clinically relevant anticoagulant drug interactionsapr 01, 2019 · anticoagulant use increases...
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Clinically Relevant Anticoagulant Drug Interactions
Sara R. Vazquez, PharmD, BCPS, CACPClinical Pharmacist
University of Utah Health Thrombosis Service
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Disclosures
• Contributor, editorial consult for UpToDate®
(Wolters Kluwer)
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Audience: In your opinion, which is the most clinically relevant drug interaction with oral anticoagulants?
1. CYP or p-gp inducers2. CYP or p-gp inhibitors3. Antiplatelet agents4. Non-steroidal anti-inflammatory
drugs (NSAIDs)
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Outline
All AnticoagulantsDOACsWarfarin
Practical DDI Management
Principles
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How to decide what DDIs are clinically relevant?• Look at human in vivo data
– Best is data in actual patients vs healthy volunteers• When available, focus on ADVERSE OUTCOMES resulting from DDIs• Therapeutic index of substrate drug (narrow vs wide)• Assess the relative contributions of drug absorption, metabolic and
elimination pathways and their clinical significance• Recognize DDIs may involve multiple pathways
and multiple individual patient characteristicsà consider the NET effect
• Drug Interaction Probability Scale (DIPS)• Naranjo Algorithm
Horn, JR, et al. Ann Pharmacother 2007;41:674-80.
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DDI Resources
• Utilize and interpret the literature and references within their limits
• Tertiary online drug interaction databases– Examples: Micromedex®, Lexi-Comp Online®
• Primary literature for case reports/case series• REPEAT searches frequently!
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Warfarin: CYP Inhibitors à FAB-Four• No, not the British band…
Nutescu E, et al. J Thromb Thrombolysis 2011;31:326-43.Thi L, et al. Consult Pharm 2009;24:227-230.
CYP2C9 CYP3A4 CYP1A2 CYP2C19
Fluconazole X X X
Amiodarone X X
Bactrim®(sulfamethoxazole + trimethoprim)
X
Flagyl®(metronidazole)
X
S-warfarin R-warfarin
PLUS displaces warfarin from protein binding sites
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Warfarin: CYP Inducers
Nutescu E, et al. J Thromb Thrombolysis 2011;31:326-43.
CYP2C9 CYP3A4 CYP1A2 CYP2C19Carbamazepine X XPhenobarbital X X XPrimidone X X XPhenytoin X XRifampin X X X X
S-warfarin R-warfarin
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Audience: When faced with a DOAC drug interaction I now feel more comfortable addressing it than I did in 2013.
1. Yes2. No
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What drugs might be concerning DOAC DDIs?P-gp Modifiers
Inhibitors InducersAmiodaroneAzithromycin
ClarithromycinDronedaroneErythromycinFostamatinibItraconazole
KetoconazoleLapatinibNeratinibRitonavir
VerapamilHCV antivirals
ApalutamideCarbamazepine
FosphenytoinPhenytoinRifampin
St John’s Wort
COMBINED p-gp ANDSTRONG CYP3A4 Modifiers
Inhibitors InducersClarithromycinItraconazole
KetoconazoleOmbitasvirParitaprevir
Ritonavir
ApalutamideCarbamazepine
FosphenytoinPhenytoinRifampin
Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. 2019; April 1, 2019.
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Narrow vs Wide Therapeutic Index
Rothman SA. Am J Med 2013;126. Samuelsen BT, et al. Chest 2017; 151:127-38.
Dabi64 443Peak
31 225Trough
Riva 6 87Trough
Apixa41 230Trough
Edoxa 10 40Trough
120 250Peak
189 419Peak
91 321Peak
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Practical Management of DOAC DDIs
• P-gp/CYP3A4 Inducers– Avoid for all DOACs
if possible– Consider patient’s
thrombotic risk
Perlman A, et al. J Thromb Thrombolysis, 2019 Jan 8, Epub ahead of print.
Engage the Patient! Shared Decision-Making!
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Practical Management of DOAC DDIs
• P-gp Inhibitors (dabi/edoxa)– Follow manufacturer
dose adjustments
• Combined p-gp/ STRONG CYP3A4 Inhibitors (riva/apixa)– Avoid with riva/apixa
if possible
Engage the Patient! Shared Decision-Making!
Consider patient’s bleeding risk factors
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Audience:The single most impactful drug interaction intervention clinicians can make is considering additive bleeding effect of antiplatelet or NSAID therapy with anticoagulants.
1. Agree2. Disagree
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OAC+APT: Bleeding Risk is Additive
Sorensen R, et al. Lancet 2009;374:1967-74. Crowther MA, Eikelboom JW. Kardiol Pol 2018;76:937-44.Lopes RD, et al. N Engl J Med 2019 Mar 17; Epub ahead of print.Cohen AT, et al. Thromb Haemost 2019;119:461-66.
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
APIX+APT APIX+NO APT WARF+APT WARF+NO APT
1.2%0.44%
4.1%
1.4%
Major Bleeding
0.0%2.0%4.0%6.0%8.0%
10.0%12.0%14.0%
APIX+APT APIX+NO APT WARF+APT WARF+NO APT
4.5% 3.7%
13.1%
7.1%
CRNMB
Riva 15 +
P2Y12inh
Warfarin +
DAPT
Riva 2.5 BID +
DAPT
PIONEER-AF PCI
Warfarin +
DAPTDabi
110 BID +
P2Y12inh
Warfarin +
DAPT
Dabi150 BID
+ P2Y12inh
RE-DUAL
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NSAID + Anticoagulant Use Increases Bleeding Risk
Davidson BL, et al. JAMA Intern Med 2014;174:947-53.
Hazard Ratios for Clinically Relevant and Major Bleeding in NSAID or Aspirin Users vs Nonusers, Adjusted for Sex, Age, and Creatinine Clearance
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Ensure APT is absolutely necessary!
Schaefer JK, et al. JAMA Intern Med 2019 Mar 4. Epub ahead of print.
• N=6539 patients• 2453 warfarin + ASA with no clear indication
vs 4086 warfarin monotherapy• Propensity score-matched
Cohort study
•↑ overall bleeding (26% vs 20.3%, p<0.001) •↑ major bleeding (5.7% vs 3.3%, p<0.001)•↑ ED visits for bleeding (13.3% vs 9.8%)•↑ hospitalizations for bleeding
(8.1% vs 5.2%, p=0.001)
↑ Bleeding at 1 year
with Warfarin + ASA
• No difference in thrombotic events• No difference in ED visits or
hospitalizations for thrombosis• No difference in mortality
No difference
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2019 ACC/AHA Guideline for Primary Prevention of Cardiovascular Disease
Arnett DK, et al. J Am Coll Cardiol 2019 March 17, Epub ahead of print.
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Pharmacodynamic Interactions: What to do?
ASK THE PATIENT routinely about APT and NSAID use and document accordingly.
Assess continued need for APT or NSAID.
• Communication among providers of different disciplines• Shared decision-making
For NSAID use:
• Are there acceptable alternatives?• If not, is the patient a candidate for a COX-2 selective agent or PPI?
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Take-Home Points
• Warfarin– Focus on inhibitors/inducers of CYP2C9 and CYP3A4– Use reactive INR monitoring and dose adjustment
• DOACs– Avoid inducers, pay less attention to the rest
• All Anticoagulants– Pay MORE attention to concomitant APT and NSAIDs
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Thank You!