I NAO: Complicanze ed effetti collaterali

nell’anziano

Gualtiero PalaretiBologna

AcEMC, Verona 16-17 Maggio 2014

Età avanzata: problema rilevante per l’anticoagulazione

Safety of OAT in the elderly: a review (Hutton et al. Drugs & Aging 1999)

Indication Ages Major bleeds% y/treat.

Rate ratios

AF >75 vs <75 4.2 vs 1.7 2.5

Miscellaneous >70 vs <70 2.9 vs 0.5 5.8

MHV prosthesis >60 vs <60 3.7 vs 2.7 1.4

VTE >60 vs <60 1.4 vs 0.8 1.8

Factors for higher bleeding risk in elderly anticoagulated pts

More:• Adverse drug reaction• Comorbidity• Comedication• Vascular and endothelial fragility• Effect of coumarinsLess:• Attention degree • Compliance

NAO e pazienti anziani

Elderly patients included in the NOA AF trials and in a “real-life” registry

Study Patients > 75 y (%)RE-LY (dabigatran) 39.9Rocket (rivaroxaban) 43.3Aristotle (apixaban) 31.2Engage (edoxaban) 40.1START-Register (VKA) 72.0

• Dati al al 20/12/2013

• 5.600 pazienti che hanno cominciato AC• Età Mediana (IQ range) 74 a. (64-80) • 61% per FA non Valvolare • Età > 75 a. nel 72% dei paz inclusi per FANV

Clinical considerations on NOA use in elderly pts

• Right indications and doses• Drug Interactions

- fewer interactions- < INR controls due to addition of drugs- lower risk of anticoagulant effect variability

• Renal Impairment• Adherence and dementia

Indicazioni e dosi Pradaxa: 110 mg x 2

Età compresa tra 75 e 80 anni = considerare dose di 110 mg x 2,

>= 80 anni usare dose di 110 mg x 2

Negli anziani (> 75 anni), funzionalità renale valutata prima dell’inizio del trattamento per escludere ClCr < 30 ml/min, ed almeno ogni anno

Indicazioni e dosi rivaroxaban (Xarelto)

• 20 mg x 1• 15 mg x 1 per pazienti con insufficienza renale:

moderata (ClCr = 30-49 ml/min) o grave (15-29 ml/min); sconsigliato l’uso in pazienti con ClCr <15 ml/min.

Indicazioni e dosi apixaban (Eliquis)

• 5 mg x 2

• 2,5 mg x 2 se almeno due delle seguenti caratteristiche:eta ≥80 anni, peso ≤ 60 kg, creatinina ≥ 1,5 mg/dl

Corrette indicazioni e dosi

Molte complicanze dovute a sbagliate indicazioni e/o dosi

- 83-y man in the ED after a ground-level fall at home. -One month earlier, he had started on dabigatran 150 mg x 2 by

his primary care physician for AF- recombinant factor VII was administered because a rapid onset of action.

Harper et al., NEJM 2012

New Zeland44 cases of bleeding in patients treated with dabigatran

30 cases >= 80 y18 = 220 mg/day7 = 300 mg/day5 = NA

Arch Intern Med2011

Thromb Haemost2012

…severe bleeding (was) associated with very high levels of dabigatranplasma concentration (5,660 and 2,630 ng/ml). All these cases demonstrate the major involvement of renal impairment indabigatran accumulation and the need for a repeated monitoring of renal function …., as recommended recently in Australia

Elderly subpopulations in the trials

RE-LY(dabigatran)

40% ≥ 75 yNo interaction between age and efficacyMajor bleeding similar to W with both dosesNo difference for intracranial bleeding

ROCKET(rivaroxaban)

38% ≥ 75 yNo interaction between age and efficacyStroke & Embolism: 4.06% riv. vs 5.0% WSimilar rates of major bleeding

ARISTOTLE(apixaban)

31% ≥ 75 yNo interaction between age and efficacyStroke & Embolism: 1.6% apix. vs 2.0% Wmajor bleeding: 3.3% apix. vs 5.2% W

A significant treatment-by-age interaction for major bleeding

dabigatran 110 mg BID vs W=lower risk < 75 y (1.89% vs 3.04%; P.001) similar risk > 75 y (4.43% vs 4.37%; P0.89)

P for interaction 0.001dabigatran 150 mg BID vs W =

lower risk < 75 y (2.12% vs 3.04%; P0.001)trend toward higher risk >75 y (5.10% vs 4.37%; P0.07)

P for interaction 0.001Interaction with age only for extracranial bleeding

Eikelboom et al., Circulation 2011

Among the 39% of study subjects > 75 years, bleeding was increased among those treated with dabigatran (150 mg)

(HR, 1.18 95% CI , 0.98-1.43)

Not attributed solely to poor renal function: in subanalysis of subjects > 75 years with normal renal function dabigatran150mg was still associated with > bleeding (HR 1.219 95% CI, 0.65-2.266)

Arch Intern Med 2011

Gender had no significant influence on rivaroxabanThe AUC was 41% > in elderly vs young subjects, result of reducedclearance in elderly due to decreased renal function

The influence of age was not considered clinically relevant

Fattori che aumentano il livello plasmatico di dabigatran

• Età ≥ 75 a• Insuff. renale moderata (ClCr 30-50 ml/min)• Basso peso corporeo (< 50 Kg)• Assunzione di inibitori della P-gp

NVAF pts enrolled in the START-Register, vs those in randomized trials on NOACs

START-Register

RE-LY (dab.) Rocket-AF (riv.)

Aristotle(apix.)

Age yrs 74.6±9.6 72±9 73 (65,78) 70 (63,76)

CrCl ml/min %30-5930-50< 30< 15

39.723.95.30.02

19.3Excluded

20.8Excluded

15.11.5 &

BMI 28.3±5.1 82.6Kg±19.9 28 (25,32) 82 Kg (70-95)

History of ACS % 20 17 17 15

Diabetes % 21 23 40 19.4

CHADS2 score 2.1±1.1 2.1±1.1 3.5±0.9 2.1±1.1

(from Deedwania, Am J Med 2013)

CASE-CONTROL STUDY ONCOMPLIANCE IN OAT PATIENTS

(Arnsten et al., Am J Med 1997)More non-compliant cases if:• young• male• without a regular physician• not knowing why OAT was prescribed• feeling burdened by OAT• not perceiving benefits

2013

Patient selection•advanced age, •impaired renal or liver function, •low body weight, •presence of multiple co-morbidities, •need for concomitant therapies

2013

“..it is likely that very elderly patients with concomitant renal insufficiency and/or additional co-morbidities and concomitant therapies were not sufficiently, if at all, represented in these (NOAC) trials”

Terapia delle complicanze emorragiche in corso di NAO

Alikhan et al., EmergMedJ 2013

Alikhan et al., EmergMedJ 2013

(Warkentin, Blood 2012)

A79-year-old, 80-kg male, with diabetes and chronic renal insufficiency ( CrCl 36 mL/min), treated with dabigatran 150 mg twice-daily. Dabigatran was discontinued 2 days (4 doses) before surgery.

Surgery: tissue aortic valve replacement and singlevesselcoronary artery bypass using cardiopulmonary bypass with standard heparin anticoagulation (35 000 units)Postoperatively, severe bleeding ( 1500 mL/hr)

(Warkentin, Blood 2012)

Specifici antidoti sono in avanzata fase di studio