insufficienza renale cronica, fibrillazione atriale e doacs · cardioluccaevolution lectures...

CardioLucca Evolution Lectures

Insufficienza renale cronica,fibrillazione atriale e DOACs:

scelte antitrombotiche ragionevoli tra i limiti del rischio emorragico e le opportunità nella riduzione degli eventi ischemici

Niccolò Marchionni

Ordinario di Medicina Interna ‐ Geriatria, Università di FirenzeDirettore Dipartimento Cardiotoracovascolare Azienda Ospedaliero‐Universitaria Careggi

Outline

NVAF – CKD: una relazione complessaCKD – anticoagulanti: farmacocinetica,

farmacodinamica, sovra- e sotto-dosaggioCKD – anticoagulanti: meta-analisi e sub-

analisi dei trialCKD – anticoagulanti: studi real worldVKA e danno renaleAnticoagulanti nel paziente con NVAF e

CKD: indicazioni pratiche

Boriani G, Europace EP 2018

12,5

9,6 10 9,8 10,4

17,9

8,3

0

5

10

15

20

Patie

nts

(%)

Chronic kidney disease, by AF type(N=11096; Age; 71 years; 250 Centers, 27 European Countries; 2013-6)

P <0.0001

Years

0 8 10 122 4 6Cum

ulat

ive

inci

denc

e of

AF

0.12

0.16

0

0.04

0.08

CrCl >90(N=3014, age: 60 yrs.)

CrCl 60-89(N=6051, age: 63 yrs.)

CrCl <60(N=1263, age: 66 yrs.)

CrCl HR>90 160-89 1.2730-59 1.5715-29 2.84

Alonso A, Circulation 2011

Go AS et al. Circulation 2009

Estimated Glomerular Filtration Rate (mL/min/1.73 m2)

Thrombo

embo

lism Rate

(per 100

person‐years)

Study period:From July 1996 – December 1997 through September 30, 2003

EventsN = 676 / 10908

1.63

2.76

4.22

≥60N=769072 yrs

45‐59N=249976 yrs

<45N=133878 yrs

3,6 3,5

1,9

6,4

8,8

5,85,6

8,9

6

0

2

4

6

8

10

Stroke / TE Bleeding MI

Even

t Rat

e (p

er 1

00 P

erso

n-ye

ar)

RD: renal disease; ESRD: end-stage RD; RRT: renal replacement therapy; TE: thromboembolism

Discharged with non-valvular AF (1997-2008)No RD: 127884 (96.6%; 73 years); No-ESRD: 3587 (2.7%; 76 years); RRT: 901 (0.7%; 67 years)

Olesen JB et al. N. Engl. J. Med 2012

No RD

No ESRD

RRT

Outline





Dabigatran Apixaban Edoxaban RivaroxabanBiodisponibilità 3-7% 50% 62% 66%

100% pastiProfarmaco Si No No NoEliminazione renale

80% 27% 50% 35%

CYP3A4 No Minore Minima SiInterazione con cibo

No No + 6-22% + 39%

Raccomandato ai pasti

No No / Si

Anti-H2/PPI - 12-30% No No NoEmivita 12-17 12 9-11 5-9 Y

11-13 E

Assorbimento e metabolismo dei NOACs

Heidbuchel H, et al; Europace 2013

Multi-dosing in a Patient With Impaired Renal FunctionResults in Drug Bioaccumulation

Chan KE, JACC 2016

1,87

1,29

0,83

0,56 0,50,62

0,86

0,7

0,97

0

0,4

0,8

1,2

1,6

2

<30 30-4950-79 ≥80 0-1 2 >2 0-1 >1

Mea

n C

once

ntra

tion

(ng/

ml/m

g)

CHA2DS2-VASc

Dose-Normalized Trough Plasma Concentrations of Dabigatran by Renal Function and Risk Scores in the RE-LY Trial

CrCl (ml/min) HAS-BLED

Mean: 0.79

N = 8449

Reilly PA, et al. JACC 2014

Probability of Clinical Outcomes vs. Dabigatran Trough Plasma Concentrations, by Age in the RE-LY Trial


Cox Regression Analyses of Ischemic Stroke/SEE and Major Bleeding Risk Versus Trough Plasma Concentration of Dabigatran in patients with median

CHADS2 score (2.0) and median age (71 yrs.) years in the RE-LY Trial


Conclusions: Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit–risk might be improved by tailoring dabigatran dose after considering selected patient characteristics

UnderdosingOverdosing

Prevalence of Inappropriate NOACs Dosing(OptumLabs Data Warehouse and Medicare Advantage, 2010-2015; N=14865)

Yao X et al.,JACC 2017

Appropriately dosed (No renal indicationfor dose reduction)

Appropriately dosed (Renal indication for

dose reduction)

Outcomes Associated With NOACs Underdosing

Apixaban

Dabigatran

Rivaroxaban

Stroke / SE

Major bleeding

Stroke / SE

Major bleeding

Stroke / SE

Major bleeding

Favors Reduced Dose Favors Standard Dose

0.02

Reduced Standard

Event rate (100 p-years) HR (95%CI)

4.87

Yao X et al. JACC 2017

Yao X et al. JACC 2017

Outcomes Associated With NOACs Overdosing

Reduced StandardEvent rate (100 p-years) HR (95%CI)

Favors Standard Dose Favors Reduced Dose

S/SE

Major bleeding

0.032.19

Outline





Estimated Major Bleeding Rates for Patients on Warfarinby Creatinine Clearance

Creatinine Clearance (mL/min)

6,2 8,3

30,5

54

100

0

20

40

60

80

100

>=60 30-59 <30 DialysisLow

DialysisHigh

Even

ts p

er 1

00 p

atie

nt-y

ears

Chan KE, et al JACC 2016

Low / High: lower / higher event rate

Efficacy outcomes among participants with a CrCl <50 ml/mingiven a NOAC or a VKA

Harel Z, J Am Soc Nephrol 2014

Stroke /SE in NVAF

Atrial fibrillation

Major and clinically relevant non-major bleedings among participants with CRCl ≤50 mL/min given a NOAC or a VKA

Harel Z, J Am Soc Nephrol 2014

CrCl (mL/min)

Abso

lute

Rat

es(%

/yea

r)

2,7

1,9

0,8

2,3

1,5

1,1

0

1

2

3

30-50 >50-95 >95

P interaction = 0.08

Bohula EA, Circulation 2016

Primary efficacy and safety end points byexploratory CrCl subgroups

5,3

3,4

2,3

4

3

1,4

0

1

2

3

4

5

6

30-50 >50-95 >95

VKA

EDO 60 mg

P interaction = 0.11

Stroke or SE Major Bleeding

Chan KE, et al. JACC 2016

Substantial and Growing Use of NOACs in Advanced CKD and on Dialysis

23.5% 11.6%

Outline





0,79

0,88

0,73

0,99

0,98

1,34

0 1 2 3 4 5 6

Stroke / SE

As-treated analyses of the comparative effectiveness and safety of NOACs vs. VKAs in 2664 pairs of CKD patients

(over 670 UK primary care practices - the Clinical Practice Research Datalink, 2011-6)

Chronic Kidney Disease N=13706/34093 (40%)Age: 78 yearsWomen: 47%

Adjusted HR (95% CI) Loo SY, et al. BMJ Open 2018

Major bleedingIntracranial

bleedingGI bleeding

Myocardial infarction

Death

NOACs better VKAs better

Even

t-fre

e su

rviv

al

Time (days)

Siontis KC, et al. Circulation 2018

Stroke / SE Major Bleeding

Survival curves for the apixaban group and a score-matched warfarin cohort(Age: 68 years; CHA2DS2-VASc: 5.2; Apixaban – N=2351; Warfarin - N=7053; Ratio: 1:3;

Medicare beneficiaries in the USRDS; 2010 - 2015)

HR=0.7295%CI: 0.59-0.87

Average timeApixaban: 105 daysWarfarin: 157 days

6.4%

1.6%

29.1%

HR=2.60 95%CI=2.00-3.38

HR=2.42 95%CI=1.44-4.05

HR=0.82 95%CI=0.74-0.91

Kaplan-Meier survival curve by anticoagulation status in 2424 pairs from the Royal College of General Practitioners Research and Surveillance Centre

2006-2016 Use of Anticoagulation in Age >65 and eGFR <50: N=2424/6977 (35%)

Age: 82 years; Men: 45.3%; CHA2DS2-VASc:4.2; eGFR: about 38 mL/min/1.73 m2

Follow-up: 506 days

Kumar S, BMJ 2018

Outline





Warfarin (5594): ‐3.7

DE 150 mg(5472): ‐2.5

DE 110 mg(5424): ‐2.6

66 mL/min

**

****: P<0.001 vs. Warfarin

eGFR Changes From Baseline Over Time

Bohm M, et al., JACC 2015

Inhibition of the Vitamin K-Dependent Protein Matrix -Carboxyglutamic Acid by VKA

Gla/MGP:-Carboxyglutamic Acid

Vascular protection Renal vascular calcification Decline in renal function

Bohm M, et al., JACC 2015

Cum

ulat

ive

risk

Follow-up (years)

The risk curves of acute kidney injury for NVAF CKD patients taking different oral anticoagulants (NHI Database, Taiwan – 2012-6; N=14699)

Chan YH, et al. Int J Cardiol 2018

Outline





NOACs and renal function

Steffel J, et al.Eur Heart J 2018

Conclusioni

Nella NVAF (soprattutto permanente), la prevalenza di CKD è elevata e si associa ad aumentato rischio di ictus, infarto miocardico ed emorragie maggiori; CKD aumenta il rischio incidente di NVAF

Sia negli studi registrativi che in quelli di mondo reale su pazienti con NVAF e associata CKD, rispetto ai VKA i NOAC mostrano [almeno] pari efficacia e [tendenzialmente] maggiore sicurezza

Meccanismi molecolari vitamina K- dipendenti sembrano giustificare la maggiore incidenza di danno renale durante terapia con VKA

La scelta del NOAC e la sua titolazione individualizzata ma coerente con le linee-guida è essenziale per evitare sovra- e sotto-dosaggio, entrambi associati ad aumentato rischio di eventi emorragici e/o embolici

insufficienza renale cronica, fibrillazione atriale e doacs · cardioluccaevolution lectures...

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