why does dicumarol still have such a high rate in our ... · the journal of clinical pharmacology...

WHY DOES DICUMAROL STILL HAVE

SUCH A HIGH RATE IN OUR COUNTRY?

13th International Meeting

Atrial Fibrillation and Heart Failure

Bologna, February 14, 2019

Giuseppe Di Pasquale, MD, FESC, FACC

Director Department of Medicine

Director Division of Cardiology

Maggiore Hospital, Bologna, Italy

Giuseppe Di Pasquale Disclosures

• Member of the Steering Committee of the RELY, PALLAS, and

GLORIA AF

• Member of Advisory Board of Dabigatran,

Rivaroxaban, Apixaban, Dronedarone, Edoxaban

• Consulting fees / honoraria

Boehringer Ingelheim, Bayer AG, Sanofi Aventis

BMS / Pfizer, Daiichi Sankyo

Global MAT Q3 2018 Value $LC Value growth

vs prev year

Volume growth

vs prev year

VKA 456,989 -10.0% -6.3%

DOACS 20,856,036 28.6% 26.3%

TOTAL 21,313,025 27.4% 5.8%

Total Global OAC Volume Growth 2012 - 2018

IQVIA MIDAS 2018

LCD = Local Currency US Dollar

DoT = Days of Therapy

MAT = Moving Annual Total

Global USA Germany Italy UK Spain Belgium S. Korea Brazil

20.1% 21.8% 29.0% 20.2% 20.0% 11.3% 27.6% 23.3% 37.6%

18.4% 29.6% 30.9% 17.9% 23.2% 12.4% 26.0% 15.6% 9.5%

6.3% 3.1% 5.1% 12.4% 2.6% 6.3% 10.8% 7.2% 6.4%

3.3% 0.1% 10.4% 6.5% 2.4% 3.7% 10.9% 16.2% 0.2%

0.0% 0.0%

48.1% 54.6% 75.4% 57.0% 48.2% 33.7% 75.2% 62.2% 53.6%

51.9% 45.4% 24.6% 43.0% 51.8% 66.3% 24.8% 37.8% 46.4%

100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

DOAC TOTAL 60.9%

VKAs 39.1%

TOTAL 100.0%

DABIGATRAN 7.3%

EDOXABAN 15.4%

BETRIXABAN

Country Comparison -

Qtr 09/18 - Volume

Japan

RIVAROXABAN 18.7%

APIXABAN 19.4%

IQVIA MIDAS 2018

VKAs vs DOACs Country Comparison - Market Share

Barriers to the growth in DOAC use

• Long-standing solid experience in the use of VKA

• Concerns for DOAC use in the elderly

• Concerns for DOAC use in patients with CKD

• Fears for the lack of antidote

• Italian Medicines Agency (AIFA) regulatory authority prescription rules

• Referral to authorized centers and role of Anticoagulation Clinics

• Modalities of follow up

• Concerns for budget impact

Country distribution of mean time in therapeutic range (TTR) in the RE-LY trial

Wallentin L., et al. The Lancet. Published online August 29, 2010 DOI:S0140-6736(10)61194-4

BO.N.TAO

Bologna.Network.Terapia Anticoagulante Orale

PROVINCIA DI BOLOGNA

Rete di punti di prelievo e

di centri prescrittori:

Punti di prelievo (54)

Centri ospedalieri (11)

Specialisti territoriali

MMG

Ospedale Bazzano

Ospedale Porretta

Ospedale Loiano

Ospedale Budrio

Ospedale Vergato

Ospedale S. Giovanni in Persiceto

Ospedale Bentivoglio

Ospedale Maggiore

Policlinico S.Orsola (2)

Ospedale Bellaria

BO.N.TAO 2012

Mean TTR in 18 Centers

0

10

20

30

40

50

60

70

80

90

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Centers

%

Anticoagulation Control in Real Life in Italy

% of INR Determinations by Range in VKA Treated Patients

Range INR VKA

Experienced mean median (p25 - p75)

% INR < 2 No 33.4% 28.8% (15.4% - 47.9%)

% INR < 2 Yes 25.3% 20.0% (7.7% - 36.4%)

% INR 2.0-3.0 No 47.9% 50.0% (33.3% - 66.7%)

% INR 2.0-3.0 Yes 56.3% 58.3% (42.5% - 73.1%)

% INR > 3 No 16.9% 13.3% (0.0% - 25.0%)

% INR > 3 Yes 17.9% 14.3% (4.0% - 26.7%)

Which information on DOACs in the elderly?

Ruff CT et al, Lancet 2014

Efficacy: stroke or systemic embolic events

0.85

0.78

RR

Safety: major bleedings

0.79

0.93

RR

Circulation 2015;131:157-164

Anticoagulation Clinic - Maggiore Hospital, Bologna

Period : 1/1/2014 - 31/12/2016 Patients over 85 with AF starting OAC

0.96%

0,59%

0,71%

0,72%

ICH Admissions

Stroke/TIA Admissions

2.18%

1.49%

1,74%

1,76%

N° pts Incidence

x100 pts/year

Circulation 2014;129:961-70

Results from RE-LY®: patients with moderate renal impairment (CrCl <50 mL/min)

HR = hazard ratio;

Error bars = 95% confidence intervals

1. Connolly S et al. NEJM 2009; 361:1139–51;

2. Eikelboom J et al. Circulation 2011;123:2363–72 23

Stroke and systemic embolism Study drug

(%/yr) Warfarin (%/yr)

HR

Dabigatran 150 mg 1.52 2.78 0.55

Dabigatran 110 mg 2.15 2.78 0.77

Favours NOAC Favours warfarin 1 0.5 1.5

Study drug (%/yr)

Warfarin (%/yr)

HR

Dabigatran 150 mg 5.44 5.41 1.01

Dabigatran 110 mg 5.29 5.41 0.98

Favours NOAC Favours warfarin 1 0.5 1.5

Major bleeding

P=0.0002

P=0.0008

Decline in GFR at 30 months was significantly reduced with both doses of dabigatran vs VKA

27

*According to CKD-EPI equation CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; HR = hazard ratio; SE = standard error Böhm M et al. Presented at ESC 2014

BMC Nephrology (2016) 17:157

Tan et al. BMC Nephrology (2016) 17:157

Meta-analysis of outcome in patients with end stage renal disease

and atrial fibrillation by warfarin use

STROKE BLEEDING

J Am Coll Cardiol 2016;67: 2888-99

Use of Nonvitamin K-Dependent Oral Anticoagulant Agents in Pts With

Advanced CKD and on Dialysis: Substantial and Growing

Prevalence of NOAC use is rising among patients with advanced CKD and those on dialysis

anticoagulated for AF.

Pharmacotherapy 2017;37(4):412–419

The Journal of Clinical Pharmacology 2016, 56(5) 628–636

Annals of Pharmacotherapy 2017, Vol. 51(6) 445–450

RENal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation

Christopher Granger1

1Duke University Medical Center

RENAL-AF

432IT17NP00872

Apixaban 5 mg twice daily (2.5 mg twice daily in selected patients)

Primary Outcome

Time (measured in days) from randomization to the onset of first major

bleeding/clinically relevant non-major bleeding event, as described by ISTH

Key Secondary Outcomes

Stroke or systemic embolism

Mortality

Warfarin Daily dose adjusted to target INR of 2-3

Study Design: NVAF Patients Undergoing Hemodialysis in the US

CHA2DS2-VASc, Congestive heart failure, Hypertension, Age ≥75 (doubled), Diabetes, Stroke/transient ischemic

attack (doubled), Vascular disease, Age 65–74, and Sex (female); ESRD, end-stage renal disease;

GI, gastrointestinal; HD, hemodialysis; ICH, intracranial hemorrhage; INR, international normalized ratio;

ISTH, International Society on Thrombosis and Haemostasis; NVAF, non-valvular atrial fibrillation, R, randomization.

*Or the local age of consent, whichever is greater. †For example, hemoglobin <8.5 g/dL, history of ICH, active bleeding, recent GI or retroperitoneal bleed,

severe hepatic impairment, or anaphylactic reaction to apixaban.

Select Exclusion Criteria

Not considered by treating physician(s) to be candidate for oral anticoagulation†

Moderate or severe mitral stenosis

Need for aspirin at a dose >81 mg a day or need for P2Y12 antagonist therapy

15 months

R

RENAL-AF

Fo

llo

w-u

p

15

mo

nth

s

Christopher Granger, Duke University Medical Center. Trial to evaluate anticoagulation therapy in hemodialysis

patients with atrial fibrillation (RENAL-AF). Available from: https://clinicaltrials.gov/ct2/show/NCT02942407.

NLM Identifier: NCT02942407. Accessed on February 09, 2017.

Inclusion Criteria

≥18 years of age*

NVAF

CHA2DS2-VASc ≥2

ESRD treated with HD for ≥3 months

Reversal of Anticoagulation

Anticoagulant Antidote

Warfarin Vitamin K

Prothrombin Complex Concentrate (PCC)

Heparin Protamine sulphate

LMWH (Enoxaparin) No effective antidote

(only partially reversed by protamine)

Fondaparinux No effective antidote

Bivalirudine No effective antidote

Niessner A et al. Eur Heart J 2017;38:1710-1716

New reversal agents for non-vitamin K antagonist oral anticoagulants

N Engl J Med 2017;377:431-441

Idarucizumab for specific dabigatran reversal

42

Results:

Idarucizumab provided immediate,

complete, and sustained reversal of

dabigatran anticoagulation

Objective:

To demonstrate the extent of reversal of the

anticoagulant effect of dabigatran in patients

who have uncontrolled/life-threatening

bleeding, or those requiring emergency

surgery/other invasive procedures for which

normal haemostasis is desirable

Time post-idarucizumab

Group A: uncontrolled bleeding

(N=293)

dT

T (

s)

110

70

60

50

40

30

100

90

80

1h 2h 4h 12h 24h 10–30

min

0

Idarucizumab

2×2.5 g

120

Group B: emergency surgery or

procedure (N=195)

30

1h 2h 4h 12h 24h 10–30

min

0

Time post-idarucizumab

Idarucizumab

2×2.5 g

110

70

60

50

40

100

90

80

120

10th/90th percentiles 5th/95th percentiles Median and 25th/75th percentiles Assay upper limit of normal

2017 = 503

Pollack et al. N Engl J Med 2017

N Eng J Med 2019, February 7

Piani terapeutici AIFA a confronto: ultimo aggiornamento 2 luglio 2014

Dabigatran Rivaroxaban Apixaban

Condizioni di

ingresso

Paziente con

Fibrillazione Atriale

Non Valvolare

(FANV)

Età >18 anni

Paziente con


Non Valvolare

(FANV)

Età >18 anni

Paziente con


Non Valvolare

(FANV)

Età ≥18 anni

Ai fini dell'eleggibilità bisogna rientrare in una delle seguenti

condizioni (1, 2 o 3)

Gruppo 1 CHA2DS2-VASc ≥1

e HAS-BLED >3

CHA2DS2-VASc >3

e HAS-BLED >3

CHA2DS2-VASc ≥1

e HAS-BLED >3

Gruppo 2 TTR negli ultimi 6

mesi ≤70

TTR negli ultimi 6

mesi ≤60

TTR negli ultimi 6

mesi ≤70

Gruppo 3 Il trattamento

anticoagulante non

è attuabile per

difficoltà oggettive

ad eseguire i

controlli di INR.

Il trattamento

anticoagulante non

è attuabile per


ad eseguire i

controlli di INR.

Il trattamento

anticoagulante non

è attuabile per


ad eseguire i

controlli di INR.

Piani terapeutici AIFA a confronto

Dabigatran Rivaroxaban Apixaban

Condizioni di

ingresso

Paziente con


Non Valvolare

(FANV)

Età >18 anni

Paziente con


Non Valvolare

(FANV)

Età >18 anni

Paziente con


Non Valvolare

(FANV)

Età ≥18 anni

Ai fini dell'eleggibilità bisogna rientrare in una delle seguenti

condizioni (1, 2 o 3)

Gruppo 1 CHA2DS2-VASc ≥1

e HAS-BLED >3

CHA2DS2-VASc >3

e HAS-BLED >3

CHA2DS2-VASc ≥1

e HAS-BLED >3

Gruppo 2 TTR negli ultimi 6

mesi ≤70

TTR negli ultimi 6

mesi ≤60

TTR negli ultimi 6

mesi ≤70

Gruppo 3 Il trattamento

anticoagulante non

è attuabile per


ad eseguire i

controlli di INR.

Il trattamento

anticoagulante non

è attuabile per


ad eseguire i

controlli di INR.

Il trattamento

anticoagulante non

è attuabile per


ad eseguire i

controlli di INR.

Dall’ 11 giugno 2014 Precedentemente

autorizzato solo su FA permanente

Dal 2 luglio 2014 Precedentemente autorizzato solo per età > 65 anni

Dal 2 luglio 2014 Precedentemente

autorizzato solo per CHA2DS2-VASc ≥ 3




•Concerns for DOAC use in patients with CKD

•Fears for the lack of antidote

•Italian Medicines Agency (AIFA) regulatory authority prescription rules

•Referral to authorized centers and role of Anticoagulation Clinics

•Modalities of follow up

•Concerns for budget impact

“Anticoagulation should be monitored

by specialized anticoagulation clinics

to minimize the risks”

Rosendaal FR

N Engl J Med 1996; 335: 587-589

“Anticoagulation (with warfarin)

should be monitored by specialized

anticoagulation clinics to minimize

the risks”

Rosendaal FR

N Engl J Med 1996; 335: 587-589

Structured follow-up of patients on NOACs

Drug Daily cost

Warfarin € 0.05

Dabigatran € 1.73

Rivaroxaban € 1.72

Apixaban € 1.92

Edoxaban € 1.85

Costs Of Anticoagulant Therapies for AFib

Contribution of hospitalizations, drugs, and other resource use

to direct annual costs of atrial fibrillation

Wolowacz SE et al. Europace 2011;13:1375-1385

Costs for Management of

Oral Anticoagulation Therapy with VKAs

THE ITALIAN EXPERIENCE

Value in Health 2004

• Total cost per patient per year = 943 €

• Medical costs = 525 €

• Non-medical costs (transportation) = 220 €

745 € direct costs

198 € indirect costs

- OAT drug (5%)

- INR tests (18%)

- monitoring visits (44%)

- admissions (33%)

The costs of stroke

Costs per Patient After Stroke

Persson J et al. BMC Health Serv Res

2012; 12:341

Costs per pt

during 3 years in Sweden Mean 1-year costs per pt in Finland

Meretoja A et al. Stroke 2012; 42:2007-17

Pharmaceuticals Hospital Care

Primary Care

Reduces the

overall efficiency

of the health care

system

“It should be much more efficient for expenditure control to be exercised at

the level of disease category or therapeutic area allowing the most efficent

mix of services to be used to achive the desired health outcome”

Value in Health, 2003

Costs vs value…………..

Eur Heart J 2018; 39: 2975-2983

Stroke

OAC

Antiplatelet

Temporal trend in AF-related stroke per 100,000 pts with AF

and CHA2DS2-VASc ≥2 and uptake of OAC and antiplatelet drugs

Campbell Cowan J et al, Eur Heart J 2018; 39, 2975-2983

why does dicumarol still have such a high rate in our ... · the journal of clinical pharmacology...

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