Novel Anticoagulation Agentsutcomchatt.org/docs/FMU2015_12_Haynes_Anticoagulation_Update.pdfFerns...
Transcript of Novel Anticoagulation Agentsutcomchatt.org/docs/FMU2015_12_Haynes_Anticoagulation_Update.pdfFerns...
6/12/2015
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Novel Anticoagulation
Agents
James W. Haynes, MD
Department of Family Medicine
Univ of TN Health Science Center (Chattanooga)
DISCLOSURES
Objectives
• Understand mechanism of action behind the
NOAC agents
• Understand FDA approved indications/dosing for
each agent
• Understand the risks of using these agents
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF ACTION Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS
DOSING
RENAL DOSING
PEAK LEVELS
ARTHROPLASTY
DVT PROPH
COAG TEST
EFFECT
ATRIAL FIBRILLATION
TRIALS
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RE-LY Trial • Compared dabigatran to warfarin in 18,113 patients with AF at
risk for stroke (PROBE - Prospective, randomized, outcome blinded trial)
• The mean CHADS 2 2.1, and median follow-up duration was 2 years
• Randomly assigned to 1 of 2 blinded doses of dabigatran, 110 or 150 mg twice daily, or open-label, dose-adjusted warfarin to study primary outcome of stroke or systemic embolization.
• Event rates of 1.71% per year in the warfarin group; 1.54% per year in the dabigatran 110 mg twice daily group( P <.001 for noninferiority to warfarin); and 1.11% per year with dabigatran, 150 mg twice daily ( P <.001 for superiority to warfarin).
• Significantly lower rates of intracerebral hemorrhage were noted with both doses of dabigatran when compared with warfarin.
RE-LY Trial • The higher dose of dabigatran yielded a higher rate of GI Bleed
but a similar rate of major bleeding as compared with warfarin
• All-cause mortality was lower with dabigatran (4.13% per year for warfarin; 3.75% per year for dabigatran, 110 mg twice daily; and 3.64% per year for dabigatran, 150 mg twice daily) but did not reach statistical significance ( P = .13 and P = .051 for the 110 and 150 mg twice daily doses, respectively)
• Following RE-LY, dabigatran, 150 mg twice daily, was approved to reduce the risk of stroke and systemic embolism in patients with NVAF worldwide
• Although patients with severe renal impairment (CrCl <30 mL/min) were excluded from RE-LY, the FDA approved a dose of 75 mg twice daily for patients with CrCl 15 to 30 mL/min, based on pharmacokinetic modeling
ROCKET-AF • Randomized, double-blind, double-dummy study carried
out over a median follow-up of 1.9 years comparing rivaroxaban with warfarin in 14,264 patients with NVAF who were at increased risk for stroke
• The study included patients with high stroke risk with a mean CHADS2 score of 3.5, with 55% of patients having a prior stroke or transient ischemic attack (TIA)
• Study arm patients received fixed-dose rivaroxaban, 20 mg once daily (15 mg daily for those with CrCl 30–49 mL/min)
• Rivaroxaban was superior to warfarin (hazard ratio [HR], 0.88; P = .015) in preventing stroke or systemic embolism
• Rivaroxaban reduced the frequency of hemorrhagic strokes compared with warfarin by 41% (HR, 0.59)
ARISTOTLE • 18,201 patients with NVAF and at least 1 additional risk factor for stroke
(mean CHADS2 , 2.1) were evaluated in a randomized, double-blind study comparing apixaban (5 mg twice daily [2.5 mg twice daily in high-risk patients]) with warfarin; median follow up was 1.8 yrs
• The lower dose was used for those with 2 or more of the following factors associated with increased drug exposure: age greater than 80 years, body weight less than 60 kg, or serum creatinine level greater than 1.5 mg/dL. About 19% of these patients had a previous TIA, stroke, or systemic embolism
• Apixaban was superior to warfarin in preventing stroke or systemic embolism (HR with apixaban, 0.79; 95% confidence interval [CI], 0.66–0.95; P <.001 for noninferiority; P = .01 for superiority)
• Apixaban also caused less bleeding and resulted in lower mortality (HR, 0.89; 95% CI, 0.80–0.99; P = .047) and reduced hemorrhagic stroke by 49% compared with warfarin ( P = <.001)
“Aristotle Relies on Rockets”
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
Stroke Prev Nonvalv
AFib
Stroke Prev Nonvalv
AFib
DOSING
RENAL DOSING
PEAK LEVELS
ARTHROPLASTY
DVT PROPH
COAG TEST
EFFECT
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Vasa 2014, 43: 353-364
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Acute DVT/PE
• All 3 agents were NON-INFERIOR to Warfarin
• Lower rates major bleeding
• Rivaroxaban, Apixaban fewer bleeding events
• Dabigatran non-inferior bleeding event rate
VTE Recurrence
• Dabigatran NON-INFERIOR to Warfarin
• Lower bleeding risk
• All 3 superior to placebo prevention VTE recurrence
• Apixaban did not have significantly higher rates of
long-term major bleeding (Dab + Riv did)
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING
RENAL DOSING
PEAK LEVELS
ARTHROPLASTY
DVT PROPH
COAG TEST
EFFECT
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30 mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60
kg; sCr >1.5)
PEAK LEVELS
ARTHROPLASTY
DVT PROPH
COAG TEST
EFFECT
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NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev
Nonvalv AFib
-VTE Tx
-Recurrent VTE
Prev
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30
mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60
kg; sCr >1.5)
PEAK LEVELS 2 h 2 - 4 h 3 h
ARTHROPLASTY
DVT PROPH
COAG TEST
EFFECT
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30 mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60
kg; sCr >1.5)
PEAK LEVELS 2 h 2 - 4 h 3 h
ARTHROPLASTY
DVT PROPH
10 mg daily 2.5 mg bid
COAG TEST
EFFECT
Use of Assays • Dabigatran
• Thrombin Clotting Time (TCT) most sensitive assay to determine presence
• aPTT – if normal then Dabigatran not contributing significantly to bleeding
• Rivaroxaban
• PT – if normal suggests level is not high; does not exclude presence
• No effect on TCT
• Apixiban
• Normal PT or aPTT DOES NOT rule out significant anticoag effect
• NOTE: RECORDING LAST DOSE TIME IMPORTANT FOR INTERPRETATION
NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
Stroke Prev Nonvalv AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after Hip/Knee
Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30 mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60 kg;
sCr >1.5)
PEAK LEVELS 2 h 2 - 4 h 3 h
ARTHROPLASTY
DVT PROPH
10 mg daily 2.5 mg bid
COAG TEST
EFFECT
INCR: aPTT, TCT
INCR Anti-factor Xa
INCR or =: PT, aPTT
NO CHANGE: TCT
INCR Anti-factor Xa
INCR or =: PT, aPTT
NO CHANGE: TCT
SWITCHING AGENTS
SWITCHING TO(FROM) A NOAC
Transition FROM Warfarin
to NOAC
Transition TO Warfarin
from NOAC
- Monitor INR closely
- Start NOAC when INR <
2
- Parenteral Anticoag not
necessary
Dabigatran
- Start Warfarin 1-3 days prior to d/c
- Consider parenteral “bridging” if
high risk
Apixiban / Rivaroxaban
- DO NOT overlap agents
- STOP Agent – START Warfarin
when next dose due
- Consider parenteral “bridging” if
high risk
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SWITCHING TO(FROM) A NOAC Transition FROM
UFH/LMWH to NOAC
Transition TO UFH/LMWH
from NOAC
- Start NOAC 2 hrs after
UFH discontinued
- Start NOAC at next
sched LMWH dose
- Start UFH/LMWH when
next dose NOAC due
Risk of major bleeding in different indications for new
oral anticoagulants: Insights from a meta-analysis of
approved dosages from 50 randomized trials
International Journal of Cardiology, 2015-01-20, Volume 179, Pages 279-287
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COST
• ~ 7K pt on warfarin or NOAC studied over 33 month
period
• Out of pocket for patient - 5x higher
• Insurer costs - 15 x higher; ~ $900 / month
• Warfarin - most “$4 lists”; NOACs $250-350/mo
Advantages
• Convenience for patients
• No lab monitoring
• Lower rates of MAJOR bleeds
• No bridging therapy
• Potentially less HIT (decr use bridging therapy)
• Less drug / diet interactions
Disadvantages • No antidote / reversal agents
• Measuring Compliance / Drug concentration
• Dabigatran - aPTT normal; little to none present
• Rivaroxaban - PT normal; little to no presence
• Higher GI bleeding rate
• Higher cost
• Contraindicated mechanical heart valves / severe renal impairment
Other Issues
• Dabigatran - Dyspepsia (33%)
• P-gp transport system
• CYP3A4 enzyme system
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Drug interactions
Ideal Candidate
• < 65
• NL Renal Function
• Uncontrolled INR w/ compliance
• Non-compliance monitoring
NOT!!!!!!
• Mechanical Valves
• Dabigatran - incr risk bleeding and stroke vs.
Warfarin
• Renal dysfunction - check at baseline (especially
dabigatran)
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NOAC Comparison DRUG DABIGATRAN
(PRADAXA)
RIVAROXABAN
(XARELTO)
APIXIBAN
(ELIQUIS)
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
Stroke Prev Nonvalv AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after Hip/Knee
Surg*
Stroke Prev Nonvalv
AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after
Hip/Knee Surg*
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30 mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60 kg;
sCr >1.5)
PEAK LEVELS 2 h 2 - 4 h 3 h
ARTHROPLASTY
DVT PROPH
10 mg daily 2.5 mg bid
COAG TEST
EFFECT
INCR: aPTT, TCT
INCR Anti-factor Xa
INCR or =: PT, aPTT
NO CHANGE: TCT
INCR Anti-factor Xa
INCR or =: PT, aPTT
NO CHANGE: TCT
QUESTIONS?
REFERENCES 1. Ferns SJ, Naccarelli GV. New Oral Anticoagulants – Their role in stroke
prevention in high-risk patients with Atrial Fibrillation. Med Clin N Am 2015,
99: 759-780
2. Vandiver JW, et al. Is a novel anticoagulant right for your patient? J Fam
Prac, Jan 2014, 63(1): 22-28
3. Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous
thromboembolism – a systematic review with indirect comparisons. VASA
2014, 43: 353-364
4. Shivanshu M, et al. Use of novel oral anticoagulation agents in atrial
fibrillation: current evidence and future perspectives. Cardiovasc Diagn Ther
2014, 4(4): 314-323.
BACKGROUND
NOAC Comparison DRUG DABIGATRAN RIVAROXABAN APIXIBAN
MECH OF ACTION Direct Thrombin Inhibitor Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv AFib
-VTE Tx,
-VTE Prev
Stroke Prev Nonvalv AFib
-VTE Tx,
-Recurrent VTE Prev
-VTE Proph after Hip/Knee Surg
Stroke Prev Nonvalv AFib
- VTE Proph after Hip/Knee Surg
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
CrCl 15-30 mL/min
15 mg daily
CrCl 15-50 mL/min 2.5 mg bid
Age > 80; Wt < 60 Kg;
sCr > 1.5 BIOAVAILABILITY 3-7% 80-100% 50%
PEAK PLASMA LEVELS 2 h 2 - 4 h 3 h
HALF-LIFE
12-17 h 5-9 h 8-15 h RENAL ELIMINATION > 80% 66% 25-27%
MONITORING None None None
COAG TEST EFFECT
INCR: aPTT, TCT
INCR or =: PT
INCR Anti-factor
Xa
INCR or =: PT,
aPTT
NO CHANGE:
INCR Anti-factor Xa
INCR or =: PT,
aPTT
NO CHANGE: TCT
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RESULTS
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NOAC Comparison DRUG DABIGATRAN RIVAROXABAN APIXIBAN
MECH OF
ACTION
Direct Thrombin
Inhibitor
Direct Xa inhibitor Direct Xa inhibitor
INDICATIONS Stroke Prev Nonvalv
AFib
-VTE Tx
-VTE Prev
Stroke Prev Nonvalv AFib
-VTE Tx
-Recurrent VTE Prev
-VTE Proph after Hip/Knee
Surg
Stroke Prev Nonvalv
AFib
- VTE Proph after
Hip/Knee Surg
DOSING 150 mg bid 20 mg daily 5 mg bid
RENAL DOSING 75 mg bid
(CrCl 15-30 mL/min)
15 mg daily
(CrCl 15-50 mL/min)
2.5 mg bid
(Age >80; Wt < 60 kg;
sCr >1.5)
PEAK PLASMA
LEVELS
2 h 2 - 4 h 3 h
HALF-LIFE 12 – 17 h 5 – 9 h 8 - 15 h
COAG TEST
EFFECT
Acute Bleeding
• Mild to Mod
• Stop Medication & Supportive Measures
• Acute Ingestion or Overdose
• Activated Charcoal if ingestion within 3 hours
Severe Bleeding
• Hemodialysis for Dabigatran
• Most effective intervention
• 75-80 units/kg Activated Prothrombin Complex
Concentrate (aPCC)
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Perioperative Use
• Primarily based on expert opinion