The frequency of prescription of P-glycoprotein-affecting drugs in atrial fibrillation

Authors


Claudia Stöllberger, Steingasse 31/18, A-1030 Wien, Österreich, Austria.
Tel.: +43 1 945 42 91; fax: +43 1 945 42 91.
E-mail: claudia.stöllberger@chello.at

Vitamin K antagonists (VKAs) are well established for the prevention of stroke or embolism in atrial fibrillation (AF) patients. VKAs are underused in AF, because of concerns about bleeding risk, drug and food interactions, and laboratory monitoring [1]. There is a need for anticoagulant agents that would overcome these obstacles by being effective, safe and convenient to use. Dabigatran is a new oral thrombin inhibitor. The Re-Ly study, supported by Boehringer Ingelheim, was a non-inferiority trial in which fixed doses of dabigatran were compared with adjusted-dose warfarin in 18 113 AF patients [2]. Dabigatran was found to have a similar effect as warfarin in stroke prevention, but with a lower complication rate [2]. One of the advantages of dabigatran as compared with VKA should be its lower rate of drug and food interactions. However, dabigatran absorption is dependent on the P-glycoprotein (P-gp) system in the gut, which is influenced by drugs and food components [3–5].

The aim of our cross-sectional study in AF patients was to assess the prescription frequency of P-gp-affecting drugs. The embolic risk was assessed by the CHADS2 score, an acronym for congestive heart failure, hypertension, age > 75 years, diabetes mellitus, and prior stroke or transient ischemic attack.

P-gp-affecting drugs were searched for in the literature and are listed in Table 1 [3–5]. Consecutive patients with AF hospitalized between December 2009 and January 2010 were included. The CHADS2 score was obtained, and the medication was registered and screened for P-gp-affecting drugs.

Table 1.   Drugs, food components and herbs known to affect P-glycoprotein activity (according to [3–5])
DrugFood component, herb
AmiodaroneBlack pepper (Piper nigrum)
AmitriptylineGinkgo (Gingko biloba)
AmprenavirGinseng (Panax ginseng)
AstemizoleGrapefruit juice
BepredilLicorice root
BromocriptineSeville orange (Citrus aurantium)
CarvedilolSt John’s wort (Hypericum perforatum)
ChlorpromazineValerian (Valeriana officinalis)
Clarithromycin 
Clotrimazole 
Colchicine 
Cortisol 
Cyclosporine 
Desipramine 
Dexamethasone 
Diethazine 
Diltiazem 
Dipyridamole 
Disulfiram 
Doxepin 
Dronedarone 
Erythromycin 
Felodipine 
Fluphenazine 
Haloperidol 
Imatinib 
Imipramine 
Indinavir 
Itraconazole 
Ketoconazole 
Levomepromazine 
Lovastatin 
Mefloquine 
Mesylate 
Nelfinavir 
Nicardipine 
Nifedipine 
Ofloxacin 
Perphenazine 
Probenecid 
Progesterone 
Propafenone 
Propranolol 
Quinidine 
Reserpine 
Rifampin 
Ritonavir 
Saquinavir 
Silymarin 
Simvastatin 
Sirolimus 
Tacrolimus 
Tamoxifen 
Terfenadine 
Testosterone 
Thiethylperazine 
Thioridazine 
Trifluperazine 
Troleandomycin 
Valspodar 
Verapamil 
Vinblastine 
Vitamin E 
Yohimbine 

Among 100 patients (47 females, mean age 74 ± 12 years), heart failure was present in 53, hypertension in 70, diabetes in 33, and prior stroke in 14. The mean CHADS2 score was 2.4 ± 1.4. VKAs were received by 54 patients: 2/8 with CHADS2 0, 8/20 with CHADS2 1, 15/27 with CHADS2 2, 15/24 with CHADS2 3, 10/14 with CHADS2 4, 2/5 with CHADS2 5, and 2/2 with CHADS2 6. Forty-two patients took at least one P-gp-affecting drug, and 5/42 took two P-gp-affecting drugs: simvastatin (n = 22), amiodarone (n = 8), vitamin E (n = 8), carvedilol (n = 4), diltiazem (n = 2), dipyridamole (n = 1), propranolol (n = 1), and verapamil (n = 1). Twenty-six of the 54 VKA-receiving patients took one (n = 23) or two (n = 3) P-gp-affecting drugs.

Interactions between dabigatran and P-gp-affecting drugs have only been studied in phase I trials in healthy volunteers [6]. Verapamil and amiodarone elevated dabigatran concentrations by 50–60% and clarithromycin by 19% [6]. Food–drug and herb–drug interactions with dabigatran are unknown.

We conclude that 42% of hospitalized AF patients and 48% of VKA-receiving patients take P-gp-affecting drugs. Although most of these drug–drug interactions should result in weak clinical consequences, more information on the relevance of drug and food interactions is needed before dabigatran is widely used for stroke prevention. It should be investigated whether a dose reduction of dabigatran should be suggested in cases of coprescription of P-gp-affecting drugs. As the present study does not provide any evidence, we suggest to reanalyse bleeding and embolic events in dabigatran-investigating trials according to presence or absence of comedication with P-gp-affecting drugs.

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

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