L approccio per paziente nella gestione dei NAO: analisi per età e funzionalità renale. Niccolò Marchionni

(1)

Niccolò Marchionni

Cattedra di Geriatria, Università di Firenze Azienda Ospedaliero-Universitaria Careggi, Firenze

Società Italiana di Cardiologia Geriatrica

Chaiperson, Geriatric Expert Group, European Medicines Agency, London

L’approccio per paziente nella

gestione dei NAO:

(2)

2009

2011

(3)

RR (95% CI) 0.5 1.0 2.0 0.66 0.66 0.88 0.88 0.80 0.80 0.88 0.88 0.0001 0.0001 0.12 0.012 0.012 0.10 P RR=0.810.81 (0.75-0.91), P<0.0001 NOA – N=42411, Age: 71.671.6 y Warfarin – N=29272, Age: 71.571.5 y

Stroke or systemic embolic events

Ruff CT, 2014 0.85 0.85 0.78 0.78 RR

(4)

Ruff CT, 2014 0.2 0.5 1.0 2.0 Efficacy Efficacy Safety Safety RR (95% CI) P 0.92 0.92 0.49 0.49 0.97 0.97 0.90 0.90 0.10 <0.0001 <0.0001 0.77 0.0003 0.0003 0.48 0.48 1.25 1.25 <0.0001<0.0001 0.043 0.043

Secondary efficacy and safety outcomes

RR (95%CI) 0.71 0.71 0.80 0.80 Major bleeding Major bleeding

(5)

Anziano & NAO:

una relazione

(6)

FA e NAO:

perché l’anziano è un paziente “particolare” ?

Key points

• Elevata prevalenza di FA

• ↑

rischio cardioembolico (CH

A

₂

DS

₂

-VASC )

→

_{Comorbilità (… CKD)}

(7)

OR OR 95%CI p Age Age / / NS Female Female / / NS Lives alone Lives alone / / NS Education Years Education Years / / NS Depressive Symptoms Depressive Symptoms 5.14 1.84-14.34 <0.05 Cognitive impairment Cognitive impairment 6.27 2.54-15.36 0.001 CHA

CHA₂₂DSDS₂₂VASc scoreVASc score / / NS

HAS

HAS--BLED scoreBLED score 2.52 1.03-6.16 <0.05

Multivariate Predictors of the Absence of Oral Anticoagulation Therapy

(N=137; Age: 82 years82 years; Permanent AF: 70%70%; NotNot anticoagulated: 51%51%; High risk – CHA₂DS₂VASc: 99%99%; HAS-BLED: 39%39%)

Depressive Symptoms:Geriatric Depression Scale >5; Cognitive impairment: Mini-Mental State Examination ≤₂₃

Sá_{nchez-Barba B, 2013}

ARE GERIATRIC SYNDROMES ASSOCIATED WITH

RELUCTANCE TO INITIATE ORAL ANTICOAGULATION

THERAPY IN ELDERLY ADULTS WITH NONVALVULAR ATRIAL FIBRILLATION?

(8)

Anziano & NAO:

sub-analisi e

(9)

Dabigatran Apixaban Edoxaban Rivaroxaban Biodisponibilità 3-7% 50% 62% 66% 100% pasti Profarmaco Si No No No Eliminazione renale 80% 27% 50% 35% CYP3A4 No Minore Minima Si Interazione con cibo No No + 6-22% + 39% Raccomandato ai pasti No No / Si Anti-H2/PPI - 12-30% No No No Emivita 12-17 12 9-11 5-9 Y 11-13 E

Assorbimento e metabolismo dei NAO

Heidbuchel H, 2013

(10)

Dabigatran 110 BD Dabigatran 150 BD Warfarin Stroke/SE 0.81 0.81 Age < 75 1.32 0.90 1.43 Age ≥75 1.89 1.43 2.14 Major Bleeding <0.001 <0.001 Age < 75 1.89 2.12 3.04 Age ≥75 4.43 5.10 4.37 ICH 0.28 0.91 Age <75 0.14 0.26 0.61 Age ≥75 0.37 0.41 1.00 Extracranial Bleeding 0.001 <0.0001 Age <75 1.76 1.91 2.44 Age ≥75 4.10 4.68 3.44 1 0.5

1. Adapted from Eikelboom JW et al. Circulation_{2011;123:2363-2372.}

RE-LY: With comparable efficacy for Stroke/SE and safety for ICH, rates of major bleeding and extracranial bleeding were higher in subjects ≥ 75 years compared to younger subjects

Rates of stroke, major bleeding, ICH and extracranial bleeding with Dabigatran 110 and 150 mg BD vs. warfarin in patients aged < 75 (n=10,865) and _≥75 (n=7258) years

Interaction

Pvalue

Dabigatran Better Warfarin Better

Interaction

Pvalue

Dabigatran Better Warfarin Better

(11)

RE

RE--LY LY –– Extracranial Major Bleeding Rate, by AgeExtracranial Major Bleeding Rate, by Age--GroupGroup

E v e n t ra te ( % /y e a r) 10 8 6 4 2 0 Age (years) <55 55-64 65-74 75-84 85+ Warfarin Dabigatran 150 Dabigatran 110 Dabigatran 110 vs. Warfarin – p=0.006 Dabigatran 150 vs. Warfarin – p=0.002 Dabigatran 110 vs. Warfarin – p=0.006 Dabigatran 150 vs. Warfarin – p=0.002 Eikelboom JW, 2011

(12)

M e a n C o n c e n tra ti o n (n g /m l/ m g ) Age (years)

Dose-Normalized Plasma Through Concentrations of Dabigatran by Demographic Characteristics in the RE-LY Trial (1)

Reilly PA, 2014

Gender Weight (Kg)

(13)

M e a n C o n c e n tra ti o n (n g /m l/ m g ) CHA₂DS₂-VASc

Dose-Normalized Plasma Through Concentrations of Dabigatran by Demographic Characteristics in the RE-LY Trial (2)

Reilly PA, 2014

CrCl (ml/min) HAS-BLED

(14)

S tr o k e /S y s te m ic E m b o li s m ( % )

Months since Randomization

2.85% 2.85%/year 2.10% 2.10%/year 2.29% 2.29%/year 2.00% 2.00%/year Age <75 years

Age <75 years (N=8035) (N=8035) –– Age: 66 y66 y, CHA₂DS₂: 3.303.30 Age

Age >>75 years75 years(N=6229) (N=6229) –– Age: 79 y79 y, CHA₂DS₂: 3.693.69 R

R

W

Rivaroxaban

Rivaroxabanvs. vs. WarfarinWarfarin

Age >>75 years75 – HR: – 0.800.80, (0.63-1.02)

Age <75 <75 years– HR: – 0.950.95, (0.76-1.19)

P for interaction = 0.3131

Cumulative proportion of patients experiencing primary end

points over 24 months by age

points over 24 months by age--groupgroup

(15)

Stroke / Systemic embolism All-cause mortality E v e n ts ( % / y e a r) Age-groups (years) P interaction = 0.11 P interaction = 0.43

The effect of apixaban vs. warfarin according to age (1)

Halvorsen S, 2014

(16)

All bleeding Intracranial bleeding E v e n ts ( % / y e a r) Age-groups (years) P interaction = 0.94 P interaction = 0.20

The effect of apixaban vs. warfarin according to age (2)

Halvorsen S, 2014

(17)

A b s o lu te r is k r e d u c ti o n

ISTH major bleeding

Toda Kato E, 2014 1.8 1.8 3.33.3 4.84.8 0.30.3 0.90.9 1.21.2 Warfarin Warfarin rate (%/y) rate (%/y) Intracranial hemorrhage Intracranial hemorrhage <65 years – N=5497 65-74 years – N=7134 >74 years – N=8474 <65 years – N=5497 65-74 years –N=7134 >74 years – N=8474 Both P interaction vs. Warfarin=NS

(18)

Rivaroxaban ROCKET-AF Subtotal Apixaban ARISTOTLE Subtotal AVERROES Dabigatran RE-LY Subtotal Total Total Odds Ratio Odds Ratio MH 95%CI NOAC Control Favors OR=0.65– NNT=71 95%CI=0.48-0.87 NOAC – N: 11562 Control –N: 9177

NNT:number needed to treat

NOAC: 3.3 vs. C: 4.7%

Sardar P, 2014

Patients aged more than 75 years: Stroke or systemic embolism

New oral anticoagulants vs.

conventional therapy for participants aged >75 years

(19)

Rivaroxaban ROCKET-AF Subtotal Apixaban ARISTOTLE Subtotal AVERROES Dabigatran RE-LY Subtotal Total Total Odds Ratio Odds Ratio MH 95%CI NOAC Control Favors OR=1.02 95%CI=0.73-1.43 NOAC – N: 13625 Control –N: 11083 NOAC: 6.4 vs. C: 6.3% Sardar P, 2014

Patients aged more than 75 years: Major or clinically relevant bleeding

EINSTEIN

EINSTEIN-Extension EINSTEIN PE

New oral anticoagulants vs.

conventional therapy for participants aged >75 years

(20)

(21)

(22)

Drug-safety investigation, focused on the occurrence of bleeding, promoted by Food and Drug Administration (FDA) over the period October 19, 2010 to December 31, 2011. Mini-Sentinel March 13, 2013.

(23)

(24)

Incidence rate per 1,000 person-years

Adjusted hazard ratio (95% CI) Pradaxa (dabigatran) Warfarin Ischemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial hemorrhage 3.3 9.6 0.34 (0.26-0.46) Major GI bleeding 34.2 26.5 1.28 (1.14-1.44) Acute MI 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96)

Possibile causa dell’aumento dei sanguinamenti gastrici potrebbe essere il fatto che in USA l’uso del 110 mg non è registrato e la popolazione di pazienti studiata èpiù anziana rispetto al MiniSentinel.

(25)

30 ottobre 2014

New-user cohorts of PSM elderly patients enrolled in Medicare

(Oct. 2010 – Dec. 2012) n= 134,314

(26)

30 ottobre 2014

New-user cohorts of PSM elderly patients enrolled in Medicare

(27)

23% stroke rate reduction

25% reduction in the rate of major hemorrhage

2 large US health insurance databases From Oct 2010 to Dec 2012

(28)

Department of Defense Military Health System database. From October 1, 2009 to July

(29)

Almost 200,000 pt

~ 134,000 pt

~

38,000 pt

(30)

CKD & NAO:

(31)

New oral New oral anticoagulant anticoagulant better better Warfarin Warfarin better better HR HR (95%CI) Hart RG, 2013 1.5% 1.5% per year 2.2% 2.2% per year 2.8% 2.8% per year 25 25--50 50 mL/min mL/min 30 30--49 49 mL/min mL/min Cr Cl – Cockcroft-Gault equation RE-LY – N=3505; ROCKET-AF – N=2950; ARISTOTLE – N=3017 Cr Cl –Cockcroft-Gault equation RE-LY –N=3505; ROCKET-AF – N=2950; ARISTOTLE –N=3017 Cr Cl Cr Cl

HRs for patients with stage III CKD from randomized trials

comparing NOACs with warfarin for stroke and systemic embolism

(32)

Hart RG, 2013 HRs for patients with stage III CKD from randomized trials compa

HRs for patients with stage III CKD from randomized trials comparing ring NOAs with warfarin for major bleeding

NOAs with warfarin for major bleeding

New oral New oral anticoagulant anticoagulant better better Warfarin Warfarin better better HR HR (95%CI) 3,2% 3,2% per year 6,4% 6,4% per year 25 25--50 50 mL/min mL/min 30 30--49 49 mL/min mL/min Cr Cl Cr Cl Hemorrhagic stroke Hemorrhagic stroke –– HR=0.06 0.06 (0.01-0.46)

(33)

Savalieva I, 2014 Possible considerations for selecting between NOA based on patie

Possible considerations for selecting between NOA based on patient nt characteristics

(34)

Feb 2013

NOACs in patients with renal impairment:

EU labels

BID = twice daily; EU = European Union; OD = once daily

Pradaxa®: EU SmPC, 2012; Xarelto: EU SmPC, 2012; Eliquis: EU SmPC, 2012

Patient population Dosing recommendations according to EU label

Mild renal impairment (CrCl 50–≥_{80 mL/min)}

Dabigatran 150 mg BID Rivaroxaban 20 mg OD Apixaban 5 mg BID Moderate renal impairment

(CrCl 30–50 mL/min)

Dabigatran 150 mg BID (110 mg BID should be considered in patients at high bleeding risk) Rivaroxaban 15 mg OD

Apixaban 5 mg BID Severe renal impairment

(CrCl 15–29 mL/min)

Dabigatran contraindicated

Rivaroxaban 15 mg OD Apixaban 2.5 mg BID

(35)

NOACs in patients with renal

impairment: ESC guidelines

(36)

Feb 2013

2012 ESC guidelines update

ALL NOACs are not recommended in patients with

severe renal impairment (CrCl <30 mL/min)

CrCl = creatinine clearance; ESC = European Society of Cardiology; NOAC = novel oral anticoagulant; NVAF = nonvalvular atrial fibrillation

Camm AJ et al. Eur Heart J 2012;33:2719–47

Recommendation Class Level

Baseline and subsequent regular assessment of renal function (by CrCl) is recommended in patients following initiation of any NOAC, and

should be done annually but more frequently in those with moderate renal impairment, where CrCl should be assessed 2–3 times per year

IIa A

NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended

(37)

Feb 2013

2012 ESC guidelines update: patients with

moderate renal impairment (CrCl 30–49 mL/min)

BID = twice daily; CrCl = creatinine clearance; ESC = European Society of Cardiology; OD = once daily Camm AJ et al. Eur Heart J 2012;33:2719–47

Recommendation Class Level

When dabigatran is prescribed, a dose of 150 mg BID should be considered for most patients in preference to 110 mg BID, with the latter dose recommended in:

• elderly patients, age ≥_{80 years}

• concomitant use of interacting drugs (e.g. verapamil) • high bleeding risk (HAS-BLED score ≥₃₎

• moderate renal impairment (CrCl 30–49 mL/min)

IIa B

Where rivaroxaban is being considered, a dose of 20 mg o.d. should be considered for most patients in preference to 15 mg OD, with the latter dose recommended in:

• high bleeding risk (HAS-BLED score ≥₃₎

• moderate renal impairment (CrCl 30–49 mL/min)