Drug interactions with new oral anticoagulants in elderly patients.

Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Drug interactions with new oral anticoagulants in elderly patients Claudia Stöllberger To cite this article: Claudia Stöllberger (2017): Drug interactions with new oral anticoagulants in elderly patients, Expert Review of Clinical Pharmacology, DOI: 10.1080/17512433.2017.1370369 To link to this article: http://dx.doi.org/10.1080/17512433.2017.1370369

Accepted author version posted online: 21 Aug 2017.

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Date: 22 August 2017, At: 02:20

Review

Drug interactions with new oral anticoagulants in elderly patients Claudia Stöllberger Krankenanstalt Rudolfstiftung, 2. Med. Abt., Juchgasse 25, A-1030 Wien

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Corresponding Author Claudia Stöllberger

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Tel.: +43 676 403 11 87, Fax: +43 1 71165 2209

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[email protected]

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A-1030 Wien, Österreich

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Abstract

Introduction: This review attempts to summarise what is known about Drug-drug interactions (DDIs)

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of the new oral anticoagulants (NOACs) in elderly patients. The literature was searched for: “CYP3A4”, “CYP2C9”, “P-glycoprotein”, “acetylsalicylic-acid”,

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“non-steroidal anti-inflammatory”, “clopidogrel”, “ticagrelor”, “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 interacting drugs. Reports about DDIs of cardiovascular drugs, were most frequent, followed by antiinfective and nervous system drugs. Reports about elderly were found for only 47 patients. DDIs were

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reported most frequently 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 determine whether the higher number of reports about DDIs with dabigatran compared with other NOACs is due to a higher rate of DDIs or to the length of time during which this drug has been in use. Most of the data is derived from subgroup-analyses of trials, sponsored by NOAC manufacturers, consequently

there is a lack of independent data. Because of the scarcity of data, the clinical relevance of DDIs of NOACs is uncertain at present, especially in elderly patients.

Keywords: Anticoagulation, Atrial fibrillation, Venous thromboembolism, Geriatry, Rivaroxaban,

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Apixaban, Dabigatran, Edoxaban

1. Introduction The new oral anticoagulants (NOACs), also termed “non vitamin-K-antagonist oral anticoagulants” or “direct oral anticoagulants” (DOACs) comprise the thrombin-inhibitor dabigatran and the factor Xainhibitors rivaroxaban, apixaban and edoxaban. All these substances have been compared with the

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vitamin-K-antagonist (VKA) warfarin in large randomised trials in patients with venous thromboembolism (VTE) and atrial fibrillation (AF) (Table 1).[1][2][3][4][5][6][7][8][9][10][11]

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hemorrhages which have been observed in the trials listed in table 1. Furthermore, NOACs are

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assumed to have fewer drug–drug interactions (DDIs) than VKAs. DDIs of VKAs have been known for decades and there are many reports in the literature about deviations of the coagulation tests,

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bleeding and thrombotic events in patients under VKAs due to DDIs.

NOACs, however, also have the potential for DDIs. DDIs of NOACs may occur due to different

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mechanisms: The first mechanism is caused by drugs which affect the platelet-activity , such as acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel, nonsteroidal anti-inflammatory drugs

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(NSAIDs), selective serotonin-reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Concomitant intake of these platelet-aggregation inhibiting drugs with any

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anticoagulant drug, VKAs, heparins or NOACs, increases the rate of bleeding complications. The second mechanism for DDIs of NOACs is comedication with drugs which affect the activity of the cytochrome P450 isoenzymes 3A4 (CYP3A4), 2J9 (CYP2J9) and the drug efflux pump Pglycoprotein (P-gp). Thirdly, there are indications that NOACs may influence the serum - or tissue-

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One of the frequently mentioned advantages of NOACs over VKAs is the lower rate of cerebral

levels of several immunosuppressant, analgesic and antidepressive drugs. A further mechanism is the effect of proton pump inhibitors (PPIs) which may lead to changes of the gastric PH and thus influence NOAC bioavailability. The assumption that NOACs have fewer DDIs than VKAs is based mainly on data on healthy young subjects, in whom the interaction of a single drug with a NOAC has been investigated (Tables 25).[12][13][14][15][16][17][18][19][20][21][22][23] Patients with AF, however, are frequently on multiple medications. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared

With Vitamin K Antagonism for Prevention of Stroke 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 Reduction Of Stroke And Other Thromboembolic Events In Atrial Fibrillation (ARISTOTLE) trial, the rate of polymedication (≥5) was even 77%.[62] In both trials, polymedication was more frequent in older than in younger patients. The prevalence of AF is

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age-dependent and increases, especially in the >75 years group.[63] Although patients >75 years comprised only up to 40% of the population of the NOAC-investigating

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several countries.[64][65][66][67] A time-series analysis of prescription trends between 2010 and

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2012 in Ontario, Canada, for all orally administered anticoagulants (warfarin, dabigatran and

rivaroxaban) found that prescription rates of dabigatran were accelerated among patients 85 or

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older.[64] Using Danish nationwide administrative registers, all oral anticoagulation-naïve AF patients initiating oral anticoagulation from August 2011 through October 2013 were identified. Older age was

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some of the factors associated with NOAC use vs. warfarin.[65] A further study from New Zealand investigated patients on dabigatran, who were admitted to Auckland City Hospital between July and

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December 2011.The mean age of patients was 76 ± 1.7 (range:19–93, median 84) years.[66] A study from Austria analysed the accounting data of insurance funds from 2011-2014, covering >97 % of the

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population. In 2011, the age of patients receiving VKAs was higher than NOACs (72 vs. 68 years), whereas in 2014, the age of the patients receiving VKAs was lower than NOACs (73 vs. 74 years). The proportion of patients ≥80 years receiving VKAs declined from 26 to 21 % of all oral anticoagulants, while those receiving DOACs increased from 1 to 12 %. Among nonagenarians, the

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trials (Table 1), a steep increase in the prescription rate of NOACs to elderly patients is reported by

proportion of patients receiving VKAs remained 2 %, whereas the proportion of patients receiving DOACs increased 40-fold.[67] Thus, DDIs with NOACs in elderly patients are a matter of concern and the aim of the present review is to summarise the current state of knowledge about DDIs of NOACs in elderly patients. 2. Methods 2.1 Literature search

A literature search was carried out using PubMed from 1970 to March 2017 with the search terms: “CYP 3A4”, “CYP3A4” “CYP2C9” CYP2C9”, “P-glycoprotein”, “P-gp”, “acetylsalicylic acid”, “non-steroidal anti-inflammatory”, “clopidogrel”, “ticagrelor”, “prasugrel” and “dabigatran”, “rivaroxaban”, “edoxaban”, or “apixaban”. Furthermore, PubMed was used to search for publications relevant for the drugs listed in the tables 2-5, known to affect platelet function or CYP3A4-, CYP2C9-

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or P-Gp-activity, and “dabigatran”, “rivaroxaban”, “edoxaban”, or “apixaban”.[68][69] Randomised clinical trials, subgroup analyses from randomised trials, longitudinal studies, case series and case

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animal experiments were not considered. Care was taken to assess 1) the patients’ age, 2) if the

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NOACs dabigatran, apixaban, rivaroxaban and edoxaban vary regarding their DDIs, 3) if DDIs differ regarding patients’ age and 4) if DDIs with NOACs are dose-dependent. In order to give a better

2.2 Definition of “elderly “

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system was used to report the findings.[70]

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overview of the various interacting drugs, the Anatomical Therapeutic Chemical (ATC) classification

The global population is ageing and, according to the World Health Organization (WHO), in 2050, the

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population aged 60 years or more will double, whilst those aged 80 years or more will number 400 million people.[71] Unfortunately, there is no uniformly accepted definition of ‘elderly’ persons.[72]

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Since the prevalence of AF, the most frequent indication for oral anticoagulation, is steeply increasing in patients >75 years, for the current review we have defined “elderly” as being ≥75 years.[63] 3. Results

3.1 Subgroup analyses of randomised trials

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reports have been included. Only data with regard to humans were considered, but invitro studies and

Subgroup analyses of elderly patients, included in the large randomised studies investigating NOACs in AF-patients, were carried out for rivaroxaban, apixaban, edoxaban and dabigatran.[73][74][75][76] In these subgroup analyses, a higher rate of strokes and bleeding events in elderly than in younger patients is reported, but no information is given about the influence of comedication on these events. Post-hoc analyses of two of these trials investigated the influence of concomitant medication on outcome events.[61][62] In these analyses, however, different dosages of rivaroxaban (20 mg versus 15 mg once daily) and apixaban (5 mg versus 2.5 mg twice daily) were not considered. In ROCKET-

AF, an increased number of concomitant drugs were associated with a higher risk of bleeding, but not stroke. There was no evidence of differential outcomes in those treated with ≥1 combined CYP3A4 and P-gp inhibitors and those treated with none inhibitor. Use of ≥2 combined inhibitors was associated with higher bleeding rates in those treated with rivaroxaban compared with warfarin, yet, the sample size was limited.[61]

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In ARISTOTLE, greater numbers of concomitant drugs were used in older patients. The number of comorbidities rose across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs). Mortality also

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combined CYP3A4 and P-glycoprotein inhibitors.[62] 3.2 Influence of age on plasma-NOAC-levels

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major bleeding. Rates of major bleeding did not differ significantly between patients with, or without,

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Whereas the effect of VKAs is easily assessed by measurement of the international normalised ratio (INR), the anticoagulant effects of NOACs cannot be measured by routinely available laboratory tests.

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Measurement of plasma-NOAC levels requires a sophisticated technology which is not available in the routine clinical setting. The influence of age on plasma concentrations of the NOACs is confounded

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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 are recommended for elderly

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patients with impaired renal function.

Plasma-levels of NOACs have been studied in different populations of different ages, and only few studies were carried out independently of the drug manufacturer.[45][77] In healthy people, the absorption of dabigatran was subject to high variability.[45][77] In elderly patients with AF, plasma

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rose significantly with the number of drug treatments, as did rates of stroke or systemic embolism and

dabigatran levels were found to be dependent on renal function.[78] Similarly, dependence of plasma

rivaroxaban and edoxaban levels on age and renal function, were indicated by subgroup analyses of the ROCKET-AF and ENGAGE AF-TIMI 48-trials.[79][53] The influence of age on plasma apixaban-levels has only been studied in healthy subjects.[80] In essence, factors which contribute to the age-dependency of plasma-NOAC levels comprise renal impairment, comorbidities, comedication, and age-related changes in intestinal transport, absorption and metabolism of NOACs.

The clinical relevance of increasing age on occurrence of bleeding events during NOAC-therapy is substantiated by a study which analysed hemorrhagic events in the gastrointestinal and nervous system, recorded in the Food and Drug administration (FDA) Adverse Event Reporting System database between 2004 and 2014,using an adjusted reporting odds ratio (ROR).[81] The analysis showed that the rate of dabigatran-associated gastrointestinal hemorrhages was significantly increased

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in patients over 80 years of age. The RORs of dabigatran increased with age, although aging had little effect on VKA-associated gastrointestinal hemorrhage. The ROR for anticoagulant-associated nervous

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indicate that the excretion of dabigatran may be affected by aging, as compared to VKA, probably due

3.3 Comedication and adverse events of NOACs

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to renal function decline.[81] Unfortunately, the comedication was not investigated in that analysis.

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DDIs of VKAs can be easily revealed by unexpected INR-deviations, while DDIs of NOACs are more difficult to detect. They would require measurements of NOAC plasma concentrations, which are not

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available in routine care of patients. Thus, DDIs will be detected only if a complication - either bleeding or thromboembolism - occurs.

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An analysis of 16,160 spontaneous reports from Australia, Canada and USA found that gastrointestinal disorders were the most common adverse events associated with dabigatran, ranging

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from 29% for Australia to 41% for USA. In that analysis, use of concomitant medicines with the potential to increase bleeding risk ranged from 34% for Australia to 51% for the USA.[82] Among the concomitant medications with the potential to increase bleeding risk the most frequently used were acetylsalicylic acid, NSAIDs, SSRIs, amiodarone and dronedarone. The mean age of the 16,160

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system hemorrhage was not affected by aging, as compared to gastrointestinal hemorrhage. These data

patients was 76 years, there were, however, no details about age-associated severity of the adverse event and no information was provided about the dabigatran dose.[82] 3.2 DDIs of NOACs with drugs affecting platelet function

Concomitant use of drugs affecting hemostasis might increase the bleeding risk. Drugs which inhibit platelet function comprise acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel, NSAIDs, SSRIs and SNRIs.[83][84][85][86][87][88]

In RE-LY, 38% of patients at some point received, in addition to warfarin or dabigatran, acetylsalicylic acid or clopidogrel. Concomitant use of a single antiplatelet increased the risk of major bleeding, and dual antiplatelet increased this even more.[89] In RE-LY, the rate of gastrointestinal bleeding was higher with the twice daily regimen of 150 mg dabigatran than with warfarin.[90] This is why, in many countries, a dabigatran dose of 110 mg twice daily is recommended for patients over the

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age of 80 years, or for those 75 years or older with risk of bleeding. Regardless of age, in RE-LY the risk of intracranial bleeding was lower with dabigatran than with warfarin.[90] Therefore, despite the

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protected from bleeding when dabigatran is applied, and not warfarin. This tendency is also observed

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with other NOACs.

In the ENGAGE AF-TIMI 48 trial, patients selected by their physicians to receive single antiplatelet

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therapy (32%) in addition to warfarin or edoxaban (high-dose as well as lower dose) were at a similar risk of stroke or embolism and higher rates of bleeding than those not receiving single antiplatelet

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therapy.[91] The influence of age on the occurrence of bleeding under concomitant antiplatelettherapy was not analysed in the RE-LY or the ENGAGE AF-TIMI 48 trial. A case report described

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spinal subarachnoid hemorrhage in cortical superficial siderosis after apixaban 2.5 mg bid and clopidogrel therapy in a 78-year-old patient.[92]

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In the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials, which compared rivaroxaban with enoxaparin-VKA treatment, concomitant use of an NSAID or acetylsalicylic acid was associated with an increased risk of clinically relevant and major bleeding.[93] A population-based study in Finland found that the use of NSAIDs increased in the total population of

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association between age and decreased renal function, there are indications that the brain is better

rivaroxaban and dabigatran initiators.[94] The authors speculate that, while interactions between VKAs and NSAIDs are acknowledged, interactions between NOACs and NSAIDs have not been much discussed in the literature and may not be recognised because of the lack of strong evidence.[94] SSRIs and SNRIs block the reuptake of serotonin in platelets as well as in neural tissue.[88] SSRIs and SNRIs induce a qualitative platelet defect by a mechanism, which is different from that of acetylsalicylic acid or clopidogrel. Our literature research yielded only 2 reports about DDIs with

rivaroxaban (dose unknown) and SSRIs, as listed in table 2.DDIs of NOACS with drugs affecting absorption, metabolism and excretion of anticoagulant drugs. Metabolism and excretion of rivaroxaban, apixaban and edoxaban are modulated by CYP3A4 and CYP2J9.Thus, concomitant intake of CYP3A4- or CYP2C9-inhibitors can predispose patients to bleeding, and intake of CYP3A4- or CYP2C9-inducers - to thromboembolism (Tables 3 and 4). There

that CYP3A4 plays only a small role in the metabolism of edoxaban.[95]

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are indications that the intensity of this modulation may differ between NOACs. It has been shown

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of xenobiotics. The activity of P-gp is modulated by several drugs (Table 5).[68] Concomitant intake

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of NAOCs and P-gp–modulating drugs can increase the risk of adverse effects, bleeding or thromboembolism.

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The following paragraph will present an overview of the state of knowledge on DDIs of drugs which

for classification of the drugs.

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affect the activity of CYP3A4, CYP2C9 and P-gp with NOACs (Tables 2-5). The ATC system is used

3.5.1Cardiovascular system (in alphabetical order)

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Aliskirenis a renin-inhibitor and a P-gp-inhibitor. Bleeding events in patients treated with aliskiren and either rivaroxaban (20 mg) or dabigatran (300 mg) were described in two case reports.[24][39] Both

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patients were on polypharmacy and ≥75 years.

Amiodarone is an antiarrhythmic drug, an inhibitor of CYP2C9 as well as CYP3A4 and P-gp. A retrospective analysis of patients admitted to an emergency unit disclosed that 44% of those who suffered from bleeding events under dabigatran or rivaroxaban had a comedication of amiodarone. The

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All four NOACs are substrates for P-gp, a drug efflux pump involved in the metabolism of a number

mean age of the patients was 76 years. The NOAC dose is not reported.[96] Bleeding events in patients treated with amiodarone and either rivaroxaban (20 mg, n=3; 15 mg, or dabigatran (300 mg n=3; 220 mg n=1; 150 mg n=1) have been described in several case reports, seven of these patients were ≥75 years.[24][25][26][41] The effects of a comedication with amiodarone have been reported in subgroup-analyses of the dabigatran-, apixaban- and edoxaban-investigating randomised trials. In a subgroup-analysis of the RE-LY trial, concomitant medication with amiodarone significantly affected the bioavailability of

dabigatran, which, according to the authors, “showed only small to moderate effects (< 26% change in exposure at steady state)”.[42] In ARISTOTLE, 11% of the patients received amiodarone at randomisation. A subgroup-analysis found that the interaction values for amiodarone use by apixaban treatment effects were not significant.[27] Similar findings resulted from a subgroup-analysis of the edoxaban-investigating trials.[28] DDIs of amiodarone with edoxaban were studied in healthy

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subjects: Edoxaban exposure increased by 40% after concomitant administration of edoxaban with amiodarone, which was assessed as a modest effect.[12]

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NOACs: Dabigatran malabsorption was reported caused by acceleration of intestinal transit due to

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amiodarone-induced thyrotoxicosis.[40]

Atorvastatin is a lipid modifying agent and a P-gp-inhibitor. Bleeding events in patients treated with

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atorvastatin and either rivaroxaban (20 mg, n=1) or dabigatran (300 mg, n=2; 150 mg, n=2) have been described in several case reports, five of the patients were ≥75 years.[24][43][44]

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DDIs of atorvastatin with rivaroxaban, edoxaban and dabigatran have been studied in healthy subjects: Atorvastatin did not affect the pharmacokinetic profile or the pharmacodynamics of rivaroxaban.[19]

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Coadministration of atorvastatin had relatively minor effects on the pharmacokinetics of edoxaban.[12] Atorvastatin had no influence on the pharmacokinetic/pharmacodynamic profile of

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dabigatran.[20]

Bisoprolol is a betablocking agent and a P-gp-inducer. Bleeding events in patients with polymedication, comprising bisoprolol and either rivaroxaban (20 mg, n=1; 15 mg, n=2) or dabigatran (300 mg, n=1; 220 mg, n=3)), have been described in several case reports, six of the patients were ≥75

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A further side effect of amiodarone, hyperthyroidism, might also influence the anticoagulant effects of

years.[24][26][44] Carvedilol is a betablocking agent and a P-gp-inhibitor. Bleeding events in patients taking carvedilol and either rivaroxaban or dabigatran (300 mg, n=3) have been described in several case reports, three of the patients were ≥75 years.[24]

Diltiazem is a calcium channel blocker and a CYP3A4- and P-gp-inhibitor. Gastrointestinal hemorrhage and fatal multi-organ failure have been reported in a 84-year-old female treated with diltiazem and dabigatran 300 mg.[24] DDIs of diltiazem with apixaban have been studied in healthy

subjects and a 1.4-fold increase in apixaban exposure was observed with co-administration of diltiazem.[14] Dronedarone is an antiarrhythmic drug and a P-gp-inhibitor. Bleeding events in patients taking dronedarone and rivaroxaban (20 mg, n=1) or dabigatran (300 mg, n=1) have been reported, one of the patients was ≥75 years.[24][43] An increased serum dabigatran level was measured in a patient with

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concomitant application of dronedarone and dabigatran 300mg.[49] Concomitant use of dronedarone with dabigatran in patients with AF was investigated prospectively in a small cohort of 33 patients

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dabigatran were similar to trough plasma concentrations of dabigatran without concomitant

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dronedarone in 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.[50] The

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findings of that study have to be interpreted with caution: The patients were relatively young and it is unknown if these findings can also be applied to patients ≥75 years, the patients had less

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comedications than those included in RE-LY and, last but not least, three of the five authors declared an interest with the manufacturer of dabigatran.[50] DDIs of dronedarone with edoxaban have been

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studied in healthy subjects, and coadministration of dronedarone increased edoxaban exposure.[12] Fluvastatin is a lipid modifying agent and a CYP2C9-inhibitor. Bleeding events in patients with a

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medication of fluvastatin and rivaroxaban have been reported in several cases, one of the patients was ≥75 years.[24]

Lovastatin is a lipid modifying agent and a CYP2C9- and P-gp-inhibitor. In a population-based, nested case–control study involving 45,991 Ontario residents ≥66 years who started dabigatran between 2012

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with a mean age of 64 years, concomitantly treated with dabigatran. Trough plasma concentrations of

and 2014, use of lovastatin was associated with a higher risk of major hemorrhage.[52] It remains unclear in that study if patients ≥75 years had a higher bleeding risk than younger patients, and if the

bleeding risk was influenced by the dabigatran dose. Propranolol is a beta blocking agent and a P-gp-inhibitor. A bleeding event has been reported in an 80year-old patient treated with propranolol and dabigatran (220 mg, n=1).[24] Quinidine is an antiarrhythmic drug and a P-gp-inhibitor. The effects of a comedication with quinidine have been reported in subgroup-analyses of edoxaban-investigating trials and were shown to increase

the bioavailability of edoxaban.[53] DDIs of quinidine with edoxaban have been studied in healthy subjects: Concomitant medication with quinidine increased total edoxaban exposure by 35% and total edoxaban clearance decreased by 25%.[12][21] Simvastatin is a lipid modifying agent and a P-gp-inhibitor. In a population-based, nested case–control study involving 45,991 Ontario residents ≥66 years who started dabigatran between 2012 and 2014,

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use of simvastatin was associated with a higher risk of major hemorrhage.[52] Bleeding events in patients taking simvastatin and rivaroxaban (20 mg, n=1; 15 mg, n=1) as well as dabigatran (300 mg,

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Verapamil is a calcium channel blocker and a CYP3A4- and P-gp-inhibitor. In a study in 137 AF-

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patients on dabigatran, multivariate analysis revealed that verapamil use was independently associated with elevated dabigatran concentrations.[56] A bleeding event is reported in a 72-year-old patient with

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a polymedication comprising verapamil and dabigatran 300 mg.[24] In a subgroup-analysis of the RELY trial, concomitant medication with verapamil significantly affected the bioavailability of

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dabigatran, which, according to the authors, “showed only small to moderate effects (< 26% change in exposure at steady state)”[42] DDIs of verapamil with edoxaban and dabigatran have been studied in

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healthy subjects: Coadministration of verapamil increased edoxaban and dabigatran exposure.[12][22] No information about DDIs with NOACS was found for the following cardiovascular system drugs

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which are known to affect activity of CYP3A4-, CYP2C9 or P-gp: Bepridil, fenofibrate, mibefradil, nicardipine, nifedipine, propafenone, reserpine, rosuvastatin and talinol. 3.5.2 Alimentary tract and metabolism

Loperamide is an antipropulsive drug and a P-gp-inhibitor. Acute hepatic failure was reported in an

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n=5; 220 mg, n=1) have been reported, eight of the patients were ≥75 years.[24][54]

87-year-old female on polymedication comprising dabigatran 220 mg and loperamide.[24] No information about DDIs with NOACs was found for the following alimentary tract and metabolism drugs, which are known to affect activity of CYP3A4-, CYP2C9 or P-gp: Aprepitant, cimetidine, dexamethasone, pioglitazone and troglitazone. 3.5.3 Blood and blood forming organs No information about DDIs with NOACs was found for dipyridamole. 3.5.4 Genitourinary system and sex hormones

No information about DDIs with NOACs was found for the following genitourinary system drugs and sex hormones known to affect activity of CYP3A4-, CYP2C9 or P-gp: Gestodene, mifepristone, mirabegron and progesterone. 3.5.5 Systemic hormonal preparations No information about DDIs with NOACs was found for glucocorticoids and hydrocortisone.

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3.5.6 Anti-infective drugs Clarithromycin is a macrolide and a CYP3A4- und P-gp-inhibitor. Bleeding events have been reported

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concomitant clarithromycin have been studied in healthy subjects: Concomitant clarithromycin

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increased plasma levels of rivaroxaban as well as dabigatran. This was found both, in studies by the manufacturer and by independent investigators.[13][34][45]

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Erythromycin is a macrolide and a CYP3A4- and P-gp-inhibitor. A fatal gastrointestinal hemorrhage is reported in a 92-year-old patient treated with dabigatran 300 mg and erythromycin.[51] DDIs of

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NOACs with concomitant erythromycin have been studied in healthy subjects: Concomitant erythromycin increased plasma levels of rivaroxaban as well as edoxaban.[13][16] In patients with

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mild to moderate renal impairment, concomitant erythromycin resulted in increases in rivaroxaban exposure that were assessed as “slightly more than additive”.[15]

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Fluconazole is an antimycotic and a CYP3A4- and CYP2C9 inhibitor. DDIs of NOACs with concomitant fluconazole have been studied in healthy subjects: Concomitant fluconazole increased plasma levels of rivaroxaban.[13]

Ketoconazole is an antimycotic and a CYP3A4 and P-gp-inhibitor. DDIs of NOACs with concomitant

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in patients treated with clarithromycin and rivaroxaban (20 mg, n=1).[24][33] DDIs of NOACs with

ketoconazole have been studied in healthy subjects: Concomitant ketoconazole increased plasma levels of rivaroxaban, apixaban and edoxaban.[13][14][16] Metronidazole is an antibacterial and a CYP2C9 inhibitor. Fatal acute hepatic failure is reported in a 90-year-old patient taking rivaroxaban and metronidazole.[24] Nevirapine is an antiviral and a CYP2C9- and CYP3A4 inducer. Venous thrombosis after total knee replacement despite rivaroxaban 10 mg is reported in a patient on permanent nevirapinemedication.[31]

Rifampicin is an antimycobacterial and a P-gp-inducer. A case of fatal pulmonary embolism is reported in a patient treated with AF under rivaroxaban 20 mg and rifampicin. The plasma rivaroxaban level was below the 5th percentile of what could be predicted, based on pharmacokinetic studies.[32] DDIs of NOACs with concomitant rifampicin have been studied in healthy subjects: Concomitant rifampicin reduced plasma levels of apixaban, edoxaban and dabigatran.[17][18][23]

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Ritonavir is an antiviral and a CYP3A4- and P-gp inhibitor. Bleeding events under rivaroxaban (10 mg, n=2) for venous thromboembolism prophylaxis after orthopedic surgery have been reported in

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have been studied in healthy subjects: Concomitant ritonavir increased plasma levels of

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rivaroxaban.[13]

No information about DDIs with NOACs were found for the following anti-infective drugs which are

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known to affect activity of CYP3A4-, CYP2C9 or P-gp: Amprenavir, boceprevir, cefoperazone, chloramphenicol, ciprofloxacin, clotrimazole, daclatasvir, delavirdine, efavirenz, indinavir, isoniazid,

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itraconazole, nelfinavir, norfloxacin, ofloxacin, roxithromycin, saquinavir, sulfamethoxazole, sulfaphenazole, telaprevir, telithromycin and voriconazole.

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3.5.7 Antineoplastic and immunomodulating drugs Ciclosporin is an immunosuppressant and a P-gp inhibitor. Increased plasma levels of rivaroxaban

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were found in patients treated with ciclosporin after liver transplantation.[47] In healthy subjects, coadministration of ciclosporin increased the exposure to edoxaban.[16] Tacrolimus is an immunosuppressant and a P-gp inhibitor. No increase in plasma levels of rivaroxaban were found in patients treated with tacrolimus after liver transplantation.[47] A bleeding event is

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patients with concomitant ritonavir-medication.[35][36] DDIs of NOACs with concomitant ritonavir

reported in a patient on polypharmacy comprising tacrolimus and dabigatran.[55] Tocilizumab is an immunosuppressant and a P-gp inducer. A fatal mesenteric artery thrombosis is reported in a patient on polypharmacy comprising dabigatran and tocilizumab.[60] No information about DDIs with NOACs were found for the following antineoplastic and immunomodulating drugs which are known to affect activity of CYP3A4-, CYP2C9 or P-gp: Enzalutamide, imatinib, ponatinib, tamoxifen and teniposide. 3.5.8 Musculoskeletal system

No information about DDIs with NOACs was found for phenylbutazone and probenecid. 3.5.9 Nervous system Carbamazepine is an antiepileptic drug and a CYP3A4-, CYP2C9- and P-gp inducer. Venous thromboembolism under rivaroxaban (20 mg, n=1; 10 mg, n=1) is reported in two patients on concomitant carbamazepine medication.[29][30]

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Oxcarbazepine is an antiepileptic drug and a CYP3A4-inducer. A left atrial appendage thrombus was reported in a patient with AF, rivaroxaban 20 mg and concomitant medication of oxcarbazepine.[38]

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an 81-year-old patient on polymedication including rivaroxaban and paroxetine.[24]

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Phenobarbital is an antiepileptic drug and a P-gp-inducer. In a series of 52 AF patients, aged 38-94 years, treated with dabigatran, a reduced dabigatran exposure was found in a patient after co-

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administration of dabigatran 220 mg with phenobarbital.[57]

Phenytoin is an antiepileptic drug and a CYP3A4- and P-gp inducer. In a series of 52 AF patients,

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aged 38-94 years, medicated with dabigatran, a reduced dabigatran exposure was found in a patient following co-administration of dabigatran 220 mg with phenytoin.[57] Development of a left atrial

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thrombus has been reported after coadministration of dabigatran and phenytoin.[58] In another case, a reduced anticoagulant effect of dabigatran was detected in a patient receiving concomitant

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phenytoin.[59]

Sertraline is an antidepressant, a SSRI and a CYP2C9-inhibitor. A bleeding event was reported in an 88-year-old patient on polypharmacy, including rivaroxaban and sertraline.[24] No information about DDIs with NOACs was found for the following nervous system drugs known to

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Paroxetine is an antidepressant, a SSRI and a CYP2C9-inhibitor. Hepatic failure has been reported in

affect activity of CYP3A4-, CYP2C9 or P-gp: Buprenorphine, chlorpromazine, citalopram, disulfiram, doxepin, duloxetine, escitalopram, fluoxetin, fluphenazine, fluvoxamine, haloperidol, milnacipran, modafinil, nefazodone, norfluoxetine, phenobarbital, secobarbital and venlafaxine. 3.5.10 Respiratory system No information about DDIs with NOACs was found for astemizole and zafirlukast. 3.5.11Various

Cobicistat is a CYP3A4- and P-gp-inhibitor and is used as an enhancer of other antiretroviral agents in the treatment of HIV infection. In healthy HIV-negative subjects simultaneous administration of cobicistat resulted in significant increases in dabigatran exposure.[46] 3.5.12 Fruits and herbal products Grapefruit juice, saw palmetto, star fruit and St. John’s wort are known to affect CYP3A4-activity.

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Saw palmetto, used in alternative medicine to treat benign prostatic hyperplasia, is a CYP3A4inhibitor. Hemopericardium has been reported in a patient on rivaroxaban with concomitant intake of

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CYP2C9 inducer, are reported.

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3.6 DDIs of NOACs changing the metabolism of concomitant drugs.

Little is known how NOACs affect the metabolism of concomitant drugs. The effects of rivaroxaban

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and apixaban on the disposition of ciclosporin and tacrolimus were assessed retrospectively in transplant recipients and showed considerable variability between individual patients, but no clear

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pattern. Both, increased ciclosporin/tacrolimus plasma levels (which would occur if NOACs inhibited CYP3A and/or P/-gp) and decreased ciclosporin/tacrolimus plasma levels (which would occur if

ed

NOACs induced CYP3A and/or P/gp), were found.[48] A potential interaction between methadone and apixaban has been postulated, based on the

ce pt

observation of cases in which the methadone-dose had to be increased to achieve control of pain after initiation of apixaban.[97]

Aggravation of depressive symptoms after initiation of dabigatran is reported. As the presumed pathomechanism, it has been hypothesised that dabigatran may decrease brain concentrations of

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saw palmetto.[37] No DDIs with hypericum perforatum, a P-gp inducer, nor with St. John’s wort, a

antidepressant drugs.[98] 3.7 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 the concomitant medication with PPIs might influence serum dabigatran levels. An acidic environment is required for the dissolution of dabigatran, so the increase in gastric pH induced by PPIs might affect the solubility and absorption of dabigatran. The available data about DDIs of dabigatran with PPIs is confusing; it is uncertain, therefore, whether different PPIs have similar

effects: An in vitro and in vivo study evaluated DDIs between dabigatran and the PPIs in healthy volunteers.[77] Concomitant administration of PPIs did not change dabigatran pharmacokinetics. Dabigatran levels, however, varied considerably thus precluding evaluation of an effect of PPIs on its pharmacokinetics.[77] A decrease in dabigatran bioavailability has been reported in patients with concomitant PPIs in the RE-LY trial.[42] In contrast, a prospective pilot study in patients with AF

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found higher serum dabigatran levels in those who were treated with PPIs than in those who were not.[100]

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Polymedication may comprise drugs which differently affect the metabolism of NOACs. This is

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illustrated by the following case: Gastrointestinal bleeding under dabigatran occurred in an 83-yearold female on comedication with digitoxin, levothyroxine, nebivolol, simvastatin, furosemide,

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pantoprazole, risperidone, meloxicam, rivastigmin, sertraline, indapamide and ramipril. Among these drugs are inhibitors as well as inducers of P-gp and CYP3A4 and, additionally, platelet inhibitors.

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Thus, it is impossible to assess the impact of a single drug on the bleeding event.[101] An analysis of the reports about drug-induced liver injury associated with dabigatran and rivaroxaban

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of the FDA Adverse Event Reporting System found a similar accumulation of polymedication. In that analysis, 56% of patients were ≥75 years.[24] Limitations

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4

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

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3.8 Combined comedication with CYP3A4/CYP2C9- and P-gp-inhibitors and inducers

We restricted our literature research to publications included in PubMed. Thus, publications in journals not included in PubMed have not been covered. The scientific quality of the presented data is impaired by two factors: First, most of the data are case reports with their inherent methodological limitations. Secondly, they derive from subgroup-analyses of randomised trials and registries, sponsored and carried out by NOAC manufacturers, written by authors who indicated conflicts of interest with NOAC manufacturers.[102]

5

Expert commentary

Our research identified 140 drugs with the potential to interact with NOACs as listed in tables 2-5. Yet, publications on DDIs of NOACs have been found for just 49 of those drugs (35%). Reports about DDIs with NOACs have been found for 44% of P-gp-affecting drugs, 36% for CYP2C9-affecting drugs, 27% for CYP3A4-affecting drugs and 22% for SSRIs/SRNIs. Reports about DDIs of

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cardiovascular drugs with NOACs were prevalent, comprising 54% of cardiovascular drugs with the potential to interact with NOACs, followed by anti-infective drugs with 27% and nervous system

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Due to the age-related increase of the prevalence of renal dysfunction, polymorbidity and

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polymedication, DDIs are expected to occur more frequently in elderly than in younger patients. Detailed reports were found, however, for only 47 elderly patients. DDIs of NOACs are described

an

mainly as bleeding or thrombotic events. We found no indications that the types DDIs of NOACs differed relative to age. Although NOACs are prescribed increasingly to elderly patients, our

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knowledge about DDIs in this group of patients is very limited.

The NOAC dose was not always reported in the publications used for the present review. It seems that

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bleeding complications occur more frequently with higher than with lower NOAC doses. There is, however, no systematic analysis of DDIs with NOACs dose dependence.

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DDIs with dabigatran were most frequently reported. Dabigatran was the first NOAC approved for clinical use. It cannot be assessed, therefore, if the prevalence of reports about 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 interact with PPIs. On the basis of the present data, it

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drugs with 24%.

cannot be determined, if the NOACs dabigatran, apixaban, rivaroxaban and edoxaban vary regarding their DDIs.

Unbiased, manufacturer-independent data about safety and efficacy of NOACs are rare. Because of the scarcity of data, the clinical relevance of DDIs of NOACs is at present uncertain, 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 not been investigated. When studying DDIs of NOACs, care should be taken to include the elderly, patients with impaired renal function and patients on polymedication. It should be assessed, if the NOACs dabigatran, apixaban, rivaroxaban and edoxaban vary regarding their DDIs.

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The influence of NOAC dose on DDIs should be studied more extensively. Bleeding and thromboembolic events, which occur under NOACs, and a comedication with an interacting potential

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Studies about DDIs of NOACs would become much easier, if the availability of plasma NOAC-level

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measurement increased. Although it is known that plasma NOAC-levels have a high inter- and intrapatient variability, and uncertainties exist about the therapeutic range of NOACs, measurements of

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NOAC-levels could reveal clinically relevant DDIs at an early stage before an event – bleeding or embolism – occurs.[103]

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The best remedy of the lack of data about NOACs in elderly patients would be a randomised trial, but that would require a large amount of time, effort and funds. In the meantime, we suggest to carry out

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subgroup analyses addressing the relevance of DDIs of VKAs versus NOACs in elderly patients, who have been included in previously completed or still ongoing trials or registries. This would be both

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feasible and desirable in view of the large amount of data already accumulated. Independent research, carried out by academic institutions, health care providers or public health bodies, and not by NOAC manufacturers, is urgently needed. For clinical practice, we suggest to review critically the comedication of any patient under NOAC

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should be reported to the national pharmacovigilance bodies.

therapy at each visit. Concomitant therapy with platelet-affecting drugs should be restricted to timelimited situations like implantation of a drug-eluting stent into a coronary or peripheral artery. Generally, drugs with the potential to interact with NOACs should be avoided and they should be replaced by drugs which do not have that potential. If such a replacement is not possible, a change from NOAC to VKA should be considered because of the possibility to control the anticoagulant effect and to detect DDIs easily by deviations of the INR.

7. Key issues •

DDIs of NOACs may occur due to different mechanisms by concomitant use of drugs affecting a) platelet-activity; b) activity of the cytochrome P450 isoenzymes 3A4, 2J9 and the drug efflux pump P-glycoprotein; c) metabolism of concomitant drugs by various mechanisms; and d) - only for dabigatran - changing the gastric PH. Publications about DDIs of NOACs with one of 140 potentially interacting drugs were found

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•

for 35% of these drugs.

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Reports about DDIs of cardiovascular drugs with NOACs were most frequent, comprising 54% of cardiovascular drugs with the potential to interact with NOACs, followed by anti-

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infective drugs (27%) and nervous system drugs (24%). Detailed reports were found for only 47 elderly patients.

Although NOACs are prescribed increasingly to elderly people, our knowledge about DDIs in

an

•

this group of patients is very limited. Because of the scarcity of data, the clinical relevance of

•

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DDIs of NOACs is at present uncertain, especially in elderly patients. Concomitant therapy with platelet-affecting drugs should be restricted to time-limited

•

ed

situations, like implantation of a drug-eluting stent into a coronary or peripheral artery. Generally, drugs with the potential to interact with NOACs should be avoided and replaced by

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drugs which do not have that potential. If such a replacement is not possible, a change from NOAC to VKA should be considered.

Funding

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•

This paper was not funded. Declaration of Interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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103 Chan NC, Coppens M, Hirsh J, et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J. Thromb. Haemost.13(3), 353-359 (2015). *= of importance since it describes

ce pt

ed

M

an

the high variability of plasma dabigatran concentrations9

Ac


102 Stöllberger C, Schneider B, Finsterer J. There is a need for independent studies about new oral

Table 1 NOAC investigating trials Author

Drug Trial name

Funding Indication Patients

Mean

Follow-

years

age,

up,

years

months

71

24

Dabi

RE-LY

Man

AF

18,113

40%

[2]

Dabi

RE-COVER

Man

VTE

2,564

NR

Man

VTE

2,589

Man

VTE

ip t

[1]

Dabi

RE-COVER II RE-MEDY

[5]

Apix

ARISTOTLE Man

[6]

Apix

AMPLIFY

Man

[7]

Riva

ROCKET

Man

[8]

Riva

EINSTEIN

55

6

NR

55

16

18,201

31%

70

22

VTE

5,395

NR

57

6

AF

14,264

38%

73

20

VTE

3,449

NR

57

3-12

Man

VTE

4,832

NR

58

9

Man

AF

21,105

40%

72

34

Man

VTE

8,292

13%

56

9

AF

ed

AF

6

4,219

an

Dabi

M

[4]

NR

us

[3]

54

cr

I

Man

[9]

ce pt

DVT

Riva

EINSTEIN PE

[10]

Edox

Ac


≥ 75

[11]

Edox

ENGAGE AF-TIMI

HOKUSAI VTE

NOAC = non vitamin-K-antagonists oral anticoagulants Dabi = Dabigatran Riva = Rivaroxaban

Man = manufacturer-sponsored trial Apix = Apixaban Edox = Edoxaban AF = atrial fibrillation



ip t

VTE = venous thromboembolism

Table 2 Interactions between Selective Serotonin Reuptake Inhibitors (SSRIs), SerotoninNorepinephrine-Reuptake-Inhibitors (SNRIs) and NOACS Drug

Rivaroxaban

Apixaban

Edoxaban

Dabigatran Cases ≥75 a

Fluvoxamine

NR

NR

NR

NR

Fluoxetine

NR

NR

NR

NR

0

Paroxetine

CR[24]

NR

NR

NR

1

Citalopram

NR

NR

NR

Sertraline

CR[24]

NR

NR

Escitalopram

NR

NR

Venlafaxine

NR

NR

Milnacipran

NR

NR

Duloxetine

NR

ce pt

CR = case report

ip t

NR

us

1

NR

NR

0

an

cr 0

NR

NR

0

NR

NR

0

NR

NR

0

NR

ed

NR = not reported

0

NR

M

SSNRI

Ac


SSRI

Table 3 Interactions between CYP2C9 inhibitors and inducers and NOACs Drug

Rivaroxaban

Apixaban

Edoxaban

Cases ≥75 a

Fluconazole

HSM[13]

NR

NR

0

Amiodarone

CR[24][25][26]

SGART[27]

SGART[28],

2

ip t

CYP2C9 Inhibitors

NR

NR

Fenofibrate

NR

NR

Fluvastatin

CR[24]

NR

Fluvoxamine

NR

NR

Isoniazid

NR

NR

Lovastatin

NR

Metronidazole

CR[24]

Paroxetine

CR[24]

Phenylbutazone

NR

0

cr

Efavirenz

0

NR

1

NR

0

NR

0

NR

NR

0

NR

NR

1

NR

NR

1

NR

NR

NR

0

NR

NR

NR

0

CR[24]

NR

NR

1

Sulfamethoxazole

NR

NR

NR

0

Sulfaphenazole

NR

NR

NR

0

Teniposide

NR

NR

NR

0

Voriconazole

NR

NR

NR

0

Zafirlukast

NR

NR

NR

0

Carbamazepine

CR[29][30]

NR

NR

0

Enzalutamide

NR

NR

NR

0

Nevirapine

CR [31]

NR

NR

0

an M

ce pt

Sertraline

ed

Probenicid

us

NR

Ac


HSM [12]

CYP2C9 inducers

Phenobarbital

NR

NR

NR

0

Rifampicin

CR[32]

HSM[17]

HSM[18]

0

Secobarbital

NR

NR

NR

0

St. John’s Wort

NR

NR

NR

0

NR = not reported,

ip t

CR = case report; HSM = study in healthy subjects, carried out by the manufacturer



SGART = subgroup analysis of a randomised trial

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

Rivaroxaban

Apixaban

Edoxaban

Cases ≥75 a

CYP 3A4

Amiodarone

CR[24][25][26]

ip t

inhibitors SGART[27]

HSM[12],

2

NR

Boceprevir

NR

NR

Chloramphenicol NR Cimetidine

NR

Ciprofloxacin

NR

Clarithromycin

CR[24][33], HSI[34], HSM

NR

0

NR

0

NR

NR

0

NR

NR

0

NR

NR

0

NR

NR

0

an

M

[13]

cr

NR

us

Aprepitant

NR

NR

NR

0

Delavirdine

NR

NR

NR

0

Diethyl-

NR

NR

NR

0

Diltiazem

NR

HSM[14]

NR

0

Erythromycin

HSM[13][15]

NR

HSM[16]

0

Fluconazole

HSM[13]

NR

NR

0

Fluvoxamine

NR

NR

NR

0

Gestodene

NR

NR

NR

0

Grapefruit juice

NR

NR

NR

0

Imatinib

NR

NR

NR

0

Indinavir

NR

NR

NR

0

ce pt

ed

Cobicistat

dithiocarbamate

Ac


SGART[28]

NR

NR

0

Ketoconazole

HSM[13]

HSM[14]

HSM[16]

0

Mibefradil

NR

NR

NR

0

Mifepristone

NR

NR

NR

0

Nefazodone

NR

NR

NR

0

Nelfinavir

NR

NR

NR

0

Norfloxacin

NR

NR

Norfluoxetine

NR

NR

Ritonavir

CR[35][36], HSM[13]

NR

Saquinavir

NR

NR

Saw palmetto

CR[37]

NR

Star fruit

NR

Buprenorphine

NR

Telaprevir

NR

Telithromycin

NR

Verapamil Voriconazole

ip t

NR

0

NR

0

cr

NR

0

NR

0

NR

1

NR

NR

0

NR

NR

0

NR

NR

0

NR

NR

0

NR

NR

HSM[12]

0

NR

NR

NR

0

ce pt

ed

M

an

us

NR

CYP 3A4 inducers Barbiturates

NR

NR

NR

0

Carbamazepine

CR[29][30]

NR

NR

0

Efavirenz

NR

NR

NR

0

Enzalutamide

NR

NR

NR

0

Glucocorticoids

NR

NR

NR

0

Modafinil

NR

NR

NR

0

Nevirapine

CR[31]

NR

NR

0

Oxcarbazepine

CR[38]

NR

NR

0

Phenobarbital

NR

NR

NR

0

Ac


Itraconazole

Phenytoin

NR

NR

NR

0

Pioglitazone

NR

NR

NR

0

Rifampicin

CR[32]

HSM [17]

HSM[18]

0

St. John's Wort

NR

NR

NR

0

Troglitazone

NR

NR

NR

0

ip t

NR = not reported, CR = case report

cr

SGART = subgroup analysis of a randomised trial

ce pt

ed

M

an

us

HSI = study in healthy subjects, carried out independent from the manufacturer

Ac


HSM = study in healthy subjects, carried out by the manufacturer

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

Rivaroxaban

Apixaban

Edoxaban

Dabigatran

Cases ≥75 a

P-Glycoprotein

CR[39]

NR

NR

CR[24]

2

Amiodarone

CR[24][25][26]

SGART[27]

SGART[28],

CR[24][40][41],

7

cr

ip t

Aliskiren

NR

Astemizole

NR

NR

Atorvastatin

CR[24][43],

NR

HSM[19]

Carvedilol

CR[24]

Cefoperazone

NR

NR

0

NR

NR

0

HSM[12]

CR[24][44],

5

HSM[20]

NR

NR

NR

0

NR

NR

CR[24]

3

NR

NR

NR

NR

0

NR

NR

NR

NR

0

CR[24][33],

NR

NR

HSI[34][45]

0

NR

NR

NR

HSI[46]

0

Cyclosporine A

CS[47][48]

CS[48]

HSM[16]

NR

0

Daclatasvir

NR

NR

NR

NR

0

Diltiazem

NR

HSM[14]

NR

CR[24]

1

Dipyridamole

NR

NR

NR

NR

0

Disulfiram

NR

NR

NR

NR

0

Doxepin

NR

NR

NR

NR

0

Chlorpromazine

ce pt

Clarithromycin

M

NR

ed

Bepridil

SGART[42]

us

NR

HSM[12]

an

Amprenavir

HSI[34], HSM [13]

Cobicistat

Ac


inhibitors

Dronedarone

CR[43]

NR

HSM[12]

CR[24][49],

1

HSM[15][13]

NR

HSM[16]

CR[51]

1

Fluphenazine

NR

NR

NR

NR

0

Haloperidol

NR

NR

NR

NR

0

Hydrocortisone

NR

NR

NR

NR

0

Indinavir

NR

NR

NR

NR

0

Itraconazole

NR

NR

NR

NR

0

Ketoconazole

HSM[13]

HSM[F14]

HSM[16]

NR

0

Loperamide

NR

NR

NR

CR[24]

1

Lovastatin

NR

NR

NR

CCS[52]

0

Mirabegron

NR

NR

NR

NR

0

Nelfinavir

NR

NR

NR

NR

0

Nicardipine

NR

NR

NR

0

Nifedipine

NR

M

NR

NR

NR

NR

0

ed

Ofloxacin

cr

us

an

NR

NR

NR

NR

0

NR

NR

NR

NR

0

ce pt

Ponatinib

ip t

Erythromycin

Progesterone

NR

NR

NR

NR

0

Propafenone

NR

NR

NR

NR

0

Propranolol

NR

NR

NR

CR[24]

1

Quinidine

NR

NR

HSM[21][12],

NR

0

Ac


CS[50]

Ritonavir

SGART[53] CR[35][36],

NR

NR

NR

0

HSM[13] Rosuvastatin

NR

NR

NR

NR

0

Roxithromycin

NR

NR

NR

NR

0

Saquinavir

NR

NR

NR

NR

0

Simvastatin

CR[24][54]

NR

NR

CR[24],

8

CCS[52] CS[47][48]

CS[48]

NR

CR[55]

0

Talinolol

NR

NR

NR

NR

0

Tamoxifen

NR

NR

NR

NR

0

Telithromycin

NR

NR

NR

NR

0

Verapamil

NR

NR

HSM [12]

CS[56], CR[24],

ip t

Tacrolimus

0

cr

P-Glycoprotein

Bisoprolol

CR[24][26]

NR

CR[24] [44]

6

Carbamazepine

CR[29] [30]

NR

NR

NR

0

Clotrimazole

NR

NR

NR

NR

0

Dexamethasone

NR

NR

NR

NR

0

Hypericumperforatum NR

NR

NR

NR

0

Phenobarbital

NR

NR

NR

CS[57]

0

NR

NR

NR

CS[57],

0

ed

ce pt

Phenytoin

an

NR

M

inducers

us

HSM[22]

CR[58][59]

Reserpine

NR

NR

NR

NR

0

Rifampicin

NR[32]

HSM[17]

HSM[18]

HSM[23]

0

Tocilizumab

NR

NR

NR

CR[60]

0

Ac


SGART[42],

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 analysis of a randomised trial

ed

ce pt

Ac

ip t

cr

us

an

M


HSI = study in healthy subjects, carried out independent from the manufacturer

Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation?

New oral anticoagulants in the elderly: what's the evidence?

Direct oral anticoagulants--pharmacology, drug interactions, and side effects.

New oral anticoagulants in patients with atrial fibrillation.

[New oral anticoagulants. Regional anaesthesia and new oral anticoagulants].

New oral anticoagulants in patients with atrial fibrillation.

New oral anticoagulants in patients with atrial fibrillation.

New oral anticoagulants.

Direct oral anticoagulants (DOACs) versus "new" oral anticoagulants (NOACs)?

Psychological effects of treatment with new oral anticoagulants in elderly patients with atrial fibrillation: a preliminary report.

Potential for drug interactions in elderly patients with arthritis.

Pharmacodynamic profile and drug interactions with non-vitamin K antagonist oral anticoagulants: implications for patients with atrial fibrillation.

Drug interactions with new hepatitis C oral drugs.

Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring.

Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation.

Safety of new oral anticoagulants in high risk patients.

Safety of new oral anticoagulants.

The management of dental patients taking new generation oral anticoagulants.

[New oral anticoagulants in perioperative medicine].

Perioperative management of patients on new oral anticoagulants.

New oral anticoagulants for nonvalvular atrial fibrillation in the elderly: Limited applicability in primary care.

New oral anticoagulants in thrombotic antiphospholipid syndrome.

Balancing bleeding and thrombotic risk with new oral anticoagulants in patients with atrial fibrillation.

The new oral anticoagulants in oral and maxillofacial surgery.