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Le basse dosi dei NAO: uso ed abuso Giuseppe Patti Campus Bio-Medico University of Rome Dabigatran PREFER AF PROLONGATION Registry Rivaroxaban ROCKET: dose reduction from 20 mg to 15 mg if Cr Cl 30-49 ml/min 20% of patients PREFER AF PROLONGATION Registry Apixaban ARISTOTLE: dose reduction from 10 mg to 5 mg/day in presence of at least 2 of 3: age ≥80 years, Cr ≥1.5 mg/dL, weight ≤60 kg 4.6% of patients PREFER AF PROLONGATION Registry Low-Dose Apixaban in ARISTOTLE Stroke/SE interaction p-value=0.22 Major bleeding interaction p-value=0.21 n 831 (4.6%) Apixaban 2.5 mg BD vs. Warfarin n 17,370 (95.4%) Apixaban 5 mg BD vs. Warfarin 8% 6.7% 7% 6% Apixaban Warfarin Event rate (%) 5% 4% 3.3% 3.3% 3.0% 3% 2% 1.7% 2.1% 1.3% 1.5% 1% 0% Stroke/SE Major bleeding Stroke/SE Major bleeding Alexander et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2032 ENGAGE AF: Stroke or SEE (%/Year) HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) DR: HR 0.81 (0.58–1.13) Warfarin Pint=0.85 HD Edox 60 mg No dose reduction Edox Conc. (ng/mL) Anti-FXa (IU/mL) NA NA DR, dose reduction; HD, high dose; SEE, systemic embolic event 48.5 0.85 Warfarin HD Edox (dose reduced to 30 mg) Dose reduction NA NA 34.6 0.64 ENGAGE AF: Major bleed (%/Year) HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) DR: HR 0.63 (0.50–0.81) Warfarin Pint=0.02 HD Edox 60 mg No dose reduction Edox Conc. (ng/mL) Anti-FXa (IU/mL) NA NA DR, dose reduction; HD, high dose; SEE, systemic embolic event 48.5 0.85 Warfarin HD Edox (dose reduced to 30 mg) Dose reduction NA NA 34.6 0.64 Major Bleeding Subgroup Apixaban (%/yr) Warfarin (%/yr) HR (95% CI) No DR criteria 204 (1.8) 279 (2.5) 0.7 (0.6-0.9) One DR criterion 102 (3.2) 145 (4.8) 0.7 (0.5-0.9) • Creatinine ≥1.5 mg/dl 30 (4.2) 40 (5.6) 0.7 (0.5-1.2) • Weight ≤60 kg 26 (2.3) 44 (4.0) 0.6 (0.4-0.9) • Age ≥80 yrs 46 (3.5) 61 (4.9) 0.7 (0.5-1.1) Alexander et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2032 Interaction P-value=0.71 Real world data on rivaroxaban Dresda Registry (N=2,600): - 12.5% of pts had Cr Cl <50 ml/min - 32.7% received Riva 15 mg/day Xantus (N=6,784) - 14.4% of pts had Cr Cl <50 ml/min - 15% of pts with Cr Cl >50 ml/min received Riva 15 mg/day XANTUS: Outcomes According to Dosing (20/15 mg od) Incidence rate, %/year* 4.0 3.5 3.7 15 mg dose 20 mg dose 3.1 3.0 2.5 2.0 2.3 1.6 1.8 1.4 1.5 1.0 0.5 0.0 Thromboembolic events Major bleeding All-cause death NOACs concentrations and outcome Apixaban 5 mg/day Pts with Cr Cl 15-29 ml/min or >=2 factors for dose reduction 10 mg/day 18 16 Major bleed Probability of event 14 12 10 8 6 Stroke or SEE 4 2 ICH 0 0 10 Modified from Leil - Clin Pharm Ther 2010 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Trough concentration [ng/mL] NOACs concentrations and outcome Pts with Cr Cl >= 30 ml/min and <=1 factors for dose reduction Apixaban 5 mg/day 10 mg/day 18 16 Major bleed Probability of event 14 12 10 8 6 Stroke or SEE 4 2 ICH 0 0 10 Modified from Leil - Clin Pharm Ther 2010 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Trough concentration [ng/mL] Key-message NOACs low doses are effective, but inappropriate reduction of NOACs dose may compromise drug’s efficacy. Therefore….. RELAX, don’t do it!!!!!!!!