit Baseline Visit

3M 6M 1YR 2YR 6M 1YR 2YR 3YR

Status: Currently ongoing (Europe, Asia, North America, Latin America, Africa/Middle East)

Status: Ended January 2013

Status: Currently ongoing (Europe, Asia, North America, Latin America)

Huisman MV, et al. Am Heart J. 2014;167:329–334 NOAC, non-Vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist

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

Final visit: 1 year#

Data collection at initial visit, hospital discharge

(if applicable) and quarterly*

Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-CNS SE prevention

Rivaroxaban; treatment

duration and dose at

physician’s discretion

*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

Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature

1 year

N=6,784

RCP: dosi raccomandate per età e funzionalità renale

1. Apixaban SmPC 2014 2. Dabigatran SmPC 2013 3. Rivaroxaban SmPC 2013

2. 4. Edoxaban SmPc, 2016

Caratteristiche Apixaban1 Dabigatran2 Rivaroxaban3 Edoxaban4

Insufficienza renale lieve (CrCl 50–80 mL/min) 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

Controindicato

Ridurre a 15 mg OD

Ridurre a 30 mg OD

Insufficienza renale con CrCl: <15 mL/min

Non raccomandato

Controindicato Non raccomandato Non raccomandato

Età 75–80 anni 5 mg BID

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

Età >80 anni 5 mg BID

Ridurre a 110 mg BID per l’aumentato rischio di sanguinamento in questa popolazione

20 mg OD 60 mg OD

Dabigatran 110 mg BID is used more widely in clinical practice

18 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

40%

58% 2%

RE-LY®1 Prescription data2,3

(All indications; IMS data June 2014–June 2015)

50% (n=6076)

50% (n=6015)

150 mg BID

110 mg BID

75 mg BID*

Apixaban 2.5 mg dose is used more widely in clinical practice

19

*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

ARISTOTLE1 Prescription data2

(All indications; IMS data June 2014–June 2015)

8692

428 0

2000

4000

6000

8000

10000

Num

ber o

f pat

ient

s 95%

5 mg BID 2.5 mg BID

5 mg 95%

2.5 mg 5%

5 mg 59%

2.5 mg 41%

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