1. Le basse dosi dei NAO: uso ed abuso Giuseppe Patti Campus Bio-Medico University of Rome

2. Dabigatran PREFER AF PROLONGATION Registry

3. Rivaroxaban ROCKET: dose reduction from 20 mg to 15 mg if Cr Cl 30-49 ml/min 20% of patients PREFER AF PROLONGATION Registry

4. 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

5. 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 Stroke/SE Major bleeding Stroke/SE Major bleeding Event rate (%) Apixaban Warfarin Alexander et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2032

6. ENGAGE AF: Stroke or SEE (%/Year) 48.5 Edox Conc. (ng/mL) 0.85 Anti-FXa (IU/mL) No dose reductionDose reduction WarfarinHD Edox 60 mg Warfarin HD Edox (dose reduced to 30 mg) NA 34.6 0.64 NA HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) DR: HR 0.81 (0.58–1.13) P int =0.85 DR, dose reduction; HD, high dose; SEE, systemic embolic event

7. ENGAGE AF: Major bleed (%/Year) 48.5 Edox Conc. (ng/mL) 0.85 Anti-FXa (IU/mL) No dose reductionDose reduction WarfarinHD Edox 60 mg Warfarin NA 34.6 0.64 NA HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) DR: HR 0.63 (0.50–0.81) P int =0.02 DR, dose reduction; HD, high dose; SEE, systemic embolic event HD Edox (dose reduced to 30 mg)

8. Major Bleeding Interaction P-value=0.71 Alexander et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.2032 Subgroup Apixaban (%/yr) Warfarin (%/yr) HR (95% CI) No DR criteria204 (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 yrs46 (3.5)61 (4.9)0.7 (0.5-1.1)

9. 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

10. XANTUS: Outcomes According to Dosing (20/15 mg od)

11. Major bleed Stroke or SEE ICH Probability of event Trough concentration [ng/mL] 18 16 14 12 10 8 6 4 2 0 0 2030405015060708090100110120130140 NOACs concentrations and outcome 5 mg/day 10 mg/day Pts with Cr Cl 15-29 ml/min or >=2 factors for dose reduction Apixaban Modified from Leil - Clin Pharm Ther 2010

12. Major bleed Stroke or SEE ICH Probability of event Trough concentration [ng/mL] 18 16 14 12 10 8 6 4 2 0 0 2030405015060708090100110120130140 NOACs concentrations and outcome Apixaban Modified from Leil - Clin Pharm Ther 2010 Pts with Cr Cl >= 30 ml/min and <=1 factors for dose reduction 5 mg/day 10 mg/day

13. Key-message NOACs low doses are effective, but inappropriate reduction of NOACs dose may compromise drug’s efficacy. Therefore….. RELAX, don’t do it!!!!!!!!