Direct oral anticoagulants (DOACs) can potentially interact with multiple prescription medications. We examined the prevalence of co-prescription of DOACs with interacting medications and its impact on outcomes in patients with atrial fibrillation (AF). Patients with AF treated with a DOAC from 2010 to 2017 at the Mayo Clinic and co-prescribed medications that are inhibitors or inducers of the P-glycoprotein and/or Cytochrome P450 3A4 pathways were identified. The outcomes of stroke, transient ischemic attack, or systemic embolism, major bleeding, and minor bleeds were compared between patients with and without an enzyme inducer. Cox proportional hazards model was used to assess the association between interacting medications and outcomes. Of 8,576 patients with AF (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran), 2,610 (30.4%) were on at least 1 interacting agent: the majority were on an enzyme inhibitor (n = 2,592). Prescribed medications included non-dihydropyridine calcium channel blocker (n = 1,412; 16.5%), antiarrhythmic medication (n = 790; 9.2%), antidepressant (n = 659; 7.7%), antibiotic/antifungal (n = 77; 0.90%), antiepileptics (n = 17; 0.2%) and immunosuppressant medications (n = 19; 0.2%). Patients on an interacting medication were more likely to receive a lower dose of DOAC than indicated by the manufacturer’s labeling (15.0% vs 11.4%, p <0.0001). In multivariable analysis, co-prescription of an enzyme inhibitor was not associated with risk of any bleeding (hazard ratio 0.87 [0.71 to 1.05], p = 0.15) or stroke, transient ischemic attack, or systemic embolism (hazard ratio 0.82 [0.51 to 1.31], p = 0.39). In conclusion, DOACs are co-prescribed with medications with potential interactions in 30.4% of patients with AF. Co-prescription of DOACs and these drugs are not associated with increased risk of adverse embolic or bleeding outcomes in our cohort.
The efficacy and safety of direct oral anticoagulants (DOACs) in preventing stroke in patients with atrial fibrillation (AF) is well established. Polypharmacy is common in patients with AF and DOACs are prone to both pharmacodynamic and pharmacokinetic interactions with other drugs. , All DOACs are substrates for the permeability glycoprotein (P-gp) efflux transporter, also known as multidrug resistance protein 1 or adenosine triphosphate (ATP)-binding cassette subfamily B Member 1. Inhibitors of P-gp can lead to increased DOAC levels, whereas inducers can lead to decreased levels. Rivaroxaban and apixaban (but not dabigatran) are metabolized through Cytochrome P450 (CYP) Isoform 3A4, inhibitors of which can increase DOAC levels. Drug labeling for rivaroxaban and apixaban recommend avoidance and/or dose reduction in patients taking certain strong dual inhibitors or inducers of CYP3A4 and P-gp. There is no clear guidance regarding the combination of DOAC with moderate or mild inhibitors of P-gp and CYP3A4. Published clinical studies to date provide conflicting data on the impact of these medications on outcomes and a recent systematic review highlighted the paucity of data. , We sought to investigate the frequency of co-prescription of DOACs with medications with potential interactions and its impact on outcomes in a large single-center cohort of AF patients treated with DOACs.
We identified all patients with AF prescribed a DOAC (apixaban, dabigatran, rivaroxaban, and edoxaban) for stroke prevention between January 1, 2010, and July 1, 2017, at the Mayo Clinic, Rochester, Minnesota. We first screened for patients with a prescription of DOAC and identified those with an AF/atrial flutter diagnosis by International Statistical Classification of Diseases (ICD) 9 and 10 codes (ICD-9 427.31, 427.32 and ICD-10 I48.0- I48.4, I48.91, I48.92) within 3 months of this prescription. Patients with a concurrent diagnosis of deep vein thrombosis or pulmonary embolism were excluded. Patients treated with edoxaban were excluded because of the small number (n = 17) of patients not allowing for definitive conclusions to be drawn. Demographic and clinical information were obtained from the electronic medical record. The prescribed dose of DOAC was examined to assess whether it adhered to current drug labeling in the United States, based on the patient’s renal function, age, and weight as previously published. Patients were then stratified as receiving a correct dose, off-label low dose, and off-label high dose. Co-prescribed medications that were either present at the time of the first DOAC prescription or newly prescribed at the time of DOAC initiation were identified. Medication classes of interest included non-dihydropyridine calcium channel blockers (diltiazem, verapamil), antiarrhythmics (amiodarone, dronedarone, and quinidine), selective serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs) (citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, duloxetine, venlafaxine, desvenlafaxine, levomilnacipran, milnacipran), immunosuppressants (cyclosporine), antifungals (fluconazole, itraconazole, ketoconazole), antibiotics (clarithromycin, erythromycin, rifampin), and antiepileptics (carbamazepine, phenytoin).
Outcomes of interest included (1) stroke, transient ischemic attack (TIA), or systemic embolism; (2) major bleeding events; (3) clinically significant nonmajor bleeding events; and (4) any bleeding event. Stroke, TIA, or systemic embolism was defined as clinical diagnosis by a physician on the basis of patient history, physical examination, and neuroimaging. To identify these outcomes of interest, we first screened all outcomes using relevant ICD 9 and 10 codes. This was followed by manual validation of all relevant outcomes through a review of the electronic medical records ( Supplementary Table 2 ). Major bleeding was defined according to the International Society on Thrombosis and Hemostasis. , A clinically relevant non–major bleed is an acute or subacute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least 1 of the following: hospital admission for bleeding, or a physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. All acute clinically overt bleeding events that did not meet the criteria for either major bleeding or clinically relevant non–major bleeding were classified as minor bleeding. Any bleeding was defined as a composite of major bleeding, clinically significant non–major bleeding, and minor bleeding .
Continuous variables are reported using mean ± SD or median, interquartile range as appropriate and compared using the Wilcoxon rank sum test. Categorical variables are presented as numbers (%) and compared using the chi-square test. The study period for each patient was defined by the start date of the DOAC until the date of the last follow-up. Variables associated with each outcome of interest were estimated using Cox proportional hazard ratios in univariate analysis. Variables found to be significant in univariate analysis (p <0.05) and some variables that were believed to be clinically relevant were also included in the multivariable Cox regression analysis. A p value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
The cohort consisted of 8,576 patients with AF (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran). At least 1 interacting medication was co-prescribed to 2,610 (30.4%) patients at the time of DOAC prescription. The median (range) number of co-prescribed medications was 1 (1 to 3). Approximately 2 and 3 interacting medications were prescribed to 314 (3.7%) and 25 (0.3%) patients, respectively.
Enzyme inhibitors formed the majority of co-prescribed medications, with enzyme inducers (rifampicin, phenytoin, and carbamazepine, n = 18) being rare. The baseline characteristics of the entire cohort and stratified by the presence of interacting medications are listed in Table 1 . Patients on an interacting medication were younger, more likely to be female, and were more likely to receive a lower dose of DOAC than indicated by the FDA labeling ( Table 1 ). Individual drugs prescribed are listed in Table 2 .
| Characteristic | Total (n = 8,576) | Interacting Medication | p Value | |
|---|---|---|---|---|
| Yes (n = 2,610) | No (n = 5,966) | |||
| Age (years) | 69.5 (11.9) | 68.4 (11.8) | 70.0 (11.9) | <0.001 |
| Women | 3,008 (35.1%) | 1,072 (41.1%) | 1,936 (32.5%) | <0.001 |
| White | 8,094 (94.4%) | 2,486 (95.2%) | 5,608 (94.0%) | 0.23 |
| Body-mass index (kg/m 2 ) | 30.4 (6.8) | 31.1 (7.3) | 30.1 (6.6) | <0.001 |
| CHA 2 DS 2 -VASc score | 3 (2–4) | 3 (2–4) | 3 (2–4) | 0.51 |
| ATRIA bleeding risk score | 2 (1–4) | 2 (1–4) | 2 (1–3) | 0.78 |
| Charlson co-morbidity index | 2 (1–4) | 2 (1–4) | 2 (1–4) | 0.49 |
| Diabetes mellitus | 2,091 (24.4%) | 671 (25.7%) | 1,420 (23.8%) | 0.06 |
| Hypertension | 5,811 (67.8%) | 1,799 (68.9%) | 4,012 (67.2%) | 0.13 |
| Hyperlipidemia * | 4,633 (54.0%) | 1,387 (53.1%) | 3,246 (54.4%) | 0.28 |
| Heart failure | 2,801 (32.7%) | 942 (36.1%) | 1,859 (31.2%) | <0.001 |
| Myocardial infarction | 1,026 (12.0%) | 290 (11.1%) | 736 (12.3%) | 0.11 |
| Peripheral vascular disease | 787 (9.2%) | 220 (8.4%) | 567 (9.5%) | 0.11 |
| Aortic atherosclerotic disease | 751 (8.8%) | 181 (6.9%) | 570 (9.6%) | <0.001 |
| Bio-prosthetic valve | 423 (4.9%) | 112 (4.3%) | 311 (5.2%) | 0.07 |
| Anemia | 1,051 (12.3%) | 300 (11.5%) | 751 (12.6%) | 0.16 |
| Serum creatinine (mg/100 ml) | 1.1 (0.4) | 1.1 (0.5) | 1.1 (0.4) | 0.10 |
| Glomerular filtration rate (ml/min) † | 84.8 (38.1) | 86.5 (41.3) | 84.0 (36.6) | 0.10 |
| Type of DOAC | <0.001 | |||
| Apixaban | 3,312 (38.6%) | 968 (37.1%) | 2,344 (39.3%) | |
| Dabigatran | 2,198 (25.6%) | 768 (29.4%) | 1,430 (24.0%) | |
| Rivaroxaban | 3,066 (35.8%) | 874 (33.5%) | 2,192 (36.7%) | |
| Off-label DOAC dose | <0.001 | |||
| Low DOAC dose | 1,071 (12.5%) | 392 (15.0%) | 679 (11.4%) | |
| High DOAC dose | 202 (2.4%) | 70 (2.7%) | 132 (2.2%) | |
⁎ Hyperlipidemia was identified using International Classification of Diseases 9 (272.0 to 272.4, 374.51) and 10 (E78, H02.61-66) diagnostic codes.
| Medication | Frequency n (%) |
|---|---|
| Non-dihydropyridine calcium channel blocker | 1,412 (16.5%) |
| Diltiazem | 1,288 (15.0%) |
| Verapamil | 124 (1.4%) |
| Antiarrhythmic drug | 790 (9.2%) |
| Amiodarone | 633 (7.4%) |
| Dronedarone | 156 (1.8%) |
| Quinidine | 1 (0.0%) |
| Selective serotonin reuptake inhibitor (SSRI) / serotonin nor-adrenaline reuptake inhibitor (SNRI) | 659 (7.7%) |
| Citalopram | 143 (1.7%) |
| Duloxetine | 115 (1.3%) |
| Fluoxetine | 99 (1.2%) |
| Escitalopram | 98 (1.1%) |
| Venlafaxine | 84 (1.0%) |
| Paroxetine | 78 (0.9%) |
| Sertraline | 27 (0.3%) |
| Desvenlafaxine | 13 (0.2%) |
| Milnacipran | 2 (0.0%) |
| Antibiotic / antifungal | 77 (0.9%) |
| Erythromycin | 14 (0.2%) |
| Clarithromycin | 4 (0.0%) |
| Rifampin | 1 (0.0%) |
| Ketoconazole | 40 (0.5%) |
| Fluconazole | 17 (0.2%) |
| Itraconazole | 1 (0.0%) |
| Immunosuppressant | |
| Cyclosporine | 19 (0.2%) |
| Antiepileptics | 17 (0.1%) |
| Phenytoin | 12 (0.1%) |
| Carbamazepine | 5 (0.0%) |
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