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 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 coumarins Less: 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) 39.9 Rocket (rivaroxaban) 43.3 Aristotle (apixaban) 31.2 Engage (edoxaban) 40.1 START-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 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) ROCKET (rivaroxaban) ARISTOTLE (apixaban) 40% 75 y No interaction between age and efficacy Major bleeding similar to W with both doses No difference for intracranial bleeding 38% 75 y No interaction between age and efficacy Stroke & Embolism: 4.06% riv. vs 5.0% W Similar rates of major bleeding 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 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 % 30-59 30-50 <30 <15 39.7 23.9 5.3 0.02 19.3 Excluded 20.8 Excluded 15.1 1.5 & BMI 28.3±5.1 82.6Kg±19.9 28 (25,32) 82 Kg (70-95) History ofacs% 20 17 17 15 Diabetes % 21 23 40 19.4 CHADS 2 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