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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!