The application of lag times in cancer pharmacoepidemiology: a narrative review.

PURPOSE: With the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug-cancer associations. One methodology of importance in such studies is the application of lag times. METHODS: In this narrative review, we discuss the main reasons for using lag times. RESULTS: Namely, we discuss the typically long latency period of cancer concerning both tumor promoter and initiator effects and outline why cancer latency is a key consideration when choosing a lag time. We also discuss how the use of lag times can help reduce protopathic and detection bias. Finally, we present practical advice for implementing lag periods. CONCLUSIONS: In general, we recommend that researchers consider the information that generated the hypothesis as well as clinical and biological knowledge to inform lag period selection. In addition, given that latency periods are usually unknown, we also advocate that researchers examine multiple lag periods in sensitivity analyses as well as duration analyses and flexible modeling approaches.

Tranexamic acid use is not associated with the risk of melanoma in Danish women: A nested case-control study using Danish health registries.

BACKGROUND: Repurposing already approved drugs in a cancer setting has gained increasing interest in recent years. Tranexamic acid is an anti-fibrinolytic drug that has recently been suggested as an anti-cancer drug due to its anti-inflammatory and anti-carcinogenic effects in animal studies. In this study, we aimed to investigate the possible melanoma-preventive role of tranexamic acid in Danish women. METHOD: In this nested case-control study, we identified female cases 18-60 years with first-time melanoma during 2000-2015 and age-matched them with 10 female controls. The odds ratio (OR) of melanoma with tranexamic acid ever- or high use (≥ 100,000 mg) was estimated using conditional logistic regression. RESULTS: A total of 7986 women with incident melanoma were eligible for study inclusion and were matched to 79,860 controls. Most exposed cases and controls were exposed to low cumulative doses of tranexamic acid corresponding to around 5 days of continuous treatment (1000 mg 3 times daily) for the presumed main indication, i.e., menorrhagia. The crude OR associating tranexamic ever use with melanoma was 1.04 (95% CI 0.98-1.11, p = 0.20), and the adjusted OR was 1.03 (0.97-1.10, p = 0.32). We found no dose-response pattern or effect measure modification by age, histologic type, localization, or clinical stage. However, prolonged use with cumulative doses of tranexamic acid (≥ 100,000 mg) was associated with an increased risk of melanoma (adjusted OR 1.23,95 %, CI 0.96-1.56), compared with non-use. CONCLUSION: We found no association between tranexamic acid use and the risk of melanoma in Danish women. This could be explained by underlying dose- or biological factors, and sporadic use patterns. A higher risk of melanoma was seen among prolonged users which could be due to surveillance bias.

Development and Validation of a Nordic Multimorbidity Index Based on Hospital Diagnoses and Filled Prescriptions.

Purpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices. Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables. Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883-0.890) exceeded that of the CCI (0.871, 95% CI 0.868-0.874) and ECI (0.866, 95% CI 0.863-0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779-0.784) to 0.838 (95% CI 0.834-0.842). Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.

Identification of Drug-Cancer Associations: A Nationwide Screening Study.

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case-control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug-cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug-cancer pairs where an association with high use and a cumulative dose-response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies. Significance: This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.

Flecainide and risk of skin neoplasms: Results of a large nested case-control study in Spain and Denmark.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide. Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark. Methods: We conducted a multi-database case-control study in (database/study period) Spain (SIDIAP/2005-2017 and BIFAP/2007-2017) and Denmark (Danish registries/2001-2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose-response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities. Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38-2.81); NMSC: OR 1.34 (1.15-1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04-1.93); SIDIAP: OR 1.19 (0.95-1.48)]. There was a non-significant dose-response pattern for melanoma in Denmark and no apparent dose-response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide. Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose-response patterns. Further studies are needed to assess for possible unmeasured confounders.

Retinoids are not linked to risk of multiple sclerosis: A Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system with an undetermined etiology. Retinoids may have immunomodulatory effects that favorably influence MS progression. We aimed to explore the yet unknown relationship between exposure to retinoids and the risk of acquiring MS. METHODS: We performed a nationwide cohort study in the Danish population in the period 1998-2016, comparing MS incidence in three groups: users of systemic retinoids; users of topical retinoids (negative control group); and users of non-retinoid acne drugs (control group). We used data from the Danish Multiple Sclerosis Registry (DMSR), the Danish National Prescription Registry and the Danish National Patient Registry. Linkage was obtained through the personal identification number (CPR number). We addressed confounding by three-way propensity score (PS)-matching weights. Additionally, to evaluate a cumulative dose-response effect for systemic retinoids on MS incidence, we conducted a case-control study, nested within the cohort. RESULTS: A total of 257,193 users of non-retinoid acne drugs, 130,560 users of topical retinoids, and 75,610 users of systemic retinoids were included. Systemic retinoid use was not associated with a reduced risk of MS compared to non-retinoid acne drug use in crude (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61 to 1.05]) and weighted analyses (HR 0.89, 95% CI 0.67 to 1.20). There was no evidence of a cumulative dose-response association between systemic retinoids and MS incidence. CONCLUSIONS: Use of systemic retinoids was not associated with a reduced incidence of MS compared to use of non-retinoid acne drugs in this study.

Sodium-glucose cotransporter-2 inhibitors and the risk of gout: A Danish population based cohort study and symmetry analysis.

PURPOSE: Sodium-glucose cotransporter-2 inhibitors (SGLT2-I) are frequently used in type 2 diabetes and have recently been associated with lower rates of gout compared to glucagon-like peptide-1 receptor agonists (GLP1-RA). Our objective was to assess the association between SGLT2-I initiation and gout using a cohort study design and a symmetry analysis. METHODS: Using the Danish nationwide health registries, we conducted an active comparator, new user cohort study comparing the 3-year risk of gout among SGLT2-I users with propensity score matched GLP1-RA users. Individuals were followed according to the intention-to-treat, and incidence rate differences (IRD) and hazard ratios (HR) were obtained. To address unmeasured confounding that is stable over time, a corresponding symmetry analysis was performed. RESULTS: 11 047 pairs of SGLT2-I and GLP1-RA users were identified, contributing 42 201 person-years of follow-up. The incidence rate of gout was 4.1 and 7.0 events per 1000 person years among SGLT2-I and GLP1-RA users, yielding an IRD of -3.0 (95% confidence interval: -4.4 to -1.5) and HR of 0.58 (0.44 to 0.75). In the symmetry analysis, 80 individuals initiated SGLT2-Is prior to gout; 118 patients initiated treatment after gout. The trend adjusted SR was 0.63 (0.47 to 0.84) and the active comparator adjusted estimate was 0.67 (0.44 to 0.86). CONCLUSIONS: Initiation of SGLT2-Is was associated with a markedly decreased risk of gout compared to initiation of GLP1-RAs. The findings are comparable to prior studies addressing this association.

Use of ACE (Angiotensin-Converting Enzyme) Inhibitors and Risk of Lung Cancer: A Nationwide Nested Case-Control Study.

BACKGROUND: Use of angiotensin-converting enzyme inhibitors (ACEIs)was associated with increased risk of lung cancer in a cohort study from the United Kingdom. We aimed to replicate these findings in a Danish population. METHODS: We conducted a nested case-control study using data from 4 Danish national health and administrative registries. New users of ACEIs or angiotensin II receptor blockers in Denmark from January 1, 2000 were followed until December 31, 2015, incident lung cancer, death, or emigration. Each lung cancer case was matched with up to 20 controls on age, sex, duration of follow-up, and year of cohort entry using risk-set sampling. Conditional logistic regression was used to estimate odds ratios (ORs) for incident, histologically verified lung cancer with high use of ACEIs defined as a cumulative dose above 3650 defined daily doses. We examined different cumulative doses of ACEI (≤1800, 1801-3650, >3650 defined daily doses), examined whether the association varied with lung cancer histology, and repeated the analyses using thiazides as active comparator. RESULTS: We included 9652 lung cancer cases matched to 190 055 controls. High use of ACEIs was associated with lung cancer (adjusted OR, 1.33 [95% CI, 1.08-1.62]). Lower cumulative doses showed neutral associations (≤1800 defined daily doses OR, 1.01 [95% CI, 0.94-1.09]; 1801-3650 defined daily doses OR, 1.03 [95% CI, 0.90-1.19]). CIs were wide and included the null when stratifying on histology. Using thiazides as active comparator yielded comparable results (OR, 1.34 [95% CI, 0.96-1.88]). CONCLUSIONS: Use of high cumulative ACEI doses was associated with modestly increased odds of lung cancer although use of lower doses showed neutral associations. The established benefits of ACEIs should be considered when interpreting these findings.

Use of dipeptidyl peptidase-4 inhibitors and risk of splanchnic vein thrombosis: A Danish nationwide new-user active comparator cohort study.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors, on the basis of spontaneous adverse event reports, has recently been suspected of causing splanchnic vein thrombosis. Here, we report the results of a population-based new-user active comparator cohort study addressing this hypothesis, comparing DPP-4 inhibitor initiators (n = 75 042) with initiators of glucagon-like-peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose co-transporter-2 (SGLT2) inhibitors (n = 38 718). We estimated the hazard ratio (HR) associating DPP-4 inhibitor use with risk of splanchnic vein thrombosis using Cox regression. In a crude analysis, the incidence rate of splanchnic vein thrombosis was 0.22/1000 person-years among DPP-4 inhibitor initiators, compared to 0.17 among GLP-1RA/SGLT2 inhibitor initiators, corresponding to an unadjusted absolute incidence rate difference of 0.05 (95% confidence interval [CI] -0.04 to 0.14) and an HR of 1.29 (95% CI 0.78 to 2.15). Adjusting for potential confounders using stabilized inverse probability of treatment weighing, we obtained an absolute incidence rate difference of 0.03/1000 person-years (95% CI -0.07 to 0.14) and an HR of 1.18 (95% CI 0.62 to 2.26). No evidence of increased risk of splanchnic vein thrombosis was found in supplementary analyses, including an absence of any dose-response patterns. As such, we found no association between DPP-4 inhibitor use and splanchnic vein thrombosis risk.

Risk of Renal Cell Carcinoma Associated with Calcium Channel Blockers: A Nationwide Observational Study Focusing on Confounding by Indication.

BACKGROUND: We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC. METHODS: Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000-2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs). RESULTS: The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63-1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs. CONCLUSIONS: In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs.

Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: A Danish nationwide cohort study.

BACKGROUND: Concerns over the safety of non-steroidal anti-inflammatory drug (NSAID) use during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been raised. We studied whether use of NSAIDs was associated with adverse outcomes and mortality during SARS-CoV-2 infection. METHODS AND FINDINGS: We conducted a population-based cohort study using Danish administrative and health registries. We included individuals who tested positive for SARS-CoV-2 during the period 27 February 2020 to 29 April 2020. NSAID users (defined as individuals having filled a prescription for NSAIDs up to 30 days before the SARS-CoV-2 test) were matched to up to 4 non-users on calendar week of the test date and propensity scores based on age, sex, relevant comorbidities, and use of selected prescription drugs. The main outcome was 30-day mortality, and NSAID users were compared to non-users using risk ratios (RRs) and risk differences (RDs). Secondary outcomes included hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and acute renal replacement therapy. A total of 9,236 SARS-CoV-2 PCR-positive individuals were eligible for inclusion. The median age in the study cohort was 50 years, and 58% were female. Of these, 248 (2.7%) had filled a prescription for NSAIDs, and 535 (5.8%) died within 30 days. In the matched analyses, treatment with NSAIDs was not associated with 30-day mortality (RR 1.02, 95% CI 0.57 to 1.82, p = 0.95; RD 0.1%, 95% CI -3.5% to 3.7%, p = 0.95), risk of hospitalization (RR 1.16, 95% CI 0.87 to 1.53, p = 0.31; RD 3.3%, 95% CI -3.4% to 10%, p = 0.33), ICU admission (RR 1.04, 95% CI 0.54 to 2.02, p = 0.90; RD 0.2%, 95% CI -3.0% to 3.4%, p = 0.90), mechanical ventilation (RR 1.14, 95% CI 0.56 to 2.30, p = 0.72; RD 0.5%, 95% CI -2.5% to 3.6%, p = 0.73), or renal replacement therapy (RR 0.86, 95% CI 0.24 to 3.09, p = 0.81; RD -0.2%, 95% CI -2.0% to 1.6%, p = 0.81). The main limitations of the study are possible exposure misclassification, as not all individuals who fill an NSAID prescription use the drug continuously, and possible residual confounding by indication, as NSAIDs may generally be prescribed to healthier individuals due to their side effects, but on the other hand may also be prescribed for early symptoms of severe COVID-19. CONCLUSIONS: Use of NSAIDs was not associated with 30-day mortality, hospitalization, ICU admission, mechanical ventilation, or renal replacement therapy in Danish individuals who tested positive for SARS-CoV-2. TRIAL REGISTRATION: The European Union electronic Register of Post-Authorisation Studies EUPAS34734.

Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: a nationwide cohort.

BACKGROUND: Population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) is urgently needed to inform targeted protection strategies in the general population. METHODS: We examined characteristics and predictors of hospitalization and death in a nationwide cohort of all Danish individuals tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 27 February 2020 until 19 May 2020. RESULTS: We identified 11 122 SARS-CoV-2 polymerase chain reaction-positive cases of whom 80% were community-managed and 20% were hospitalized. Thirty-day all-cause mortality was 5.2%. Age was strongly associated with fatal disease {odds ratio [OR] 15 [95% confidence interval (CI): 9-26] for 70-79 years, increasing to OR 90 (95% CI: 50-162) for ≥90 years, when compared with cases aged 50-59 years and adjusted for sex and number of co-morbidities}. Similarly, the number of co-morbidities was associated with fatal disease [OR 5.2 (95% CI: 3.4-8.0), for cases with at least four co-morbidities vs no co-morbidities] and 79% of fatal cases had at least two co-morbidities. Most major chronic diseases were associated with hospitalization, with ORs ranging from 1.3-1.4 (e.g. stroke, ischaemic heart disease) to 2.6-3.4 (e.g. heart failure, hospital-diagnosed kidney disease, organ transplantation) and with mortality with ORs ranging from 1.1-1.3 (e.g. ischaemic heart disease, hypertension) to 2.5-3.2 (e.g. major psychiatric disorder, organ transplantation). In the absence of co-morbidities, mortality was <5% in persons aged ≤80 years. CONCLUSIONS: In this nationwide population-based COVID-19 study, increasing age and multimorbidity were strongly associated with hospitalization and death. In the absence of co-morbidities, the mortality was, however, <5% until the age of 80 years.

Existing Data Sources in Clinical Epidemiology: The Danish COVID-19 Cohort.

BACKGROUND: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. DATA STRUCTURE: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. CONCLUSION: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Association of Nonsteroidal Anti-inflammatory Drug Use and Adverse Outcomes Among Patients Hospitalized With Influenza.

Importance: During the ongoing coronavirus disease 2019 pandemic, case reports have suggested that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may lead to adverse outcomes. Objective: To study the association of NSAID use with adverse outcomes in patients hospitalized with influenza or influenza pneumonia. Design, Setting, and Participants: This cohort study used propensity score matching among 7747 individuals aged 40 years or older who were hospitalized with influenza, confirmed by polymerase chain reaction or antigen testing, between 2010 and 2018. Data were collected using Danish nationwide registers. All analyses reported were performed on May 29, 2020. Exposures: Prescription fill of an NSAID within 60 days before admission. Main Outcomes and Measures: Risk ratio (RR) and risk difference (RD) with 95% CIs for intensive care unit admission and death within 30 days of admission. Results: A total of 7747 patients (median [interquartile range] age, 71 [59-80] years, 3980 [51.4%] men) with confirmed influenza were identified. Of these, 520 (6.7%) were exposed to NSAIDs. In the unmatched cohorts, 104 of 520 patients (20.0%) who used NSAIDs and 958 of 7227 patients (13.3%) who did not use NSAIDs were admitted to the intensive care unit. For death within 30 days of admission, we observed 37 events (7.1%) among those who used NSAIDs compared with 563 events (7.8%) among those who did not. Current NSAID use was associated with intensive care unit admission (RR, 1.51; 95% CI, 1.26 to 1.81; RD, 6.7%; 95% CI, 3.2% to 10.3%), while NSAID use was not associated with death (RR, 0.91; 95% CI, 0.66 to 1.26; RD, -0.7%; 95% CI, -3.0% to 1.6%). In the matched cohorts, risks were unchanged for patients who used NSAIDs, while 83 ICU admissions (16.0%) and 36 deaths (6.9%) were observed among matched individuals who did not use NSAIDs. Matched (ie, adjusted) analyses yielded attenuated risk estimates for intensive care unit admission (RR, 1.25; 95% CI, 0.95 to 1.63; RD, 4.0%; 95% CI, -0.6% to 8.7%) and death (RR, 1.03; 95% CI, 0.66 to 1.60; RD, 0.2%; 95% CI, -2.9% to 3.3%). Associations were more pronounced among patients who used NSAIDs for a longer period (eg, for intensive care unit admission: RR, 1.90; 95% CI, 1.19 to 3.06; RD, 13.4%; 95% CI, 4.0% to 22.8%). Conclusions and Relevance: In this cohort study of adult patients hospitalized with influenza, the use of NSAIDs was not associated with 30-day intensive care unit admission or death in adjusted analyses. There was an association between long-term use of NSAIDs and intensive care unit admission.

Ischemic Stroke and Systemic Embolism in Warfarin Users With Atrial Fibrillation or Heart Valve Replacement Exposed to Dicloxacillin or Flucloxacillin.

The antibiotics dicloxacillin and flucloxacillin induce cytochrome P450-dependent metabolism of warfarin. We explored the influence of these drug-drug interactions on the clinical effectiveness of warfarin therapy due to atrial fibrillation or heart valve replacement. Using the population-based Danish registers, we performed a propensity-score matched cohort study including around 50,000 episodes of dicloxacillin/flucloxacillin matched to phenoxymethylpenicillin and to no antibiotic, respectively. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) by comparing 21-day (days 7-28) risks of ischemic stroke/systemic embolism (SE) following initiation of each exposure. When compared with phenoxymethylpenicillin, dicloxacillin/flucloxacillin was associated with an HR of ischemic stroke/SE of 2.09 (95% CI 1.51-2.90; strongest for dicloxacillin (HR 2.17; 95% CI 1.56-3.02)). Use of an untreated comparator strengthened the association (HR 2.84; 95% CI 1.97-4.09). Dicloxacillin should be used with caution in patients receiving warfarin. This may also apply to flucloxacillin; however, more data on the risks associated with flucloxacillin exposure during warfarin therapy are needed.

Use of antiepileptic drugs and risk of skin cancer: A nationwide case-control study.

BACKGROUND: Several antiepileptic drugs are photosensitizing; however, it is not known whether this confers an increased risk of skin cancer. OBJECTIVE: To examine the association between common antiepileptic drugs and basal cell carcinoma, squamous cell carcinoma (SCC), and malignant melanoma. METHODS: We conducted a nested case-control study identifying skin cancer patients in Denmark from 2004 through 2015 matched 1:10 with disease-free controls. We estimated odds ratios (ORs) for skin cancer associated with high cumulative use of antiepileptic drugs (≥500 defined daily doses) compared with nonuse. RESULTS: Most antiepileptic drugs were not associated with skin cancer. SCC was associated with use of carbamazepine (OR, 1.88; 95% confidence interval, 1.42-2.49) and lamotrigine (OR, 1.57; 95% confidence interval, 1.12-2.22) with evidence of a dose-response relationship for carbamazepine. The estimated absolute risks were low; for example, 6335 person-years of high cumulative exposure to carbamazepine were required for 1 additional SCC to occur. LIMITATIONS: Data on important risk factors for skin cancer, such as sun exposure, were not available. CONCLUSIONS: Most antiepileptic drugs were not associated with skin cancer; however, carbamazepine and lamotrigine were associated with SCC. These findings need to be replicated and characterized further in other settings and have no direct clinical implications.

Discontinuation of therapy among COPD patients who experience an improvement in exacerbation status.

PURPOSE: A subset of patients with chronic obstructive pulmonary disease (COPD) experience a decrease in exacerbation frequency, leading to a diminished need for treatment with inhaled corticosteroids (ICS). We investigated prescribing and discontinuation patterns of long-acting bronchodilators and ICS in COPD patients according to exacerbation frequency. METHODS: Using the nationwide Danish health registries, we conducted a drug utilization study among patients who had at least two exacerbations or one hospitalization due to an exacerbation during 2011-2012. This study population was stratified according to consistency of exacerbation occurrence after 12, 24, 36, and 48 months of follow-up and the groups were described according to use of ICS, long-acting ß2-agonists (LABA), and long-acting anticholinergics (LAMA), and combinations thereof. RESULTS: We identified 29,010 COPD exacerbators during 2011-2012. Upon inclusion, 70% received ICS-containing regimens, in combination with LABA (23%) or both LABA and LAMA (41%). The proportion of prevalent users of ICS-containing regimens decreased to 56% during follow-up among exacerbation-free individuals, while it increased to 86% in individuals who experienced at least one exacerbation annually. Persistence to ICS-containing regimens was 58% after 4 years in individuals without exacerbations compared to 74% among those with annual exacerbations. Similar patterns were observed for triple therapy which was the most extensively used drug combination regardless of consistency of exacerbation occurrence. CONCLUSIONS: The extensive use of ICS and the relatively high persistence to ICS-containing regimens in individuals who had a decrease in exacerbation occurrence highlight a need for the development and implementation of de-escalation strategies in clinical practice.

Nonaspirin Nonsteroidal Antiinflammatory Drug Use in the Nordic Countries from a Cardiovascular Risk Perspective, 2000-2016: A Drug Utilization Study.

STUDY OBJECTIVE: Evidence on the cardiotoxicity of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), particularly diclofenac and the newer selective cyclooxygenase (COX)-2 inhibitors, has accumulated over the last decade. Our objective was to examine whether the use of NSAIDs in the Nordic countries changed with the emerging evidence, regulatory statements, and clinical guidelines advocating caution for the use of specific NSAIDs. DESIGN: Drug utilization study. DATA SOURCES: Nationwide wholesale statistics and prescription registries in Denmark, Finland, Iceland, Norway, and Sweden (2000-2016). MEASUREMENTS AND MAIN RESULTS: Our main outcome measures were yearly total sales, expressed as number of sold defined daily doses (DDDs)/1000 inhabitants/day, and yearly prevalence of prescription use, expressed as number of prescription users per 1000 inhabitants. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. Total sales of NSAIDs increased in all countries and were highest in Iceland, with 74.3 DDDs/1000 inhabitants/day sold in 2016, followed by Finland (73.9), Sweden (54.4), Norway (43.8), and Denmark (31.8). Diclofenac use declined after 2008 in all countries but remained the most widely prescribed NSAID in Norway, with 63 prescription users/1000 inhabitants in 2016. Diclofenac sales also remained high in Iceland (12.7 DDD/1000 inhabitants/day), Norway (8.1), and Sweden (7.8). Since its introduction in 2003, the use of etoricoxib, a newer selective COX-2 inhibitor, increased in all countries except Denmark, with highest sales in Finland (6.7 DDD/1000 inhabitants/day in 2016). CONCLUSION: Sales and prescription patterns of NSAIDs in the Nordic countries has changed along with the accumulating evidence for the cardiovascular risks of specific NSAIDs. However, given existing evidence on the cardiovascular risks associated with the use of diclofenac and etoricoxib, the persistent high use of diclofenac in Iceland, Norway, and Sweden, the persistent over-the-counter availability of diclofenac in Norway and Sweden, and the increasing use of etoricoxib in most of the Nordic countries pose a cardiovascular health concern.