Maja Hellfritzsch

Association of Antithrombotic Drug Use With Subdural Hematoma Risk

Importance Incidence of subdural hematoma has been reported to be increasing. To what extent this is related to increasing use of antithrombotic drugs is unknown. Objectives To estimate the association between use of antithrombotic drugs and subdural hematoma risk and determine trends in subdural hematoma incidence and antithrombotic drug use in the general population. Design, Setting, and Participants Case-control study of 10 010 patients aged 20 to 89 years with a first-ever subdural hematoma principal discharge diagnosis from 2000 to 2015 matched by age, sex, and calendar year to 400 380 individuals from the general population (controls). Subdural hematoma incidence and antithrombotic drug use was identified using population-based regional data (population: 484 346) and national data (population: 5.2 million) from Denmark. Conditional logistic regression models were used to estimate odds ratios (ORs) that were adjusted for comorbidity, education level, and income level. Exposures Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), a direct oral anticoagulant, and combined antithrombotic drug treatment. Main Outcomes and Measures Association of subdural hematoma with antithrombotic drug use, subdural hematoma incidence rate, and annual prevalence of treatment with antithrombotic drugs. Results Among 10 010 patients with subdural hematoma (mean age, 69.2 years; 3462 women [34.6%]), 47.3% were taking antithrombotic medications. Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15-1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57-2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31-2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38-4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40-4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49-14.02]). The prevalence of antithrombotic drug use increased from 31.0 per 1000 individuals from the general population in 2000 to 76.9 per 1000 individuals in 2015 (P < .001 for trend). The overall subdural hematoma incidence rate increased from 10.9 per 100 000 person-years in 2000 to 19.0 per 100 000 person-years in 2015 (P < .001 for trend). The largest increase was among older patients (>75 years; n = 4441) who experienced an increase from 55.1 per 100 000 person-years to 99.7 per 100 000 person-years (P < .001 for trend). Conclusions and Relevance In Denmark, antithrombotic drug use was associated with higher risk of subdural hematoma; and the highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug. The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.

Treatment Changes among Users of Non‐Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation

Patients with atrial fibrillation discontinuing anticoagulant therapy are left unprotected against ischaemic stroke. Further, switching between oral anticoagulants may be associated with a transiently increased risk of bleeding or thromboembolism. However, there is a paucity of real‐life data on pattern of switching and discontinuation of oral anticoagulants. To address this, we conducted a nationwide drug utilization study including all registered Danish atrial fibrillation patients initiating a non‐VKA oral anticoagulant (NOAC) between August 2011 and February 2016. We assessed changes in anticoagulant treatment, including switching between oral anticoagulants and discontinuation of NOACs, and explored patient characteristics predicting these changes. We identified 50,632 patients with atrial fibrillation initiating NOAC therapy within the study period. The majority initiated dabigatran (49.9%) and one‐third had previously used VKA. Within 1 year, 10.1% switched to VKA, 4.8% switched to another NOAC and 14.4% discontinued treatment. The frequencies of switching to VKA and discontinuation were highest among NOAC users of young age (<55 years) and with low CHA2DS2‐VASc score (=0). However, the majority of patients (87.3%) stopping NOAC treatment had a CHA2DS2‐VASc score ≥1. We conclude that switching from VKA to NOAC, and to a lesser extent from NOAC to VKA, is common, as is early treatment discontinuation. The majority of treatment changes are observed in patients at increased risk of stroke. More research is warranted on the risks of bleeding and thromboembolism associated with switching and discontinuation of NOACs as well as the underlying reasons why these treatment changes occur.

Generic switching of warfarin and risk of excessive anticoagulation: a Danish nationwide cohort study

Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis.

Odense Pharmacoepidemiological Database (OPED): A Review of Use and Content

The Odense University Pharmacoepidemiological Database (OPED) is a prescription database established in 1990 by the University of Southern Denmark, covering reimbursed prescriptions from the county of Funen in Denmark and the region of Southern Denmark (1.2 million inhabitants). It is still active and thereby has more than 25 years of continuous coverage. In this MiniReview, we review its history, content, quality, coverage, governance and some of its uses. OPEDs data include the Danish Civil Registration Number (CPR), which enables unambiguous linkage with virtually all other health-related registers in Denmark. Among its research uses, we review record linkage studies of drug effects, advanced drug utilization studies, some examples of method development and use of OPED as sampling frame to recruit patients for field studies or clinical trials. With the advent of other, more comprehensive sources of prescription data in Denmark, OPED may still play a role as in certain data-intensive regional studies.

Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation

Abstract Aims Switching between oral anticoagulants and treatment discontinuation are common events related to therapy with non-vitamin K antagonist oral anticoagulants (NOACs). However, knowledge on the reasons leading to these treatment changes is scarce. The aim of this study was to identify clinical events preceding anticoagulant switching and NOAC discontinuation during oral anticoagulant therapy in patients with atrial fibrillation. Methods and results We performed a nationwide register-based study including Danish atrial fibrillation patients initiating a NOAC between August 2011 and February 2016 (n = 50 623). We explored potential reasons leading to changes in anticoagulant treatment by identifying clinical events preceding switches from vitamin K antagonists (VKA) to NOAC, switches from NOAC to VKA, and discontinuations of NOACs. Among 23 531 anticoagulant users changing treatment, we identified 13 295 switches from VKA to NOAC, 5206 switches from NOAC to VKA, and 8995 discontinuations of NOACs. Approximately half of all treatment changes were preceded by a hospitalization. A relevant specific clinical event or procedure was identified prior to 18.3% of switches from VKA to NOAC, prior to 23.0% of switches from NOAC to VKA, and prior to 26.6% of discontinuations. Switches from VKA to NOAC were most often preceded by thromboembolic events (7.0%), whereas cardioversion was the most common specific event prior to a switch from NOAC to VKA (11.4%). Discontinuations were most often preceded by bleeding events (7.6%). Conclusion For about one in five patients, treatment changes during anticoagulant therapy were preceded by a major clinical event. However, the majority of patients changed treatment for reasons not recorded in health registries.

Statin-associated rhabdomyolysis triggered by drug–drug interaction with itraconazole

A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug–drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins—simvastatin, atorvastatin and lovastatin—are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment.

Use of direct oral anticoagulants in the first year after market entry of edoxaban: A Danish nationwide drug utilization study

To describe the early uptake of edoxaban; the fourth direct oral anticoagulant (DOAC) to enter the market.

Topical Antimycotics for Oral Candidiasis in Warfarin Users

Treatment for oral candidiasis in warfarin users may be complicated by drug–drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross‐over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998–2012 (n ≈ 7400). We collected data on cohort members’ measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1–2.8) to 3.8 (95% CI: 2.8–4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3–2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3–3.1) before and 2.5 (95% CI: 2.2–2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug–drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.

Switching, Adverse Effects and Use of Over-the-Counter Analgesics among Users of Oral Anticoagulants: A Pharmacy-based Survey

Oral anticoagulants are widely used but information on important aspects in that respect is not available from medical registers or clinical databases. Therefore, we conducted a survey including patients filling a prescription for oral anticoagulants at two large Danish community pharmacies. We collected information concerning the patients’ knowledge of their anticoagulant treatment including prior drug switching. Further, patients were asked about use of over‐the‐counter analgesics, adverse effects and how the treatment affected their everyday life. Among 335 eligible patients, 301 (90%) agreed to participate. Atrial fibrillation was the most common indication (65%), and most patients filled a prescription for a non‐vitamin K antagonist oral anticoagulant (NOAC) (58%). Among the 12% (n = 35) of participants who had switched oral anticoagulant treatment, 69% had switched from a vitamin K antagonist (VKA) to a NOAC. Switching was most frequently caused by inconvenience (34%) and adverse effects (23%). Although half of all patients had recently bought over‐the‐counter analgesics, purchase of ibuprofen and aspirin was rare (6%). More VKA users than NOAC users felt limited in their everyday life because of anticoagulant treatment (18% versus 9%). Among non‐incident NOAC users, 21% had experienced adverse effects during their current treatment. Based on first‐hand information from a large sample of anticoagulant users, we conclude that the main drug‐related issues leading to anticoagulant switching and perceived limitations in everyday life were inconvenience and adverse effects. This varied between drug groups. Further, use of NSAIDs obtained over the counter was rare.

Inconsistencies in reporting of renal elimination among NOACs: the case of apixaban.

Dear Sir, We would like to discuss an apparent lack of consistency in the reporting of renal elimination data for non-vitamin K antagonist oral anticoagulants (NOACs) and potential clinical consequences with special reference to apixaban. Four NOACs are currently approved: dabigatran, rivaroxaban, apixaban, and edoxaban. For the principal clinical indications, non-valvular atrial fibrillation, and venous thromboembolism (VTE), all NOACs have demonstrated at least non-inferiority with respect to efficacy and adverse reaction profile compared with warfarin.1,2 Choosing the most appropriate NOAC depends on individual patient factors, among which renal function is of particular clinical relevance, because patients with renal insufficiency have an increased risk of thrombosis and bleeding.3,4 When assessing the safety profile of NOACs in patients with impaired renal function, knowledge of renal clearance is crucial. However, as the renal clearance can be reported as the percentage excreted through the kidneys of either (a) intravenously administered drug or (b) absorbed drug after oral intake, differences may occur when reporting this measure. Currently, there is no specific guidance from regulatory authorities on how renal clearance should be reported, as part of either total clearance, apparent oral clearance, or absolute clearance.5,6 Consequently, the reporting of renal elimination of NOACs is inconsistent and nontransparent (Table 1). To illustrate the issue, consider apixaban, which is approved for use in patients with creatinine clearance (CrCl) ≥15mL/min7,8. The Summary of Product Characteristics (SmPC) states that “renal excretion of apixaban is about 27% of total clearance.”7,8 This likely reflects the results from intravenous phase I trials presented as conference abstracts in 2008 and 2009, but without subsequent peer-review and publication.9,10 However, in the scientific literature, renal clearance of apixaban is usually referenced from a peer-reviewed mass balance study by the marketing authorization holder, stating that 22–24% of the orally ingested apixaban dose was recovered unchanged in the urine.11 Because bioavailability is about 50%, use of this reference to assess the renal contribution to elimination of systemically available apixaban may result in erroneously high estimates (44–48%). Overall, we do not believe the available data fully clarify the extent of renal elimination of apixaban after oral administration. Exploring the clinical pharmacology of apixaban in renally impaired patients further, the SmPC states that the area under the plasma concentration–time curve (AUC) is increased by 29% and 44% in patients with moderate (CrCl 30–50mL/min) and severe (CrCl 15–29mL/min) renal impairment, respectively7,8. These data are, however, based on single-dose studies in very few patients (N=7+7), with high inter-individual variability in AUC Measurements12. During continuous treatment with apixaban 5mg twice daily in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial Aristotle, patients with moderate renal impairment demonstrated an even higher AUC increase (38%).12 Although treatment with apixaban was associated with a lower risk of major bleeding compared with warfarin in clinical trials,1,2,13 patients with impaired renal function had the highest rates of major bleedings on apixaban, despite only moderate AUC increases in pharmacokinetic studies. In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy trial “(AMPLIFY)”, patients in the apixaban arm with CrCl≤50mL/min had a hazard ratio of major bleeding of 6.5 (95%CI 2.2–19) compared with patients with CrCl>50mL/min (rates for major bleeding: 2.9% [5/175] vs. 0.4% [10/2270]).3 Similarly, major bleeding rates in the treatment arm receiving 5mg apixaban twice daily in the Apixaban after the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy — Extended treatment trial “(AMPLIFY-EXT)” were 14.0% (6/43) in