I NAO: Complicanze ed effetti collaterali nell`anziano

AcEMC, Verona 16-17 Maggio 2014
I NAO: Complicanze ed effetti
collaterali
nell’anziano
Gualtiero Palareti
Bologna
Età avanzata: problema rilevante per
l’anticoagulazione
Safety of OAT in the elderly: a review
(Hutton et al. Drugs & Aging 1999)
Indication
Ages
AF
Major bleeds
% y/treat.
>75 vs <75
4.2 vs 1.7
Rate
ratios
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 coumarins
Less:
• Attention degree
• Compliance
NAO e pazienti anziani
Elderly patients included in the NOA
AF trials and in a “real-life” registry
Study
RE-LY (dabigatran)
Rocket (rivaroxaban)
Aristotle (apixaban)
Engage (edoxaban)
START-Register (VKA)
Patients > 75 y (%)
39.9
43.3
31.2
40.1
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 Zeland
44 cases of bleeding in patients treated with dabigatran
30 cases >= 80 y
18 = 220 mg/day
7 = 300 mg/day
5 = NA
Arch Intern Med
2011
Thromb Haemost
2012
…severe bleeding (was) associated with very high levels of dabigatran
plasma concentration (5,660 and 2,630 ng/ml).
All these cases demonstrate the major involvement of renal impairment in
dabigatran 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 y
No interaction between age and efficacy
Major bleeding similar to W with both doses
No difference for intracranial bleeding
ROCKET
(rivaroxaban)
38% ≥ 75 y
No interaction between age and efficacy
Stroke & Embolism: 4.06% riv. vs 5.0% W
Similar rates of major bleeding
ARISTOTLE
(apixaban)
31% ≥ 75 y
No interaction between age and efficacy
Stroke & Embolism: 1.6% apix. vs 2.0% W
major bleeding: 3.3% apix. vs 5.2% W
Eikelboom et al., Circulation 2011
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 0.001
dabigatran 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 0.001
Interaction with age only for extracranial bleeding
Arch Intern Med 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 dabigatran
150mg was still associated with > bleeding
(HR 1.219 95% CI, 0.65-2.266)
Gender had no significant influence on rivaroxaban
The AUC was 41% > in elderly vs young subjects, result of reduced
clearance 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
STARTRegister
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 %
30-59
30-50
< 30
< 15
BMI
39.7
23.9
5.3
0.02
28.3±5.1
19.3
Excluded
20.8
Excluded
15.1
1.5 &
82.6Kg±19.9
28 (25,32)
82 Kg (7095)
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 ON
COMPLIANCE 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 singlevessel
coronary 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