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Expert Review of Clinical Pharmacology

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Drug interactions with new oral anticoagulants inelderly patients

Claudia Stöllberger

To cite this article: Claudia Stöllberger (2017) Drug interactions with new oral anticoagulantsin elderly patients, Expert Review of Clinical Pharmacology, 10:11, 1191-1202, DOI:10.1080/17512433.2017.1370369

To link to this article: https://doi.org/10.1080/17512433.2017.1370369

Accepted author version posted online: 21Aug 2017.Published online: 28 Aug 2017.

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Drug interactions with new oral anticoagulants in elderly patientsClaudia Stöllberger

2. Med. Abt., Krankenanstalt Rudolfstiftung, Wien, Austria

ABSTRACTIntroduction: This review attempts to summarise what is known about Drug-drug interactions (DDIs) ofthe new oral anticoagulants (NOACs) in elderly patients. The literature was searched for: ‘CYP3A4’,‘CYP2C9’, ‘P-glycoprotein’, ‘acetylsalicylic-acid’, ‘non-steroidal anti-inflammatory’, ‘clopidogrel’, ‘ticagre-lor’, ‘prasugrel’ and ‘dabigatran’, ‘rivaroxaban’, ‘edoxaban’, or ‘apixaban’. ‘Elderly’ was defined as≥75 years.Areas covered: Publications about DDIs of NOACs were found for 35% of 140 potentially interactingdrugs. Reports about DDIs of cardiovascular drugs, were most frequent, followed by anti-infective andnervous system drugs. Reports about elderly were found for only 47 patients. DDIs were reported mostfrequently in association with dabigatran. Dabigatran is the only NOAC interacting with proton-pump-inhibitors.Expert commentary: Dabigatran was the first NOAC approved, so it is not possible to determinewhether the higher number of reports about DDIs with dabigatran compared with other NOACs is dueto a higher rate of DDIs or to the length of time during which this drug has been in use. Most of thedata is derived from subgroup-analyses of trials, sponsored by NOAC manufacturers, consequentlythere is a lack of independent data. Because of the scarcity of data, the clinical relevance of DDIs ofNOACs is uncertain at present, especially in elderly patients.

ARTICLE HISTORYReceived 3 April 2017Accepted 18 August 2017

KEYWORDSAnticoagulation; atrialfibrillation; venousthromboembolism; Geriatry;rivaroxaban; apixaban;dabigatran; edoxaban

1. Introduction

The new oral anticoagulants (NOACs), also termed ‘non-vita-min-K-antagonist oral anticoagulants’ or ‘direct oral anticoa-gulants’ (DOACs) comprise the thrombin-inhibitor dabigatranand the factor Xa-inhibitors rivaroxaban, apixaban, and edox-aban. All these substances have been compared with thevitamin-K-antagonist (VKA) warfarin in large randomized trialsin patients with venous thromboembolism (VTE) and atrialfibrillation (AF) (Table 1) [1–11].

One of the frequently mentioned advantages of NOACsover VKAs is the lower rate of cerebral hemorrhages whichhave been observed in the trials listed in Table 1. Furthermore,NOACs are assumed to have fewer drug–drug interactions(DDIs) than VKAs. DDIs of VKAs have been known for decadesand there are many reports in the literature about deviationsof the coagulation tests, bleeding and thrombotic events inpatients under VKAs due to DDIs.

NOACs, however, also have the potential for DDIs. DDIs ofNOACs may occur due to different mechanisms: The firstmechanism is caused by drugs which affect the platelet activ-ity, such as acetylsalicylic acid, clopidogrel, ticagrelor, prasu-grel, nonsteroidal anti-inflammatory drugs (NSAIDs), selectiveserotonin-reuptake inhibitors (SSRIs), and serotonin-norepi-nephrine reuptake inhibitors (SNRIs). Concomitant intake ofthese platelet-aggregation inhibiting drugs with any anticoa-gulant drug, VKAs, heparins or NOACs, increases the rate ofbleeding complications. The second mechanism for DDIs ofNOACs is comedication with drugs which affect the activity of

the cytochrome P450 isoenzymes 3A4 (CYP3A4), 2J9 (CYP2J9)and the drug efflux pump P-glycoprotein (P-gp). Third, thereare indications that NOACs may influence the serum – ortissue-levels of several immunosuppressant, analgesic andantidepressive drugs. A further mechanism is the effect ofproton pump inhibitors (PPIs) which may lead to changes ofthe gastric PH and thus influence NOAC bioavailability.

The assumption that NOACs have fewer DDIs than VKAs isbased mainly on data on healthy young subjects, in whom theinteraction of a single drug with an NOAC has been investi-gated (Tables 2–5) [13,18,23,24,27–29,39,41,50,55,59]. Patientswith AF, however, are frequently on multiple medications. Inthe Rivaroxaban Once Daily Oral Direct Factor Xa InhibitionCompared With Vitamin K Antagonism for Prevention ofStroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)trial, two-thirds of the included patients were on ≥5 and 13%were on ≥10 medications [61]. In the Apixaban For ReductionOf Stroke And Other Thromboembolic Events In AtrialFibrillation (ARISTOTLE) trial, the rate of polymedication (≥5)was even 77% [62]. In both trials, polymedication was morefrequent in older than in younger patients. The prevalence ofAF is age dependent and increases, especially in the >75 yearsgroup [63].

Although patients >75 years comprised only up to 40% ofthe population of the NOAC-investigating trials (Table 1), a steepincrease in the prescription rate of NOACs to elderly patients isreported by several countries [64–67]. A time-series analysis ofprescription trends between 2010 and 2012 in Ontario, Canada,

CONTACT Claudia Stöllberger claudia.stoellberger@chello.at Steingasse 31/18, Wien A-1030, Austria.

EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2017VOL. 10, NO. 11, 1191–1202https://doi.org/10.1080/17512433.2017.1370369

© 2017 Informa UK Limited, trading as Taylor & Francis Group

for all orally administered anticoagulants (warfarin, dabigatranand rivaroxaban) found that prescription rates of dabigatranwere accelerated among patients 85 or older [64]. Using

Danish nationwide administrative registers, all oral anticoagula-tion-naïve AF patients initiating oral anticoagulation fromAugust 2011 through October 2013 were identified. Older agewas some of the factors associated with NOAC use vs. warfarin[65]. A further study from New Zealand investigated patients ondabigatran, who were admitted to Auckland City Hospitalbetween July and December 2011.The mean age of patientswas 76 ± 1.7 (range:19–93, median 84) years [66]. A study fromAustria analyzed the accounting data of insurance funds from2011 to 2014, covering >97% of the population. In 2011, the ageof patients receiving VKAs was higher than NOACs (72 vs.68 years), whereas in 2014, the age of the patients receivingVKAs was lower than NOACs (73 vs. 74 years). The proportion ofpatients ≥80 years receiving VKAs declined from 26 to 21% of alloral anticoagulants, while those receiving DOACs increased from1 to 12%. Among nonagenarians, the proportion of patientsreceiving VKAs remained 2%, whereas the proportion of patientsreceiving DOACs increased 40-fold [67]. Thus, DDIs with NOACsin elderly patients are a matter of concern and the aim of thepresent review is to summarize the current state of knowledgeabout DDIs of NOACs in elderly patients.

2. Methods

2.1. Literature search

A literature search was carried out using PubMed from 1970 toMarch 2017 with the search terms: ‘CYP 3A4’ ‘CYP3A4’‘CYP2C9’ CYP2C9,’ ‘P-glycoprotein,’ ‘P-gp,’ ‘acetylsalicylic acid,’‘nonsteroidal anti-inflammatory,’ ‘clopidogrel,’ ‘ticagrelor,’ ‘pra-sugrel,’ and ‘dabigatran,’ ‘rivaroxaban,’ ‘edoxaban,’ or ‘apixa-ban.’ Furthermore, PubMed was used to search forpublications relevant for the drugs listed in the (Tables 2–5),known to affect platelet function or CYP3A4-, CYP2C9- orP-Gp-activity, and ‘dabigatran,’ ‘rivaroxaban,’ ‘edoxaban,’ or‘apixaban’ [68,69]. Randomized clinical trials, subgroup ana-lyses from randomized trials, longitudinal studies, case series,and case reports have been included. Only data with regard tohumans were considered, but in vitro studies and animalexperiments were not considered. Care was taken to assess(1) the patients’ age, (2) if the NOACs dabigatran, apixaban,rivaroxaban, and edoxaban vary regarding their DDIs, (3) ifDDIs differ regarding patients’ age, and (4) if DDIs withNOACs are dose dependent. In order to give a better overviewof the various interacting drugs, the Anatomical Therapeutic

Table 1. NOAC investigating trials.

Author Drug Trial name Funding Indication Patients ≥75 years Mean age, years Follow-up, months

[1] Dabi RE-LY Man AF 18,113 40% 71 24[2] Dabi RE-COVER I Man VTE 2,564 NR 54 6[3] Dabi RE-COVER II Man VTE 2,589 NR 55 6[4] Dabi RE-MEDY Man VTE 4,219 NR 55 16[5] Apix ARISTOTLE Man AF 18,201 31% 70 22[6] Apix AMPLIFY Man VTE 5,395 NR 57 6[7] Riva ROCKET AF Man AF 14,264 38% 73 20[8] Riva EINSTEIN DVT Man VTE 3,449 NR 57 3–12[9] Riva EINSTEIN PE Man VTE 4,832 NR 58 9[10] Edox ENGAGE AF-TIMI Man AF 21,105 40% 72 34[11] Edox HOKUSAI VTE Man VTE 8,292 13% 56 9

NOAC: non-vitamin-K-antagonists oral anticoagulants; Dabi: Dabigatran; Riva: Rivaroxaban; Man: manufacturer-sponsored trial; Apix: Apixaban; Edox: Edoxaban;AF: atrial fibrillation; VTE: venous thromboembolism.

Table 2. Interactions between selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine-reuptake inhibitors (SNRIs), and NOACS.

Drug Rivaroxaban Apixaban Edoxaban Dabigatran Cases ≥75 a

SSRIFluvoxamine NR NR NR NR 0Fluoxetine NR NR NR NR 0Paroxetine CR [12] NR NR NR 1Citalopram NR NR NR NR 0Sertraline CR [12] NR NR NR 1Escitalopram NR NR NR NR 0SSNRIVenlafaxine NR NR NR NR 0Milnacipran NR NR NR NR 0Duloxetine NR NR NR NR 0

NR: not reported; CR: case report.

Table 3. Interactions between CYP2C9 inhibitors and inducers and NOACs.

Drug Rivaroxaban Apixaban EdoxabanCases≥75 a

CYP2C9 InhibitorsFluconazole HSM [13] NR NR 0Amiodarone CR [12,14,15] SGART [16] SGART [17], HSM

[18]2

Efavirenz NR NR NR 0Fenofibrate NR NR NR 0Fluvastatin CR [12] NR NR 1Fluvoxamine NR NR NR 0Isoniazid NR NR NR 0Lovastatin NR NR NR 0Metronidazole CR [12] NR NR 1Paroxetine CR [12] NR NR 1Phenylbutazone NR NR NR 0Probenicid NR NR NR 0Sertraline CR [12] NR NR 1Sulfamethoxazole NR NR NR 0Sulfaphenazole NR NR NR 0Teniposide NR NR NR 0Voriconazole NR NR NR 0Zafirlukast NR NR NR 0CYP2C9 inducersCarbamazepine CR [19,20] NR NR 0Enzalutamide NR NR NR 0Nevirapine CR [21] NR NR 0Phenobarbital NR NR NR 0Rifampicin CR [22] HSM [23] HSM [24] 0Secobarbital NR NR NR 0St. John’s Wort NR NR NR 0

NR: not reported; CR: case report; HSM: study in healthy subjects, carried out bythe manufacturer; SGART: subgroup analysis of a randomized trial.

1192 C. STÖLLBERGER

Chemical (ATC) classification system was used to report thefindings [70].

2.2. Definition of “elderly”

The global population is aging and, according to the WorldHealth Organization (WHO), in 2050, the population aged60 years or more will double, whilst those aged 80 years ormore will number 400 million people [71]. Unfortunately, there

is no uniformly accepted definition of ‘elderly’ persons [72].Since the prevalence of AF, the most frequent indication fororal anticoagulation, is steeply increasing in patients>75 years, for the current review we have defined ‘elderly’ asbeing ≥75 years [63].

3. Results

3.1. Subgroup analyses of randomized trials

Subgroup analyses of elderly patients, included in the largerandomized studies investigating NOACs in AF-patients, werecarried out for rivaroxaban, apixaban, edoxaban, and dabiga-tran [73–76]. In these subgroup analyses, a higher rate ofstrokes and bleeding events in elderly than in youngerpatients is reported, but no information is given about theinfluence of comedication on these events.

Post hoc analyses of two of these trials investigated theinfluence of concomitant medication on outcome events[61,62]. In these analyses, however, different dosages of rivar-oxaban (20 mg versus 15 mg once daily) and apixaban (5 mgversus 2.5 mg twice daily) were not considered. In ROCKET-AF,an increased number of concomitant drugs were associatedwith a higher risk of bleeding, but not stroke. There was noevidence of differential outcomes in those treated with ≥1combined CYP3A4 and P-gp inhibitors and those treatedwith none inhibitor. Use of ≥2 combined inhibitors was asso-ciated with higher bleeding rates in those treated with rivar-oxaban compared with warfarin, yet, the sample size waslimited [61].

In ARISTOTLE, greater numbers of concomitant drugs wereused in older patients. The number of comorbidities roseacross groups of increasing numbers of drugs (0–5, 6–8, ≥9drugs). Mortality also rose significantly with the number ofdrug treatments, as did rates of stroke or systemic embolismand major bleeding. Rates of major bleeding did not differsignificantly between patients with, or without, combinedCYP3A4 and P-glycoprotein inhibitors [62].

3.2. Influence of age on plasma-NOAC-levels

Whereas the effect of VKAs is easily assessed by measurement ofthe international normalized ratio (INR), the anticoagulant effectsof NOACs cannot be measured by routinely available laboratorytests. Measurement of plasma-NOAC levels requires a sophisti-cated technology which is not available in the routine clinicalsetting. The influence of age on plasma concentrations of theNOACs is confounded by the influence of age on renal function,since all of the NOACs are excreted to some extent by the kidneys.This is why, in most countries, reduced dosages of NOACs arerecommended for elderly patients with impaired renal function.

Plasma levels of NOACs have been studied in differentpopulations of different ages, and only few studies were car-ried out independently of the drug manufacturer [42,77]. Inhealthy people, the absorption of dabigatran was subject tohigh variability [42,77]. In elderly patients with AF, plasmadabigatran levels were found to be dependent on renal func-tion [78]. Similarly, dependence of plasma rivaroxaban andedoxaban levels on age and renal function, were indicated

Table 4. Interactions between CYP 3A4 inducers and inhibitors and NOACs.

Drug Rivaroxaban Apixaban EdoxabanCases≥75 a

CYP 3A4 inhibitorsAmiodarone CR [12,14,15] SGART

[16]HSM [18],SGART [17]

2

Aprepitant NR NR NR 0Boceprevir NR NR NR 0Chloramphenicol NR NR NR 0Cimetidine NR NR NR 0Ciprofloxacin NR NR NR 0Clarithromycin CR [12,25], HIS

[26], HSM[13]

NR NR 0

Cobicistat NR NR NR 0Delavirdine NR NR NR 0Diethyl-dithiocarbamate NR NR NR 0Diltiazem NR HSM [27] NR 0Erythromycin HSM [13,28] NR HSM [29] 0Fluconazole HSM [13] NR NR 0Fluvoxamine NR NR NR 0Gestodene NR NR NR 0Grapefruit juice NR NR NR 0Imatinib NR NR NR 0Indinavir NR NR NR 0Itraconazole NR NR NR 0Ketoconazole HSM [13] HSM [27] HSM [29] 0Mibefradil NR NR NR 0Mifepristone NR NR NR 0Nefazodone NR NR NR 0Nelfinavir NR NR NR 0Norfloxacin NR NR NR 0Norfluoxetine NR NR NR 0Ritonavir CR [30,31], HSM

[13]NR NR 0

Saquinavir NR NR NR 0Saw palmetto CR [32] NR NR 1Star fruit NR NR NR 0Buprenorphine NR NR NR 0Telaprevir NR NR NR 0Telithromycin NR NR NR 0Verapamil NR NR HSM [18] 0Voriconazole NR NR NR 0CYP 3A4 inducersBarbiturates NR NR NR 0Carbamazepine CR [19,20] NR NR 0Efavirenz NR NR NR 0Enzalutamide NR NR NR 0Glucocorticoids NR NR NR 0Modafinil NR NR NR 0Nevirapine CR [21] NR NR 0Oxcarbazepine CR [33] NR NR 0Phenobarbital NR NR NR 0Phenytoin NR NR NR 0Pioglitazone NR NR NR 0Rifampicin CR [22] HSM [23] HSM [24] 0St. John’s Wort NR NR NR 0Troglitazone NR NR NR 0

NR: not reported; CR: case report; HSM: study in healthy subjects, carried out bythe manufacturer; SGART: subgroup analysis of a randomized trial; HSI: studyin healthy subjects, carried out independent from the manufacturer.

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 1193

by subgroup analyses of the ROCKET-AF and ENGAGE AF-TIMI48-trials [51,79]. The influence of age on plasma apixabanlevels has only been studied in healthy subjects [80].

In essence, factors which contribute to the age dependencyof plasma-NOAC levels comprise renal impairment,

comorbidities, comedication, and age-related changes inintestinal transport, absorption and metabolism of NOACs.

The clinical relevance of increasing age on occurrence ofbleeding events during NOAC-therapy is substantiated by astudy which analyzed hemorrhagic events in the

Table 5. Interactions between P-Glycoprotein inhibitors and inducers and NOACs.

Drug Rivaroxaban Apixaban Edoxaban Dabigatran Cases ≥75 a

P-Glycoprotein inhibitorsAliskiren CR [34] NR NR CR [12] 2Amiodarone CR [12,14,15] SGART [16] SGART [17], HSM [18] CR [12,35,36], SGART [37] 7Amprenavir NR NR NR NR 0Astemizole NR NR NR NR 0Atorvastatin CR [12,38], HSM [39] NR HSM [18] CR [12,40], HSM [41] 5Bepridil NR NR NR NR 0Carvedilol CR [12] NR NR CR [12] 3Cefoperazone NR NR NR NR 0Chlorpromazine NR NR NR NR 0Clarithromycin CR [12,25], HIS [26], HSM [13] NR NR HIS [26,42] 0Cobicistat NR NR NR HIS [43] 0Cyclosporine A CS [44,45] CS [45] HSM [29] NR 0Daclatasvir NR NR NR NR 0Diltiazem NR HSM [27] NR CR [12] 1Dipyridamole NR NR NR NR 0Disulfiram NR NR NR NR 0Doxepin NR NR NR NR 0Dronedarone CR [38] NR HSM [18] CR [12,46],

CS [47]1

Erythromycin HSM [13,28] NR HSM [29] CR [48] 1Fluphenazine NR NR NR NR 0Haloperidol NR NR NR NR 0Hydrocortisone NR NR NR NR 0Indinavir NR NR NR NR 0Itraconazole NR NR NR NR 0Ketoconazole HSM [13] HSM[F14] HSM [29] NR 0Loperamide NR NR NR CR [12] 1Lovastatin NR NR NR CCS [49] 0Mirabegron NR NR NR NR 0Nelfinavir NR NR NR NR 0Nicardipine NR NR NR NR 0Nifedipine NR NR NR NR 0Ofloxacin NR NR NR NR 0Ponatinib NR NR NR NR 0Progesterone NR NR NR NR 0Propafenone NR NR NR NR 0Propranolol NR NR NR CR [12] 1Quinidine NR NR HSM [18,50], SGART [51] NR 0Ritonavir CR [30,31], HSM [13] NR NR NR 0Rosuvastatin NR NR NR NR 0Roxithromycin NR NR NR NR 0Saquinavir NR NR NR NR 0Simvastatin CR [12,52] NR NR CR [12], CCS [49] 8Tacrolimus CS [44,45] CS [45] NR CR [53] 0Talinolol NR NR NR NR 0Tamoxifen NR NR NR NR 0Telithromycin NR NR NR NR 0Verapamil NR NR HSM [18] CS [54], CR [12], SGART [37], HSM [55] 0P-Glycoprotein inducersBisoprolol CR [12,15] NR NR CR [12,40] 6Carbamazepine CR [19,20] NR NR NR 0Clotrimazole NR NR NR NR 0Dexamethasone NR NR NR NR 0Hypericumperforatum NR NR NR NR 0Phenobarbital NR NR NR CS [56] 0Phenytoin NR NR NR CS [56], CR [57,58] 0Reserpine NR NR NR NR 0Rifampicin NR [22] HSM [23] HSM [24] HSM [59] 0Tocilizumab NR NR NR CR [60] 0

NR: not reported; CR: case report; CS: case series; CCS: Case control study; HSM: study in healthy subjects, carried out by the manufacturer; SGART: subgroup analysisof a randomized trial; HSI: study in healthy subjects, carried out independent from the manufacturer.

1194 C. STÖLLBERGER

gastrointestinal and nervous system, recorded in the US FDAAdverse Event Reporting System database between 2004 and2014,using an adjusted reporting odds ratio (ROR) [81]. Theanalysis showed that the rate of dabigatran-associated gastro-intestinal hemorrhages was significantly increased in patientsover 80 years of age. The RORs of dabigatran increased withage, although aging had little effect on VKA-associated gastro-intestinal hemorrhage. The ROR for anticoagulant-associatednervous system hemorrhage was not affected by aging, ascompared to gastrointestinal hemorrhage. These data indicatethat the excretion of dabigatran may be affected by aging, ascompared to VKA, probably due to renal function decline [81].Unfortunately, the comedication was not investigated in thatanalysis.

3.3. Comedication and adverse events of NOACs

DDIs of VKAs can be easily revealed by unexpected INR devia-tions, while DDIs of NOACs are more difficult to detect. Theywould require measurements of NOAC plasma concentrations,which are not available in routine care of patients. Thus, DDIswill be detected only if a complication – either bleeding orthromboembolism – occurs.

An analysis of 16,160 spontaneous reports from Australia,Canada, and the USA found that gastrointestinal disorderswere the most common adverse events associated with dabi-gatran, ranging from 29% for Australia to 41% for the USA. Inthat analysis, use of concomitant medicines with the potentialto increase bleeding risk ranged from 34% for Australia to 51%for the USA [82]. Among the concomitant medications withthe potential to increase bleeding risk, the most frequentlyused were acetylsalicylic acid, NSAIDs, SSRIs, amiodarone, anddronedarone. The mean age of the 16,160 patients was76 years, there were, however, no details about age-associatedseverity of the adverse event and no information was providedabout the dabigatran dose [82].

3.4. DDIs of NOACs with drugs affecting plateletfunction

Concomitant use of drugs affecting hemostasis might increasethe bleeding risk. Drugs which inhibit platelet function com-prise acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel,NSAIDs, SSRIs, and SNRIs [83–88].

In RE-LY, 38% of patients at some point received, in addi-tion to warfarin or dabigatran, acetylsalicylic acid or clopido-grel. Concomitant use of a single antiplatelet increased the riskof major bleeding, and dual antiplatelet increased this evenmore [89]. In RE-LY, the rate of gastrointestinal bleeding washigher with the twice daily regimen of 150 mg dabigatranthan with warfarin [90]. This is why, in many countries, adabigatran dose of 110 mg twice daily is recommended forpatients over the age of 80 years, or for those 75 years or olderwith risk of bleeding. Regardless of age, in RE-LY the risk ofintracranial bleeding was lower with dabigatran than withwarfarin [90]. Therefore, despite the association between ageand decreased renal function, there are indications that thebrain is better protected from bleeding when dabigatran is

applied, and not warfarin. This tendency is also observed withother NOACs.

In the ENGAGE AF-TIMI 48 trial, patients selected by theirphysicians to receive single antiplatelet therapy (32%) in addi-tion to warfarin or edoxaban (high-dose as well as lower dose)were at a similar risk of stroke or embolism and higher rates ofbleeding than those not receiving single antiplatelet therapy[91]. The influence of age on the occurrence of bleeding underconcomitant antiplatelet therapy was not analyzed in the RE-LY or the ENGAGE AF-TIMI 48 trial. A case report describedspinal subarachnoid hemorrhage in cortical superficial side-rosis after apixaban 2.5 mg bid and clopidogrel therapy in a78-year-old patient [92].

In the EINSTEIN deep vein thrombosis and pulmonaryembolism clinical trials, which compared rivaroxaban withenoxaparin-VKA treatment, concomitant use of an NSAID oracetylsalicylic acid was associated with an increased risk ofclinically relevant and major bleeding [93].

A population-based study in Finland found that the use ofNSAIDs increased in the total population of rivaroxaban anddabigatran initiators [94]. The authors speculate that, whileinteractions between VKAs and NSAIDs are acknowledged,interactions between NOACs and NSAIDs have not beenmuch discussed in the literature and may not be recognizedbecause of the lack of strong evidence [94].

SSRIs and SNRIs block the reuptake of serotonin in plateletsas well as in neural tissue [88]. SSRIs and SNRIs induce aqualitative platelet defect by a mechanism, which is differentfrom that of acetylsalicylic acid or clopidogrel. Our literatureresearch yielded only 2 reports about DDIs with rivaroxaban(dose unknown) and SSRIs, as listed in Table 2. DDIs of NOACSwith drugs affecting absorption, metabolism, and excretion ofanticoagulant drugs.

Metabolism and excretion of rivaroxaban, apixaban, andedoxaban are modulated by CYP3A4 and CYP2J9. Thus, con-comitant intake of CYP3A4- or CYP2C9 inhibitors can predis-pose patients to bleeding, and intake of CYP3A4- or CYP2C9inducers to thromboembolism (Tables 3 and 4). There areindications that the intensity of this modulation may differbetween NOACs. It has been shown that CYP3A4 plays onlya small role in the metabolism of edoxaban [95].

All four NOACs are substrates for P-gp, a drug efflux pumpinvolved in the metabolism of a number of xenobiotics. Theactivity of P-gp is modulated by several drugs (Table 5) [68].Concomitant intake of NAOCs and P-gp-modulating drugs canincrease the risk of adverse effects, bleeding, orthromboembolism.

The following paragraph will present an overview of thestate of knowledge on DDIs of drugs which affect the activityof CYP3A4, CYP2C9, and P-gp with NOACs (Tables 2–5). TheATC system is used for classification of the drugs.

3.4.1. Cardiovascular system (in alphabetical order)Aliskirenis is a renin-inhibitor and a P-gp-inhibitor. Bleeding eventsin patients treated with aliskiren and either rivaroxaban (20mg) ordabigatran (300 mg) were described in two case reports [12,34].Both patients were on polypharmacy and ≥75 years.

Amiodarone is an antiarrhythmic drug, an inhibitor ofCYP2C9 as well as CYP3A4 and P-gp. A retrospective analysis

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 1195

of patients admitted to an emergency unit disclosed that 44%of those who suffered from bleeding events under dabigatranor rivaroxaban had a comedication of amiodarone. The meanage of the patients was 76 years. The NOAC dose is notreported [96]. Bleeding events in patients treated with amio-darone and either rivaroxaban (20 mg, n = 3; 15 mg, ordabigatran (300 mg n = 3; 220 mg n = 1; 150 mg n = 1)have been described in several case reports, seven of thesepatients were ≥75 years [12,14,15,36].

The effects of a comedication with amiodarone have beenreported in subgroup analyses of the dabigatran-, apixaban-,and edoxaban-investigating randomized trials. In a subgroupanalysis of the RE-LY trial, concomitant medication with amio-darone significantly affected the bioavailability of dabigatran,which, according to the authors, ‘showed only small to mod-erate effects (<26% change in exposure at steady state)’ [37].In ARISTOTLE, 11% of the patients received amiodarone atrandomization. A subgroup analysis found that the interactionvalues for amiodarone use by apixaban treatment effects werenot significant [16]. Similar findings resulted from a subgroupanalysis of the edoxaban-investigating trials [17]. DDIs ofamiodarone with edoxaban were studied in healthy subjects:Edoxaban exposure increased by 40% after concomitantadministration of edoxaban with amiodarone, which wasassessed as a modest effect [18].

A further side effect of amiodarone, hyperthyroidism, mightalso influence the anticoagulant effects of NOACs. Dabigatranmalabsorption was reported to be caused by acceleration ofintestinal transit due to amiodarone-induced thyrotoxico-sis [35].

Atorvastatin is a lipid-modifying agent and a P-gp inhi-bitor. Bleeding events in patients treated with atorvastatinand either rivaroxaban (20 mg, n = 1) or dabigatran(300 mg, n = 2; 150 mg, n = 2) have been described inseveral case reports, five of the patients were ≥75 years[12,38,40].

DDIs of atorvastatin with rivaroxaban, edoxaban, and dabi-gatran have been studied in healthy subjects: Atorvastatin didnot affect the pharmacokinetic profile or the pharmacody-namics of rivaroxaban [39]. Coadministration of atorvastatinhad relatively minor effects on the pharmacokinetics of edox-aban [18]. Atorvastatin had no influence on the pharmacoki-netic/pharmacodynamic profile of dabigatran [41].

Bisoprolol is a beta-blocking agent and a P-gp inducer.Bleeding events in patients with polymedication, comprisingbisoprolol and either rivaroxaban (20 mg, n = 1; 15 mg, n = 2)or dabigatran (300 mg, n = 1; 220 mg, n = 3)), have beendescribed in several case reports, six of the patients were≥75 years [12,15,40].

Carvedilol is a beta-blocking agent and a P-gp inhibitor.Bleeding events in patients taking carvedilol and either rivar-oxaban or dabigatran (300 mg, n = 3) have been described inseveral case reports, three of the patients were ≥75 years [12].

Diltiazem is a calcium channel blocker and a CYP3A4- andP-gp inhibitor. Gastrointestinal hemorrhage and fatal multi-organ failure have been reported in a 84-year-old femaletreated with diltiazem and dabigatran 300 mg [12]. DDIs ofdiltiazem with apixaban have been studied in healthy subjects

and a 1.4-fold increase in apixaban exposure was observedwith coadministration of diltiazem [27].

Dronedarone is an antiarrhythmic drug and a P-gp inhibi-tor. Bleeding events in patients taking dronedarone and riv-aroxaban (20 mg, n = 1) or dabigatran (300 mg, n = 1) havebeen reported, one of the patients was ≥75 years [12,38]. Anincreased serum dabigatran level was measured in a patientwith concomitant application of dronedarone and dabigatran300 mg [46]. Concomitant use of dronedarone with dabiga-tran in patients with AF was investigated prospectively in asmall cohort of 33 patients with a mean age of 64 years,concomitantly treated with dabigatran. Trough plasma con-centrations of dabigatran were similar to trough plasma con-centrations of dabigatran without concomitant dronedaronein earlier studies. Median treatment length was 13 months.There was one major bleeding event (3% per patient-year),and no thrombotic events during a total of 35.5 patient-years[47]. The findings of that study have to be interpreted withcaution: The patients were relatively young and it is unknownif these findings can also be applied to patients ≥75 years,the patients had less comedications than those included inRE-LY and, last but not least, three of the five authorsdeclared an interest with the manufacturer of dabigatran[47]. DDIs of dronedarone with edoxaban have been studiedin healthy subjects, and coadministration of dronedaroneincreased edoxaban exposure [18].

Fluvastatin is a lipid-modifying agent and a CYP2C9 inhibi-tor. Bleeding events in patients with a medication of fluvasta-tin and rivaroxaban have been reported in several cases, oneof the patients was ≥75 years [12].

Lovastatin is a lipid-modifying agent and a CYP2C9- andP-gp inhibitor. In a population-based, nested case–controlstudy involving 45,991 Ontario residents ≥66 years whostarted dabigatran between 2012 and 2014, use of lovastatinwas associated with a higher risk of major hemorrhage [49]. Itremains unclear in that study if patients ≥75 years had ahigher bleeding risk than younger patients, and if the bleed-ing risk was influenced by the dabigatran dose.

Propranolol is a beta-blocking agent and a P-gp inhibitor. Ableeding event has been reported in an 80-year-old patienttreated with propranolol and dabigatran (220 mg, n = 1) [12].

Quinidine is an antiarrhythmic drug and a P-gp inhibitor.The effects of a comedication with quinidine have beenreported in subgroup analyses of edoxaban-investigating trialsand were shown to increase the bioavailability of edoxaban[51]. DDIs of quinidine with edoxaban have been studied inhealthy subjects: Concomitant medication with quinidineincreased total edoxaban exposure by 35% and total edoxa-ban clearance decreased by 25% [18,50].

Simvastatin is a lipid-modifying agent and a P-gp inhibitor.In a population-based, nested case–control study involving45,991 Ontario residents ≥66 years who started dabigatranbetween 2012 and 2014, use of simvastatin was associatedwith a higher risk of major hemorrhage [49]. Bleeding eventsin patients taking simvastatin and rivaroxaban (20 mg, n = 1;15 mg, n = 1) as well as dabigatran (300 mg, n = 5; 220 mg,n = 1) have been reported, eight of the patients were≥75 years [12,52].

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Verapamil is a calcium channel blocker and a CYP3A4- andP-gp inhibitor. In a study in 137 AF-patients on dabigatran,multivariate analysis revealed that verapamil use was indepen-dently associated with elevated dabigatran concentrations[54]. A bleeding event is reported in a 72-year-old patientwith a polymedication comprising verapamil and dabigatran300 mg [12]. In a subgroup analysis of the RE-LY trial, con-comitant medication with verapamil significantly affected thebioavailability of dabigatran, which, according to the authors,‘showed only small to moderate effects (<26% change inexposure at steady state)’ [37] DDIs of verapamil with edox-aban and dabigatran have been studied in healthy subjects:Coadministration of verapamil increased edoxaban and dabi-gatran exposure [18,55].

No information about DDIs with NOACS was found for thefollowing cardiovascular system drugs which are known toaffect activity of CYP3A4-, CYP2C9, or P-gp: Bepridil, fenofi-brate, mibefradil, nicardipine, nifedipine, propafenone, reser-pine, rosuvastatin, and talinol.

3.4.2. Alimentary tract and metabolismLoperamide is an antipropulsive drug and a P-gp inhibitor. Acutehepatic failure was reported in an 87-year-old female on poly-medication comprising dabigatran 220 mg and loperamide [12].

No information about DDIs with NOACs was found for thefollowing alimentary tract and metabolism drugs, which areknown to affect activity of CYP3A4-, CYP2C9, or P-gp:Aprepitant, cimetidine, dexamethasone, pioglitazone, andtroglitazone.

3.4.3. Blood and blood-forming organsNo information about DDIs with NOACs was found fordipyridamole.

3.4.4. Genitourinary system and sex hormonesNo information about DDIs with NOACs was found for thefollowing genitourinary system drugs and sex hormonesknown to affect activity of CYP3A4-, CYP2C9, or P-gp:Gestodene, mifepristone, mirabegron, and progesterone.

3.4.5. Systemic hormonal preparationsNo information about DDIs with NOACs was found for gluco-corticoids and hydrocortisone.

3.4.6. Anti-infective drugsClarithromycin is a macrolide and a CYP3A4- und P-gp inhibi-tor. Bleeding events have been reported in patients treatedwith clarithromycin and rivaroxaban (20 mg, n = 1) [12,25].DDIs of NOACs with concomitant clarithromycin have beenstudied in healthy subjects: Concomitant clarithromycinincreased plasma levels of rivaroxaban as well as dabigatran.This was found both, in studies by the manufacturer and byindependent investigators [13,26,42].

Erythromycin is a macrolide and a CYP3A4- and P-gp inhi-bitor. A fatal gastrointestinal hemorrhage is reported in a 92-year-old patient treated with dabigatran 300 mg and erythro-mycin [48]. DDIs of NOACs with concomitant erythromycinhave been studied in healthy subjects: Concomitant erythro-mycin increased plasma levels of rivaroxaban as well as

edoxaban [13,29]. In patients with mild-to-moderate renalimpairment, concomitant erythromycin resulted in increasesin rivaroxaban exposure that were assessed as ‘slightly morethan additive’ [28].

Fluconazole is an antimycotic and a CYP3A4- and CYP2C9inhibitor. DDIs of NOACs with concomitant fluconazole havebeen studied in healthy subjects: Concomitant fluconazoleincreased plasma levels of rivaroxaban [13].

Ketoconazole is an antimycotic and a CYP3A4 and P-gpinhibitor. DDIs of NOACs with concomitant ketoconazolehave been studied in healthy subjects: Concomitant ketoco-nazole increased plasma levels of rivaroxaban, apixaban, andedoxaban [13,27,29].

Metronidazole is an antibacterial and a CYP2C9 inhibitor.Fatal acute hepatic failure is reported in a 90-year-old patienttaking rivaroxaban and metronidazole [12].

Nevirapine is an antiviral and a CYP2C9- and CYP3A4 indu-cer. Venous thrombosis after total knee replacement despiterivaroxaban 10 mg is reported in a patient on permanentnevirapine medication [21].

Rifampicin is an antimycobacterial and a P-gp inducer. A caseof fatal pulmonary embolism is reported in a patient treatedwith AF under rivaroxaban 20 mg and rifampicin. The plasmarivaroxaban level was below the 5th percentile of what could bepredicted, based on pharmacokinetic studies [22]. DDIs ofNOACs with concomitant rifampicin have been studied inhealthy subjects: Concomitant rifampicin reduced plasma levelsof apixaban, edoxaban, and dabigatran [23,24,59].

Ritonavir is an antiviral and a CYP3A4- and P-gp inhibitor.Bleeding events under rivaroxaban (10 mg, n = 2) for VTEprophylaxis after orthopedic surgery have been reported inpatients with concomitant ritonavir-medication [30,31]. DDIsof NOACs with concomitant ritonavir have been studied inhealthy subjects: Concomitant ritonavir increased plasmalevels of rivaroxaban [13].

No information about DDIs with NOACs were found for thefollowing anti-infective drugs which are known to affect activ-ity of CYP3A4-, CYP2C9, or P-gp: Amprenavir, boceprevir, cefo-perazone, chloramphenicol, ciprofloxacin, clotrimazole,daclatasvir, delavirdine, efavirenz, indinavir, isoniazid, itracona-zole, nelfinavir, norfloxacin, ofloxacin, roxithromycin, saquina-vir, sulfamethoxazole, sulfaphenazole, telaprevir, telithromycin,and voriconazole.

3.4.7. Antineoplastic and immunomodulating drugsCiclosporin is an immunosuppressant and a P-gp inhibitor.Increased plasma levels of rivaroxaban were found in patientstreated with ciclosporin after liver transplantation [44]. Inhealthy subjects, coadministration of ciclosporin increasedthe exposure to edoxaban [29].

Tacrolimus is an immunosuppressant and a P-gp inhibitor.No increase in plasma levels of rivaroxaban were found inpatients treated with tacrolimus after liver transplantation[44]. A bleeding event is reported in a patient on polyphar-macy comprising tacrolimus and dabigatran [53].

Tocilizumab is an immunosuppressant and a P-gp inducer.A fatal mesenteric artery thrombosis is reported in a patienton polypharmacy comprising dabigatran and tocilizumab [60].

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 1197

No information about DDIs with NOACs were found for thefollowing antineoplastic and immunomodulating drugs whichare known to affect activity of CYP3A4-, CYP2C9, or P-gp:Enzalutamide, imatinib, ponatinib, tamoxifen, and teniposide.

3.4.8. Musculoskeletal systemNo information about DDIs with NOACs was found for phe-nylbutazone and probenecid.

3.4.9. Nervous systemCarbamazepine is an antiepileptic drug and a CYP3A4-,CYP2C9-, and P-gp inducer. VTE under rivaroxaban (20 mg,n = 1; 10 mg, n = 1) is reported in two patients on concomi-tant carbamazepine medication [19,20].

Oxcarbazepine is an antiepileptic drug and a CYP3A4 indu-cer. A left atrial appendage thrombus was reported in apatient with AF, rivaroxaban 20 mg and concomitant medica-tion of oxcarbazepine [33].

Paroxetine is an antidepressant, a SSRI, and a CYP2C9 inhibi-tor. Hepatic failure has been reported in an 81-year-old patienton polymedication including rivaroxaban and paroxetine [12].

Phenobarbital is an antiepileptic drug and a P-gp inducer.In a series of 52 AF patients, aged 38–94 years, treated withdabigatran, a reduced dabigatran exposure was found in apatient after coadministration of dabigatran 220 mg withphenobarbital [56].

Phenytoin is an antiepileptic drug and a CYP3A4- and P-gpinducer. In a series of 52 AF patients, aged 38–94 years, medi-cated with dabigatran, a reduced dabigatran exposure wasfound in a patient following coadministration of dabigatran220 mg with phenytoin [56]. Development of a left atrialthrombus has been reported after coadministration of dabiga-tran and phenytoin [57]. In another case, a reduced antic-oagulant effect of dabigatran was detected in a patientreceiving concomitant phenytoin [58].

Sertraline is an antidepressant, a SSRI, and a CYP2C9 inhi-bitor. A bleeding event was reported in an 88-year-old patienton polypharmacy, including rivaroxaban and sertraline [12].

No information about DDIs with NOACs was found for thefollowing nervous system drugs known to affect activity ofCYP3A4-, CYP2C9, or P-gp: Buprenorphine, chlorpromazine,citalopram, disulfiram, doxepin, duloxetine, escitalopram,fluoxetin, fluphenazine, fluvoxamine, haloperidol, milnacipran,modafinil, nefazodone, norfluoxetine, phenobarbital, secobar-bital, and venlafaxine.

3.4.10. Respiratory systemNo information about DDIs with NOACs was found for astemi-zole and zafirlukast.

3.4.11. VariousCobicistat is a CYP3A4- and P-gp inhibitor and is used as anenhancer of other antiretroviral agents in the treatment of HIVinfection. In healthy HIV-negative subjects, simultaneousadministration of cobicistat resulted in significant increasesin dabigatran exposure [43].

3.4.12. Fruits and herbal productsGrapefruit juice, saw palmetto, star fruit, and St. John’s wortare known to affect CYP3A4 activity. Saw palmetto, used inalternative medicine to treat benign prostatic hyperplasia, is aCYP3A4 inhibitor. Hemopericardium has been reported in apatient on rivaroxaban with concomitant intake of saw pal-metto [32]. No DDIs with hypericum perforatum, a P-gp indu-cer, nor with St. John’s wort, a CYP2C9 inducer, are reported.

3.5. DDIs of NOACs changing the metabolism ofconcomitant drugs

Little is known how NOACs affect the metabolism of conco-mitant drugs. The effects of rivaroxaban and apixaban on thedisposition of ciclosporin and tacrolimus were assessed retro-spectively in transplant recipients and showed considerablevariability between individual patients, but no clear pattern.Both, increased ciclosporin/tacrolimus plasma levels (whichwould occur if NOACs inhibited CYP3A and/or P/-gp) anddecreased ciclosporin/tacrolimus plasma levels (which wouldoccur if NOACs induced CYP3A and/or P/gp), were found [45].

A potential interaction between methadone and apixabanhas been postulated, based on the observation of cases inwhich the methadone-dose had to be increased to achievecontrol of pain after initiation of apixaban [97].

Aggravation of depressive symptoms after initiation ofdabigatran is reported. As the presumed pathomechanism, ithas been hypothesized that dabigatran may decrease brainconcentrations of antidepressant drugs [98].

3.6. DDIs of NOACs with proton pump inhibitors (PPIs)

No DDIs with PPIs are reported for rivaroxaban, edoxaban,and apixaban [99]. There are indications, however, that theconcomitant medication with PPIs might influence serumdabigatran levels. An acidic environment is required for thedissolution of dabigatran, so the increase in gastric pHinduced by PPIs might affect the solubility and absorptionof dabigatran. The available data about DDIs of dabigatranwith PPIs are confusing; it is uncertain, therefore, whetherdifferent PPIs have similar effects: An in vitro and in vivostudy evaluated DDIs between dabigatran and the PPIs inhealthy volunteers [77]. Concomitant administration of PPIsdid not change dabigatran pharmacokinetics. Dabigatranlevels, however, varied considerably thus precluding eva-luation of an effect of PPIs on its pharmacokinetics [77]. Adecrease in dabigatran bioavailability has been reported inpatients with concomitant PPIs in the RE-LY trial [37]. Incontrast, a prospective pilot study in patients with AFfound higher serum dabigatran levels in those who weretreated with PPIs than in those who were not [100].

3.7. Combined comedication with CYP3A4/CYP2C9- andP-gp inhibitors and inducers

Polymedication may comprise drugs which differently affectthe metabolism of NOACs. This is illustrated by the followingcase: Gastrointestinal bleeding under dabigatran occurred in

1198 C. STÖLLBERGER

an 83-year-old female on comedication with digitoxin,levothyroxine, nebivolol, simvastatin, furosemide, pantopra-zole, risperidone, meloxicam, rivastigmin, sertraline, indapa-mide, and ramipril. Among these drugs are inhibitors as wellas inducers of P-gp and CYP3A4 and, additionally, plateletinhibitors. Thus, it is impossible to assess the impact of a singledrug on the bleeding event [101].

An analysis of the reports about drug-induced liver injuryassociated with dabigatran and rivaroxaban of the FDA AdverseEvent Reporting System found a similar accumulation of poly-medication. In that analysis, 56% of patients were ≥75 years [12].

4. Limitations

We have tried our best to compile a list of all of the drugsaffecting CYP3A4-, CYP2C9-, and P-gp activity. We might havemissed some drugs. The same proviso applies to our researchfor drugs affecting platelet activity.

We restricted our literature research to publicationsincluded in PubMed. Thus, publications in journals notincluded in PubMed have not been covered.

The scientific quality of the presented data is impaired bytwo factors: First, most of the data are case reports with theirinherent methodological limitations. Second, they derive fromsubgroup analyses of randomized trials and registries, spon-sored and carried out by NOAC manufacturers, written byauthors who indicated conflicts of interest with NOAC manu-facturers [102].

5. Expert commentary

Our research identified 140 drugs with the potential to inter-act with NOACs as listed in Tables 2–5. Yet, publications onDDIs of NOACs have been found for just 49 of those drugs(35%). Reports about DDIs with NOACs have been found for44% of P-gp-affecting drugs, 36% for CYP2C9-affecting drugs,27% for CYP3A4-affecting drugs, and 22% for SSRIs/SRNIs.Reports about DDIs of cardiovascular drugs with NOACswere prevalent, comprising 54% of cardiovascular drugs withthe potential to interact with NOACs, followed by anti-infec-tive drugs with 27% and nervous system drugs with 24%.

Due to the age-related increase of the prevalence of renaldysfunction, polymorbidity, and polymedication, DDIs areexpected to occur more frequently in elderly than in youngerpatients. Detailed reports were found, however, for only 47elderly patients. DDIs of NOACs are described mainly as bleed-ing or thrombotic events. We found no indications that thetypes DDIs of NOACs differed relative to age. Although NOACsare prescribed increasingly to elderly patients, our knowledgeabout DDIs in this group of patients is very limited.

The NOAC dose was not always reported in the publica-tions used for the present review. It seems that bleedingcomplications occur more frequently with higher than withlower NOAC doses. There is, however, no systematic analysisof DDIs with NOACs dose dependence.

DDIs with dabigatran were most frequently reported.Dabigatran was the first NOAC approved for clinical use. Itcannot be assessed, therefore, if the prevalence of reportsabout DDIs with dabigatran than with other NOACs, is due

to a higher rate of DDIs or to the duration of its use.Dabigatran, however, is the only NOAC which seems to inter-act with PPIs. On the basis of the present data, it cannot bedetermined, if the NOACs dabigatran, apixaban, rivaroxaban,and edoxaban vary regarding their DDIs.

Unbiased, manufacturer-independent data about safetyand efficacy of NOACs are rare. Because of the scarcity ofdata, the clinical relevance of DDIs of NOACs is at presentuncertain, especially in elderly patients.

6. Five-year view

Studies should be carried out to investigate the role of drugs,potentially interacting with NOACs, which until now have notbeen investigated. When studying DDIs of NOACs, care shouldbe taken to include the elderly, patients with impaired renalfunction, and patients on polymedication. It should beassessed, if the NOACs dabigatran, apixaban, rivaroxaban,and edoxaban vary regarding their DDIs. The influence ofNOAC dose on DDIs should be studied more extensively.Bleeding and thromboembolic events, which occur underNOACs, and a comedication with an interacting potentialshould be reported to the national pharmacovigilance bodies.

Studies about DDIs of NOACs would become much easier,if the availability of plasma NOAC-level measurementincreased. Although it is known that plasma NOAC-levelshave a high inter- and intra-patient variability, and uncertain-ties exist about the therapeutic range of NOACs, measure-ments of NOAC levels could reveal clinically relevant DDIs atan early stage before an event – bleeding or embolism –occurs [103].

The best remedy of the lack of data about NOACs in elderlypatients would be a randomized trial, but that would require alarge amount of time, effort, and funds. In the meantime, wesuggest to carry out subgroup analyses addressing the rele-vance of DDIs of VKAs versus NOACs in elderly patients, whohave been included in previously completed or still ongoingtrials or registries. This would be both feasible and desirable inview of the large amount of data already accumulated.

Independent research, carried out by academic institutions,healthcare providers, or public health bodies, and not byNOAC manufacturers, is urgently needed.

For clinical practice, we suggest to review critically thecomedication of any patient under NOAC therapy at eachvisit. Concomitant therapy with platelet-affecting drugs shouldbe restricted to time-limited situations like implantation of adrug-eluting stent into a coronary or peripheral artery.Generally, drugs with the potential to interact with NOACsshould be avoided and they should be replaced by drugswhich do not have that potential. If such a replacement isnot possible, a change from NOAC to VKA should be consid-ered because of the possibility to control the anticoagulanteffect and to detect DDIs easily by deviations of the INR.

Key issues

● DDIs of NOACs may occur due to different mechanisms byconcomitant use of drugs affecting a) platelet-activity; b)activity of the cytochrome P450 isoenzymes 3A4, 2J9 and

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 1199

the drug efflux pump P-glycoprotein; c) metabolism ofconcomitant drugs by various mechanisms; and d) – onlyfor dabigatran – changing the gastric PH.

● Publications about DDIs of NOACs with one of 140 poten-tially interacting drugs were found for 35% of these drugs.

● Reports about DDIs of cardiovascular drugs with NOACswere most frequent, comprising 54% of cardiovasculardrugs with the potential to interact with NOACs, followedby anti-infective drugs (27%) and nervous system drugs(24%). Detailed reports were found for only 47 elderlypatients.

● Although NOACs are prescribed increasingly to elderly peo-ple, our knowledge about DDIs in this group of patients isvery limited. Because of the scarcity of data, the clinicalrelevance of DDIs of NOACs is at present uncertain, espe-cially in elderly patients.

● Concomitant therapy with platelet-affecting drugs shouldbe restricted to time-limited situations, like implantation ofa drug-eluting stent into a coronary or peripheral artery.

● Generally, drugs with the potential to interact with NOACsshould be avoided and replaced by drugs which do nothave that potential. If such a replacement is not possible, achange from NOAC to VKA should be considered.

Funding

This paper was not funded.

Declaration of interest

The author has no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

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1202 C. STÖLLBERGER

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