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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!!!!!!!!