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Novel Anticoagulants

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Kim Dharap

on 20 February 2015

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Transcript of Novel Anticoagulants

New Oral Anticoagulants
Rivaroxaban (Xarelto)
Dabigatran Etexilate (Pradaxa)
New Oral Anticoagulants
Anticipated benefits vs. Warfarin
Predictable pharmacokinetics
Lower ICH
Fewer interactions


Apixaban (Eliquis)
Drug Interactions:
Edoxaban (Savaysa)
Dabigatran in AFib (RE-LY 2009)
dabigatran 110mg PO BID &
150mg PO BID
Intervention:
prophylaxis regimens (150mg/day and 220mg/day)
Comparator:
Findings:
Mechanism of Action:
direct thrombin inhibitor
PK:
Peak levels: 1h (delayed 2h by food)
T1/2:12-17h

Adverse Effects:
GI: dyspepsia, GERD, esophagitis, gastritis-like symptoms, GI bleeds
Hematologic: hemorrhage

Contraindications:
CrCl<30mL/min
bleeding diathesis or patient with spontaneous or pharmacological hemostatic impairment
history of serious hypersensitivity reaction to dabigatran
lesions at risk of clinically significant bleeding within previous 6 months
Drug Interactions
**Caution in Geriatric patients (increased risk of bleeding)
Avoid use/Caution:
concomitant use with other anticoagulants, NSAIDs, oral ketoconazole, P-glycoprotein/ABCB1 inducers/inhibitors, amiodarone, estrogen derivatives
None

may be attempted with hemodialysis or activated charcoal if <2hr of administration
Dabigatran (Pradaxa) Landmark Trials and Indications
warfarin (target INR 2-3)
**(ASA was given in combination with anticoagulant ~40% in both groups)
1° outcome: stroke or systemic embolism
1° safety outcome: major bleeding

Dabigatran Etexilate (Pradaxa)
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)

Intervention:
Comparator:
Outcomes:
Findings:
- Dabigatran 110mg BID: non-inferior to warfarin with a significantly lower risk of major bleeding
-Dabigatran 150mg BID: superior to warfarin with a non-significantly lower rate of major bleeding**
**dabigatran 150mg BID had a significantly lower ICH rate, but significantly higher rate of GI bleeding
-Higher rates of MI with both doses of dabigatran than with warfarin
-Patients on warfarin were within targeted range 64% of time

Labeling (Non-valvular atrial fibrillation): (to prevent stroke and systemic embolism)
Dabigatran 150mg PO BID

*110mg PO BID if >80 years or >75 years + 1 risk factor for bleeding*

*moderate renal impairment, concomitant treatment with strong P-gp inhibitors, or previous GI bleed

Dabigatran in DVT Prophylaxis (RE-NOVATE, RE-MODEL, RE-MOBILIZE)
dabigatran
Comparator:
standard enoxaparin prophylaxis regimens (40mg daily started the evening before surgery, or 30mg BID started 12 to 24 hours after surgery)
Outcomes:
total VTEs and all-cause mortality
Findings:
Dabigatran prophylaxis regimes were found "noninferior” (statistically no less effective) to enoxaparin 40 mg daily in hip arthroplasty and in knee arthroplasty, but this regimen was found to be less effective than the 30mg BID regimen
Canadian Labeling (post-operative thromboprophylaxis for knee and hip replacement):

Initial: 110mg given 1 to 4 hours after completion of surgery and establishment of hemostasis OR 220mg as 1 dose in postoperative patients in whom therapy in not initiated on day of surgery

Maintenance: 220mg once daily (duration: minimum 10 to 14 days, extended duration of up to 35 days suggested)

*If patient >75 years, consider a dose of 150mg once daily
Dabigatran in Venous Thrombosis (RE-COVER 2009)
Intervention:
Dabigatran 150mg BID
warfarin (target INR 2-3)
Dabigatran found to be noninferior to warfarin (INR within targeted range 60% of time) with a non-significantly lower risk of major bleeding
Labeling (DVT and PE):
Dabigatran 150mg PO BID after 5 to 10 days of parenteral anticoagulation (UFH or LMWH)

*
110mg PO BID if >80 years or >75 years + 1 risk factor for bleeding*

*moderate renal impairment, concomitant treatment with strong P-gp inhibitors, or previous GI bleed
Mechanism of Action:
Factor Xa Inhibitor
PK:
Peak levels: 2-4h
T1/2: 5-9h
Bioavailability increased with food


Adverse Effects:
Contraindications:
concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, pregnancy, lactation
history of serious hypersensitivity reaction to rivaroxaban
lesions at risk of clinically significant bleeding
hepatic disease associated with coagulopathy and significant bleed risk
Antidote:
Reversal:
Drug Interactions:
Antidote:
Reversal:
peripheral edema, dizziness, headache, bruising, bleeding, diarrhea, epistaxis, extremity pain
Anticoagulants, CYP 3A4 inducers/inhibitors (strong), P-gp inducers/inhibitors, dabigatran
None
PCC, recombinant Factor VIIa, or activated charcoal if <2hr of administration
Intervention:
Findings:
Intervention:
Outcomes:
Comparator:
rivaroxaban 15mg BID x 3 weeks followed by 20mg once daily
Rivaroxaban (Xarelto) Landmark Trials and Indications
Rivaroxaban in AFib (ROCKET AF)
Comparator:
rivaroxaban 20mg daily (or 15mg daily if CrCl 30-49mL/min)
warfarin (target INR 2-3)
Outcomes:

1° outcome: stroke or systemic embolism
1° safety outcome: major and non-major bleeding

Rivaroxaban is non-inferior to warfarin with similar rates of bleeding (less ICH in the rivaroxaban group).
Labeling: Non-valvular AFib (to prevent stroke and systemic embolism):
Rivaroxaban 20mg PO once daily with evening meal
*15mg PO daily if CrCl 30-49mL/min
**CrCl<30mL/min avoid use
Rivaroxaban in DVT Prophylaxis (RECORD 1, 2, 3; MAGELLAN 2011)
Comparator:
rivaroxaban 10mg once daily
enoxaparin 40mg SC once daily
Findings (MAGELLAN)
Rivaroxaban is noninferior to enoxaparin for standard-duration thromboprophylaxis (day 10 analysis). Rivaroxaban did reduce VTE risk when given for an extended period (day 35 analysis), but was associated with a high risk of bleeding. Analysis showed no clinical benefit to using rivaroxaban either at day 10 or 35.

Labeling (post-operative thromboprophylaxis for knee and hip replacement):
Rivaroxaban 10mg once daily (duration: minimum 10-14 days, extended duration of up to 35 days suggested)

*Not recommended for thromboprophylaxis in acutely-ill medical patients at this time
**CrCl<30mL/min avoid use

Rivaroxaban in Venous Thrombosis (Einstein-DVT and Einstein-PE)
Intervention:
LMWH followed by vitamin K antagonists (goal INR:2-3)* warfarin group within range 57.7% of the time)
Outcomes:
Recurrent VTEs
Findings:
Rivaroxaban was found to be noninferior to enoxaparin/vitamin K antagonists in both initial-treatment studies with no significant difference in rates of fatal major bleeding.
Labeling (DVT and PE):
Initial Rivaroxaban 15 mg PO BID with food for 21 days followed by 20 mg PO once daily with food

*CrCl<30mL/min avoid use

Mechanism of Action:
Factor Xa Inhibitor
PK:
Peak levels: 3-4h
T1/2:~12h

Adverse Effects:
Contraindications:
patient with spontaneous or acquired hemostatic impairment
history of serious hypersensitivity to apixaban
hepatic disease associated with coagulopathy and significant bleed risk,
lesions at risk of clinically significant bleeding
concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors
hemorrhage, anemia, nausea
Anticoagulants, NSAIDs, CYP 3A4 inducers/inhibitors (strong), St. John’s Wort, estrogen derivatives
Antidote:
None
PCC, recombinant Factor VIIa, or activated charcoal if <3hr of administration
Intervention:
apixaban 5mg BID
Intervention:
enoxaparin 40mg SC once daily for 35 days started the evening before surgery
Comparator:
Outcomes:
Apixaban (Eliquis) Landmark Trials and Indications
Reversal:
Apixaban in AFib (ARISTOTLE 2011)
Comparator:
(ASA was given in combination with anticoagulant ~35% in both groups)
warfarin (target INR 2-3)
*(ASA was given in combination with anticoagulant ~33% in both groups)
Outcomes:
1° outcome: stroke or systemic embolism
1° safety outcome: major bleeding

Findings:
Apixaban is superior to warfarin (patient’s within target range ~66% of time) with a significantly lower rate of major bleeding.
Labeling: Non-valvular atrial fibrillation (to prevent stroke and systemic embolism):
Apixaban 5mg PO BID

*2.5mg BID if any 2 of following: Age>80years,body weight <60kg, or serum creatinine >1.5mg/dL or ~133umol/L
**CrCl<15mL/min use is not recommended

Apixaban in DVT Prophylaxis (ADVANCE 2010)
Comparator:
apixaban 2.5mg BID x 35 days (given 12 to 24 hours following surgery)
Outcomes:
asymptomatic and symptomatic DVT, PE, all-cause death
Findings:
Apixaban was found to be superior to enoxaparin for prevention of VTE without a significant increase in the risk of bleeding.
Labeling (post-operative thromboprophylaxis for knee and hip replacement):
Hip replacement surgery: Apixaban 2.5mg BID beginning 12 to 24 hours postoperatively x 35 days
Knee replacement surgery: Apixaban 2.5mg BID beginning 12 to 24 hours postoperatively x 12 days
*CrCl<15mL/min use is not recommended

Apixaban in Venous Thrombosis (AMPLIFY 2013)
Intervention:
apixaban 10 mg twice daily for 7 days then 5 mg, twice daily, 6 months
enoxaparin 1mg/kg twice daily until INR>=2 then warfarin for an INR between 2-4, once daily, 6 months
VTE recurrence or death
Findings:
Apixaban was found to be as effective as standard treatment enoxaparin followed by warfarin and was associated with a significantly less risk of major bleeding.
Unlabeled use (DVT and PE):
Initial treatment: apixaban 10mg BID x 7 days then 5 mg BID x 6 months
Extended treatment: after 6 months of initial treatment administer apixaban 2.5mg BID x 12 months

Mechanism of Action:
Factor Xa Inhibitor
PK:
Peak levels: 1-2h
T1/2: 5-10h
Bioavailability increased with food


Adverse Effects:
pharyngolaryngeal pain, headache, nuisance bleeding
Edoxaban Trials
1. Edoxaban in AFib (ENGAGE-AF TMI)
ongoing
2. Edoxaban in DVT Prophylaxis (STARS J-V)
ongoing
3. Edoxaban in Venous Thrombosis (Edoxaban Hokosai VTE) Results available

Edoxaban in Venous Thrombosis (Edoxaban Hokosai VTE)
Intervention:
Comparator:
60 mg once daily (30 mg once daily if patient's body weight <60 kg or CrCl ≥30 and ≤50 ml/min)

warfarin (target INR of 2-3)
Outcomes:
Findings:
Edoxaban was non-inferior to warfarin for efficacy, but superior with regards to safety outcomes (major or clinically relevant non-major bleeding)
recurrent DVT, non-fatal and fatal PE
Awaiting approval by Health Canada
Summary Table: New Oral Anticoagulants
Outcomes:
recurrent VTE or VTE-related death
Findings (RECORD 1, 2, 3)
Rivaroxaban is superior to enoxaparin in postoperative DVT prophylaxis and has a non-significant increase in major bleeding
1° outcome: VTE (DVT and/or PE) and death
1° safety outcome: major bleeding
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