Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
.pdf
140 Anticoagulation Therapy
https://t.me/med1917
and 7-5 below summarize management strategies for DOAC interactions.
These lists of inhibitors and inducers are not exhaustive (see Clinical Pearl).
TABLE 7-4: Apixaban and Rivaroxaban (Substrates of P-gp and
CYP3A4) DDI and Management
Drug Examples
(lists are not
exhaustive)
P-gp and STRONG
CYP3A4 inducers
P-gp and STRONG
CYP3A4 inhibitors
P-gp and MODERATE
CYP3A4 inhibitors
Barbiturate,
carbamazepine,
phenytoin, rifampin,
St. John’s Wort
Clarithromycin,
conivaptan,
grapefruit,
itraconazole,
ketoconazole,
posaconazole,
ritonavir
Cyclosporine,
diltiazem,
dronedarone,
tamoxifen, verapamil
2,3,23
Impact on
Rivaroxaban and
Apixaban
↓ Decreased levels Rivaroxaban: AVOID
↑ Increased levels Rivaroxaban: AVOID
↑ Increased levels Rivaroxaban: AVOID
Suggested
Management
USE
Apixaban: AVOID
USE
USE
Apixaban:
-If taking 5 mg or 10
mg BID, reduce dose
by 50% *
-If taking 2.5 mg BID,
AVOID USE
USE if CrCl <80 mL/
min
Apixaban: Use
with caution. No
dose adjustment
recommended
*Based on pharmacokinetic data only—not studied in safety and efficacy trials.
BID: twice daily, CrCl: creatinine clearance based on Cockcroft-Gault, CYP3A4: cytochrome P450
3A4, DDI: drug-drug interactions, mg: milligram, min: minutes, P-gp: permeability-glycoprotein
DIRECT ORAL ANTICOAGULANTS 141
https://t.me/med1917
TABLE 7-5: Dabigatran and Edoxaban (Substrates of P-gp) DDI
and Management
P-gp inducers Barbiturate, carbamazepine,
P-gp inhibitors Amiodarone, carvedilol,
*Only applies to VTE indication; does not apply to NVAF.
BID: twice daily, CrCl: creatinine clearance in mL/min based on Cockcroft-Gault, DDI: drug-drug
interactions, NVAF: non-valvular atrial fibrillation, mg: milligram, min: minutes, P-gp: permeabilityglycoprotein, VTE: venous thromboembolism
1,4,23
Drug Examples
(lists are not exhaustive)
dexamethasone, phenytoin,
rifampin, St. John’s Wort
clarithromycin, conivaptan,
cyclosporine, diltiazem,
dronedarone, erythromycin,
grapefruit, itraconazole,
ketoconazole, lapatinib,
mefloquine, nicardipine,
propafenone, quinidine, ritonavir,
tacrolimus, tamoxifen, verapamil
Impact on
Dabigatran and
Edoxaban
↓ Decreased
levels
↑ Increased
levels
Suggested
Management
Dabigatran:
AVOID USE
Edoxaban: AVOID
USE
Dabigatran:
AVOID USE if CrCl
< 50 mL/min
Edoxaban: VTE
patients: Reduce
dose from 60 mg
daily to 30 mg
daily*
• When evaluating patients for potential drug
interactions with a DOAC, other potentially
cumulative contributing factors must be
considered in tandem. These include the presence
of multiple drug interactions and factors such as
the patient’s age, weight, and renal function. For
example, if a patient has only a single weak drug
interaction, use of a DOAC might be reasonable.
However, if that same patient had an additional
contributing problematic condition, such as
diminished renal function, advanced age, low
body weight, or obesity, the drug interaction may
bear more significance. Because we have little
real-world clinical experience with the presence
of a combination of contributing factors that
affect DOAC exposure and dose-response and we
have no means to readily monitor DOACs (as we
do with the international normalized ratio (INR)
and warfarin), avoidance of DOACs in these
patients is recommended (see Figure 7-2).
142 Anticoagulation Therapy
https://t.me/med1917
• Often, clinicians will assume a medication is
okay to use with a DOAC if it is not listed as an
interaction in the package insert. Unfortunately,
package inserts often contain only information
on formally studied interactions. Other not listed
medications are frequently problematic and
should be avoided. Any interaction that likely led
to adverse patient outcomes should be reported to
the FDA.
Concomitant
medicaons
+
Renal impairment
Altered exposure
+
Advanced age
to DOAC
+
Weight extremes
FIGURE 7-2. Interactions That May Alter DOAC Exposure
SAFETY AND EFFICACY OF DOACS
Tables 7-6, 7-7, and 7-8 summarize Phase III clinical trial safety and efficacy
data pertaining to major approved DOAC indications.
30
Renal dose adjustment
Enoxaparin dose
Treatment duration
Primary endpoint (total
VTE+ all-cause mortality)
Major bleeding +
clinically relevant non-
https://t.me/med1917
RECORD 4
29
DIRECT ORAL ANTICOAGULANTS 143
Excluded CrCl
<30
(continued)
24-35
RECORD 3
28
RECORD 2
28
RECORD 1
27
RE-NOVATE II
26
RE-NOVATE
25
Dabigatran Rivaroxaban
Excluded CrCl
<30
Excluded CrCl
<30
Excluded CrCl
<30
Excluded CrCl
220 mg daily 10 mg daily 10 mg daily 10 mg daily 10 mg daily
150 mg daily or
<30
CrCl <30
Excluded
220 mg daily
10–14 days 10–14 days
Enox: 14 days
Non-inferior Superior Superior Superior Superior
(both doses)
RE-MOBILIZE
24
TABLE 7-6: Phase III Trials of Prevention of VTE in Orthopedic Surgery
Study RE-MODEL
N 2067 1896 3494 2055 4541 2509 2531 3148
Design R, DB R, DB R, DB R, DB R, DB, DD R, DB, DD R, DB, DD R, DB, DD
Population TKR TKR THR THR THR THR TKR TKR
Excluded
150 mg daily or
DOAC dose 150 mg daily or
CrCl <30
220 mg daily
Excluded CrCl
<30
220 mg daily
(mL/min)
40 mg Q 24 hr 30 mg Q 12 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 30 mg Q 12 hr
6–10 days 12–15 days 28–35 days 28–35 days 35 days Riva: 35 days
Efficacy
Inferior Non-inferior
Non-inferior
(both doses)
Safety
↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
Major bleeding
major bleeding
144 Anticoagulation Therapy
Renal dose adjustment (mL/min)
Enoxaparin dose
Treatment duration
Primary endpoint (total VTE+
all-cause mortality)
Major bleeding + clinically
relevant non-major bleeding
No significant difference between DOAC and comparator therapy.
DOAC significantly lower rate of event versus comparator therapy.↑ DOAC significantly greater rate of event versus comparator therapy.
*Non-inferiority criteria not met. There was an unexpectedly low event rate (55% of expected event rate) for the primary endpoint.
CrCl: creatinine clearance, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, Enox: enoxaparin, hr: hours, min: minutes, mL: milliliters, N:
number, R: randomized, Riva: rivaroxaban, THR: total hip replacement surgery, TKR: total knee replacement surgery, VTE: venous thromboembolism
https://t.me/med1917
35
STARS J-V
34
STARS E-3
33
ADVANCE-3
32
Apixaban Edoxaban
ADVANCE-2
31
N 3195 3057 5407 716 610
TABLE 7-6: (Continued)
Study ADVANCE-1
Design R, DB, DD R, DB R, DB, DD R, DB, DD R, DB, DD
Population TKR TKR THR TKR THR
DOAC dose 2.5 mg BID 2.5 mg BID 2.5 mg BID 30 mg daily 30 mg daily
Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30
30 mg Q 12 hr 40 mg Q 24 hr 40 mg Q 24 hr 20 mg Q 12 hr 20 mg Q 12 hr
10–14 days 10–14 days 35 days 11–14 days 11–14 days
Inferior* Superior Superior Superior Superior
↓ ↔ ↔ ↔ ↔
Efficacy
Safety
Major bleeding
↓ ↔ ↔ ↔ ↔
↔
↓
DIRECT ORAL ANTICOAGULANTS 145
Renal dose adjustment (mL/min)
Parenteral “pre-treatment”
VTE recurrence or VTE death
Major bleeding + clinically
relevant non-major bleeding
https://t.me/med1917
13
(continued)
11-17
EINSTEIN-EXT
14
EINSTEIN-PE
13
EINSTEIN-DVT
12
RE-MEDY
12
RE-SONATE
11
Dabigatran Rivaroxaban
prevention
VTE treatment VTE treatment Recurrence
Recurrence
prevention
prevention
Excluded
CrCl <30
CrCl <30
Excluded
Excluded
CrCl <30
CrCl <30
Excluded
Excluded
CrCl <30
20 mg daily
15 mg BID x 21
d; 20 mg daily
d; 20 mg daily
↔
↓ ↔
↔** ↔**
↔
↔
Not estimable
RE-COVER II
11
TABLE 7-7: Phase III Trials of VTE Treatment and Prevention of Recurrence
Study RE-COVER
N 2539 2589 1343 2856 3449 4832 661
Design R, DB R, DB, DD R, DB R, DB R, open-label R, open-label R, open-label
CrCl <30
Excluded
Excluded
CrCl <30
DOAC dose 150 mg BID 150 mg BID 150 mg BID 150 mg BID 15 mg BID x 21
VTE indication VTE treatment VTE treatment Recurrence
Comparator Warfarin* Warfarin* Placebo Warfarin* Warfarin* Warfarin* Placebo
Yes Yes NA NA No No NA
Efficacy
Non-inferior Non-inferior Superior Non-inferior Non-inferior Non-inferior Superior
Safety
↓ ↓ ↑ ↓
↔ ↔
Major bleeding
146 Anticoagulation Therapy
Renal dose adjustment (mL/min)
Parenteral “pre-treatment”
VTE recurrence or VTE death
Major bleeding + clinically
relevant non-major bleeding
*Adjusted dose warfarin with INR goal 2−3.
**The principal safety outcome was major bleeding plus clinically relevant non-major bleeding.
No significant difference between DOAC and comparator therapy.
DOAC significantly lower rate of event versus comparator therapy.↑ DOAC significantly greater rate of event versus comparator therapy.
CrCl: creatinine clearance, BID: twice daily, d: days, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, hr: hours, mL: milliliters, min: minutes,
N: number, NA: not applicable, R: randomized, VTE: venous thromboembolism
https://t.me/med1917
17
HOKUSAI-VTE
16
Apixaban Edoxaban
AMPLIFY-EXT
15
↓**
Excluded CrCl <25 Excluded CrCl <25 30 mg daily if CrCl 30–50; excluded CrCl <30
No NA NA Ye s
↓ ↔ ↔ ↔
Non-inferior Superior Superior Non-inferior
↓ ↔ ↔
Study AMPLIFY
TABLE 7-7: (Continued)
N 5395 2486 8240
Comparator Warfarin* Placebo Placebo Warfarin*
Design R, DB R, DB R, DB
DOAC dose 10 mg BID x 7 d; 5 mg BID 5 mg BID 2.5 mg BID 60 mg daily
VTE indication VTE treatment Recurrence prevention VTE treatment
Efficacy
Safety
Major bleeding
↔
↓
7-10,36
Renal exclusion
criteria (mL/min)
Stroke or systemic
Ischemic stroke
All-cause mortality
https://t.me/med1917
10
ENGAGE AF-TIMI 48
36
AVERROES
9
DIRECT ORAL ANTICOAGULANTS 147
15 mg daily if CrCl
30–50
30 mg daily if CrCl
30–50
2.5 mg BID if 2
criteria:
Scr ≥1.5 mg/dL
Age ≥80 yr
Wt ≤60 kg
(continued)
ARISTOTLE
8
ROCKET-AF
Dabigatran Rivaroxaban Apixaban Edoxaban
7
TABLE 7-8: Phase III Trials of Stroke and Systemic Embolism Prevention in Non-Valvular Atrial Fibrillation
Study RE-LY
2.5 mg BID if 2
criteria:
Scr ≥1.5 mg/dL
Age ≥80 yr
R, DB R, DB R, DB R, DB, DD
warfarin
30−49
NA NA 15 mg daily if CrCl
Renal dose
adjustment
DOAC dose 150 mg BID 110 mg BID 20 mg daily 5 mg BID 5 mg BID 60 mg daily 30 mg daily
Design R, blinded dabigatran, open-label
N 18,113 14,264 18,201 5,599 21,105
(mL/min)
Wt ≤60 kg
CrCl <30 CrCl <30 CrCl <25 CrCl <25 CrCl <30
Comparator Warfarin* Warfarin* Warfarin* Warfarin* Aspirin 81–324 mg Warfarin* Warfarin*
Superior Non-inferior Non-inferior Superior ↓*** Non-inferior Non-inferior
Efficacy
embolism
↓ ↔ ↔ ↔ ↓ ↔ ↑
↓ ↔ ↔ ↓ ↔ ↔ ↓
148 Anticoagulation Therapy
*Adjusted dose warfarin, INR goal 2–3.
**The principal safety outcome in the ROCKET-AF trial was not major bleeding but major bleeding plus clinically relevant non-major bleeding.
***AVERROES was not designed as non-inferiority. Apixaban had a significantly lower rate of the primary endpoint compared with aspirin.
No significant difference between DOAC and comparator therapy.
DOAC significantly lower rate of event versus comparator therapy.↑ DOAC significantly greater rate of event versus comparator therapy.
BID: twice daily, CrCl: creatinine clearance, d: days, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, GI: gastrointestinal, mL: milliliters, min:
minutes, N: number, NA: not applicable, R: randomized
https://t.me/med1917
↓ ↔ ↓ ↓
↔**
Dabigatran Rivaroxaban Apixaban Edoxaban
↔ ↓
Safety
TABLE 7-8: (Continued)
Major bleeding
↔ ↓ ↓ ↓ ↔ ↓ ↓
↓ ↓ ↓ ↓ ↔ ↓ ↓
Fatal bleeding
Intracranial
hemorrhage
↑ ↔ ↑ ↔ ↔ ↑ ↓
GI bleeding
↔
↓
DIRECT ORAL ANTICOAGULANTS 149
https://t.me/med1917
• Dabigatran 110 mg dose is not approved
for stroke prevention in non-valvular atrial
fibrillation in the United States. However this
dose is approved in Canada and Europe.
1
Although DOACs represent a significant advance in our approach to anticoagulation therapy, it is important for clinicians to recognize that not all
patients are appropriate DOAC candidates. Patient selection is imperative
for optimizing safety and efficacy of these drugs. Additionally, because there
are now several therapeutic options for anticoagulation, shared decision
making with patients and caregivers is important to promote adherence,
patient satisfaction, and quality of life. Table 7-9 provides suggestions as
to a preferred anticoagulant based on patient characteristics, drug characteristics, and indication for anticoagulation.
PATIENT AND AGENT SELECTION
TABLE 7-9: Clinical Screening Assessment and Considerations
for Oral Anticoagulant Selection
Patient Factor Consideration Recommended Oral Agent
Indication •
Bleeding risk • History of major GI disease and/or
Significant drug
Interactions
Dual antiplatelet
therapy
Non-valvular atrial fibrillation Any oral agent
• Venous thromboembolism
treatment
Knee arthroplasty Warfarin, rivaroxaban, apixaban
•
•
Hip arthroplasty Warfarin, rivaroxaban, apixaban,
• Mechanical heart valve replacement Warfarin; DOAC should be
• Other indications (not studied) Warfarin
GI bleeding event in past year
• Ongoing need for concomitant
interacting medications
• Ongoing need for dual antiplatelet
therapy
Rivaroxaban, apixaban
dabigatran
38
avoided
Warfarin, apixaban
Warfarin
Warfarin
(continued)
Соседние файлы в папке Библиотека им академика М.И. Перельмана