i nao: complicanze ed effetti collaterali nell’anziano · i nao: complicanze ed effetti...
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I NAO: Complicanze ed effetti collaterali
nell’anziano
Gualtiero PalaretiBologna
AcEMC, Verona 16-17 Maggio 2014
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Età avanzata: problema rilevante per l’anticoagulazione
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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
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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
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NAO e pazienti anziani
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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
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• 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
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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
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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
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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.
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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
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Corrette indicazioni e dosi
Molte complicanze dovute a sbagliate indicazioni e/o dosi
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- 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.
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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
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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
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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
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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
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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
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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
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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
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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
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(from Deedwania, Am J Med 2013)
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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
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2013
Patient selection•advanced age, •impaired renal or liver function, •low body weight, •presence of multiple co-morbidities, •need for concomitant therapies
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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”
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Terapia delle complicanze emorragiche in corso di NAO
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Alikhan et al., EmergMedJ 2013
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Alikhan et al., EmergMedJ 2013
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(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)
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(Warkentin, Blood 2012)
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Specifici antidoti sono in avanzata fase di studio
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