Comparison of Rheumatoid Arthritis Information Recorded in UK CPRD Aurum and CPRD GOLD Databases (Companion Paper 3).

Purpose: To report distribution of codes associated with a rheumatoid arthritis (RA) diagnosis recorded in Clinical Practice Research Datalink (CPRD) Aurum compared to the previously validated CPRD GOLD database as a critical step toward making decisions about CPRD Aurum's suitability for medical research. Patients and Methods: We analyzed the distribution of codes for RA diagnoses, labs, and treatments in the new CPRD Aurum database, compared to the CPRD GOLD database by selecting relevant indicators of RA diagnosis, treatment, and clinical care. We included all patients in England in CPRD Aurum and CPRD GOLD with an incident diagnosis code for RA on or after 1 January 2005 and at least two years recorded data before first RA diagnosis. Results: We found 53,083 and 18,167 patients with a new diagnosis code for RA in CPRD Aurum and CPRD GOLD, respectively. In both databases approximately 67% were female with similar mean ages at first diagnosis. There were few differences in RA-related recording patterns between the two data sources. Before first RA diagnosis, CPRD Aurum patients had more RA-specific labs and other supporting clinical codes. After diagnosis, CPRD Aurum patients had more RA diagnoses coded and more often had 10+ general RA labs than patients in CPRD GOLD. More CPRD GOLD patients had 10+ prescriptions for conventional disease-modifying antirheumatic drugs (cDMARD) compared to CPRD Aurum. Otherwise, the distribution of drugs used to treat RA was similar between databases. The standardized incidence of RA was similar between databases. Conclusion: Overall, among patients with a diagnosis code for RA, recording of diagnoses, prescription drugs, and labs were similar between CPRD Aurum and CPRD GOLD. Slight differences were found for a few variables, but overall, we found consistency between the databases. In addition, standardized incidence of RA was similar between databases.

Use of the CPRD Aurum Database: Insights Gained from New Data Quality Assessments.

Ongoing evaluation of any electronic health data source is critical to assess suitability for its use in medical research. In addition, familiarity with a data source's history and recording practices is important for making informed data source selection, study design choices, and interpretation of results. In this commentary, the authors discuss three studies that assessed different aspects of the quality and completeness of information contained in Clinical Practice Research Datalink (CPRD) Aurum compared to the well-established CPRD GOLD and to other linked data sources, with the aim to describe insights gained through these data quality assessments. Our findings support the view that CPRD Aurum and GOLD are both valuable tools for studies based on information recorded in primary care but should not be used without critical consideration of strengths and limitations. Further, use of linked data should be considered for some studies, after taking into account all relevant factors.

Correctness and Completeness of Breast Cancer Diagnoses Recorded in UK CPRD Aurum and CPRD GOLD Databases: Comparison to Hospital Episode Statistics and Cancer Registry (Companion Paper 2).

Purpose: To evaluate the new Clinical Practice Research Datalink (CPRD) Aurum database, we estimated 'correctness' (ie accuracy, validity) and 'completeness' (ie presence, missingness) of malignant breast cancer diagnoses recorded in CPRD Aurum compared to external linked data sources: Hospital Episode Statistics (HES) Admitted Patient Care (APC), HES Outpatient (OP), and Cancer Registry (CR), and to the previously validated CPRD GOLD. Methods: Linkage-eligible, female patients with incident malignant breast cancer diagnosis recorded in at least one study data source were selected. Correctness was the proportion of malignant breast cancer cases recorded in CPRD Aurum or GOLD who also had a diagnosis recorded in HES APC/OP (2004-2019) or CR (2004-2016). Completeness was estimated by identifying all malignant breast cancer diagnoses in HES APC/OP or CR and calculating the proportion with a concordant diagnosis in CPRD Aurum or GOLD. Results: Compared to HES APC/OP, there were 85,659 and 31,452 eligible patients in CPRD Aurum and GOLD, respectively. Correctness estimates were high (CPRD Aurum 83.5%, GOLD 81.7%). Compared to CR, there were 70,190 and 29,597 eligible patients in CPRD Aurum and GOLD, respectively: correctness was 89.1% for CPRD Aurum and 88.2% for GOLD. Completeness estimates for CPRD Aurum and GOLD were high (>90%). Diagnoses were recorded in CPRD Aurum within -7 to 74 days of those in the linked sources. Reasons for discordant diagnostic coding included presence of treatment or other clinical codes only, diagnosis coded after end of follow-up, non-malignant breast cancer in linked data, and administrative codes in lieu of diagnostic codes. Conclusion: These results indicate that correctness and completeness of malignant breast cancer diagnoses in CPRD Aurum were high and similar to CPRD GOLD. This provides confidence in use of CPRD Aurum for research purposes. Where complete case capture is important, researchers should consider linkage to HES APC or CR.

Presence of Breast Cancer Information Recorded in United Kingdom Primary Care Databases: Comparison of CPRD Aurum and CPRD GOLD (Companion Paper 1).

Purpose: To evaluate the presence of data elements related to diagnosis and treatment of malignant breast cancer in CPRD Aurum compared to those in the previously validated CPRD GOLD. Methods: Females in CPRD Aurum or GOLD with a first-time code for malignant breast cancer, mastectomy, or ≥1 prescription for tamoxifen or aromatase inhibitors (2004-2019) were selected. We compared the presence of the codes for breast cancer diagnosis, surgeries (mastectomy, lumpectomy), tamoxifen and aromatase inhibitor prescriptions, radiation, chemotherapy, and supporting clinical codes (suspected breast cancer, lump symptoms, biopsy, lumpectomy, cancer care, referral/visit to specialist, palliative care). Age standardized incidence rates of breast cancer diagnosis in CPRD Aurum and GOLD were calculated. Results: There were 131,936 eligible patients in CPRD Aurum and 69,102 patients in GOLD. A similar proportion of patients in CPRD Aurum and GOLD had codes for breast cancer diagnosis, mastectomy, drug prescriptions, lump, biopsy, lumpectomy, chemotherapy, and cancer and palliative care coded in their electronic record during follow-up. However, suspected breast cancer, radiation, and referral/visits to specialists were coded more frequently in patients in CPRD Aurum compared to GOLD. Age-standardized incidence rates were similar for CPRD Aurum and GOLD. Conclusion: Overall, there was consistency between data elements related to malignant breast cancer recorded in CPRD Aurum and GOLD, particularly for the most informative clinical details. These findings provide reassurance that breast cancer information recorded in CPRD Aurum is generally comparable to that recorded in the previously validated CPRD GOLD and support the use of CPRD Aurum for breast cancer research.

Pharmacologically Treated Anxiety and Depression in People Diagnosed with von Willebrand Disease: Matched Cohort Study.

Background: People diagnosed with von Willebrand disease (VWD) have reduced quality of life versus the general population, and there is limited evidence of increased rates of anxiety and/or depression among people diagnosed with VWD. Aim: To understand the association between VWD and mental health outcomes. Design and Setting: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) GOLD database (1988-2016). Methods: People diagnosed with VWD were matched 1:10 to randomly selected people in the database without VWD based on sex, birth year ±2 years, CPRD record start year ±2 years, and general practice attended. Individuals were followed from VWD diagnosis or match date to censoring (first event date, CPRD end date, or death). Treated anxiety and treated depression were identified by a diagnostic Read Code and a prescription for anxiety/depression medication recorded within 90 days of each other, after VWD diagnosis/match date. Results: Treated anxiety was recorded in 89 of 1119 (8.0%) people diagnosed with VWD and 624 of 10,423 (6.0%) without VWD (age- and sex-adjusted incidence rate ratio [IRR], 1.37; 95% confidence interval [CI], 1.10-1.71). Treated depression was recorded in 119 of 1083 (11.0%) people diagnosed with VWD and 846 of 9845 (8.6%) without VWD (adjusted IRR, 1.35; 95% CI, 1.11-1.63). Females aged 20-39 and 0-19 years were at greatest risk for treated anxiety and treated depression, respectively. Conclusion: Higher rates of treated anxiety and depression were observed among people diagnosed with versus without VWD, predominantly in young females.

Quality of rheumatoid arthritis recording in United Kingdom Clinical Practice Research Datalink Aurum.

PURPOSE: While several studies have assessed quality and completeness of recording acute medical events in Clinical Practice Research Datalink (CPRD) Aurum, evaluation of additional chronic conditions is warranted. METHODS: We selected patients with a first diagnosis of rheumatoid arthritis (RA) coded in their CPRD Aurum record between 2005 and 2019. We assessed quality of RA diagnosis by evaluating additional information in the patient record that would corroborate the diagnosis. We report recording of diagnoses, prescriptions, labs, and referrals expected to be present based on NICE guidelines for RA management. RESULTS: There were 53 083 patients with a first recorded RA diagnosis during the study period: 43606 (82%) patients had RA drug treatments in their record, 7596 (14%) had supporting codes without drug treatment, and 1881 (4%) patients had only a RA diagnoses recorded in their medical record with no supporting codes or RA treatments. Patients with RA diagnosis only were more likely to be first diagnosed in the earliest time period of study. Labs for diagnosing and monitoring RA were most common among patients with RA treatment. Analgesic and glucocorticoid prescriptions were common in all study patients but were highest among patients with RA treatment. Among patients with RA diagnosis only, the overwhelming majority had only one RA diagnosis recorded (76%). CONCLUSIONS: Our findings suggest that codes expected for monitoring and treatment of RA are routinely recorded in CPRD Aurum. These results support previous assessments, which found data recorded in CPRD Aurum to be of good quality for use in research.

Impact of von Willebrand Disease on Women's Health Outcomes: A Matched Cohort Database Study.

Objective: To understand the impact of von Willebrand disease (VWD) on women's health, a retrospective cohort study was conducted using UK Clinical Practice Research Datalink (CPRD) GOLD database and Hospital Episode Statistics (HES) Admitted Patient Care data from 1988 to 2016. Materials and Methods: Hysterectomy and heavy menstrual bleeding (HMB) events were identified by recorded disease/clinical codes and compared in women with and without VWD (matched 1:10 by birth and CPRD record start years [±2 years], and general practice attended). Incidence rates and incidence rate ratios (IRR) were calculated; risks were estimated using the Kaplan-Meier method. Results: HMB was recorded after cohort entry in 388 of 1,335 women (29.1%) with VWD and 1,524 of 12,463 women (12.2%) without VWD. The cumulative incidence of HMB was higher in women with versus without VWD across all ages (p < 0.0001), and irrespective of prior HMB status (p < 0.001). Women with VWD were more likely to have HMB compared with women without VWD; IRR adjusted for age and prior HMB status was 2.74 (95% confidence interval [CI]: 2.44-3.07). Hysterectomy was recorded in 88 of 1,374 women (6.4%) with VWD and 320 of 12,791 women (2.5%) without VWD. The cumulative incidence of hysterectomy was higher for women with versus without VWD (p < 0.0001), and highest among women aged ≥30 years at cohort entry. Women with VWD aged 30 - 39 years were more likely to undergo hysterectomy than women without VWD; IRR adjusted for prior HMB was 3.58 (95% CI: 2.36 - 5.44). Conclusions: These findings highlight the substantial impact of VWD on women's health.

Presence of Codes for Indication for Use in Clinical Practice Research Datalink Aurum: An Assessment of Benign Prostatic Hyperplasia Treatments.

Background: Assessments of strengths and limitations of new data sources are critical for making decisions about suitability for specific research questions. For some studies, it is necessary to capture a drug's indication for use. Objective: To assess the presence of indications for prescription use in Clinical Practice Research Datalink (CPRD) Aurum (January 1988-June 2021) by describing the proportion of men in CPRD Aurum who had a recorded indication for use of prescriptions for 5-alpha reductase inhibitors (5-ARI), alpha blockers (AB), or tadalafil, which have multiple indications. Methods: From a random sample of 154 practices of CPRD Aurum data, we selected 85,597 male patients with a prescription for a 5-ARI, an AB, or tadalafil. Among these patients, we described presence of codes indicating whether the patient had benign prostatic hyperplasia, hypertension, erectile dysfunction, or alopecia using three indication definitions: narrow (specific diagnoses recorded within one year before and up to 90 days after the prescription), broad (specific diagnoses or supporting clinical codes in the time period described above), and widest (diagnoses or supporting codes recorded at any time before the prescription and up to 90 days after the prescription). Results: Using the narrow indication definition limited to diagnoses only, 39,861 (46.6%) patients' records contained an indication for use. The broad definitions, which additionally included supporting codes, captured indications for 62,912 (73.5%) patients and the widest definition, which additionally included supporting codes and all available data before the first prescription date, captured indications for 71,478 (83.5%) patients. Indications were present more often for prescriptions in 2005 and later (85.9%). Conclusion: The findings of this assessment suggest that CPRD Aurum can be used for studies that require information on treatment indications for BPH and potentially for treatments of other chronic diseases managed in the primary care setting.

Quality and Completeness of Myocardial Infarction Recording in Clinical Practice Research Datalink Aurum.

BACKGROUND: Validation studies of the Clinical Practice Research Datalink (CPRD) Aurum database in the UK are critical for making decisions about its suitability and validity for research purposes. OBJECTIVE: To examine data source agreement of myocardial infarction (MI) diagnoses recorded in CPRD Aurum compared with linked Hospital Episode Statistics (HES) data. This comparison provides information on CPRD Aurum data correctness (accuracy, validity) and completeness (presence, missingness). METHODS: Patients with MI diagnoses recorded in either data source were selected from a random sample of 50,000 patients in CPRD Aurum with HES linkage (1997-2017). Correctness was defined as the proportion of MI cases in CPRD Aurum with a concordant MI diagnosis recorded in HES or with strong supporting evidence in either data source. Completeness was defined as the proportion of patients with primary HES-coded MIs with strong supporting evidence that were also present in CPRD Aurum. RESULTS: There were 1260 patients with MI recorded in the CPRD Aurum sample. The overall correctness of the recorded MI diagnoses was 94%: 986 patients (78%) had concordant diagnoses in HES within 90 days; 123 (10%) were concordant with HES, but with an inconclusive date and another 71 (6%) had strong supporting evidence for being a true MI case. There were 1125 patients with MI recorded in HES primary diagnosis fields with strong supporting evidence in either data source. Of these, 880 (78%) were present in CPRD Aurum, with completeness somewhat higher in more recent years. CONCLUSION: MI diagnoses recorded in CPRD Aurum were highly likely to be correct, supporting its use in clinical research studies. Completeness was lower, indicating the need for data linkage for some studies.

The risks of major cardiac events among patients with psoriatic arthritis treated with apremilast, biologics, DMARDs or corticosteroids.

OBJECTIVES: People with PsA are at increased risk of cardiovascular disease. The objective of this study was to quantify the risk of myocardial infarction (MI), stroke and revascularizations in people with apremilast-treated PsA compared with patients receiving other PsA treatments. METHODS: We conducted a cohort study of 68 678 patients with PsA treated with apremilast, TNF inhibitor (TNF-i) biologics, IL-17 or -12/23 biologics, conventional DMARDs or CS in the United States MarketScan database. Cohort entry was date of first study drug after 21 March 2014. Cases were patients with MI, stroke or revascularization. We calculated incidence rates (IRs) and incidence rate ratios for each outcome by exposure. RESULTS: We identified 292 MI, 151 stroke and 475 revascularizations cases. IRs for MI were lowest for users of TNF-i biologics [1.4 per 1000 person-years (PY)] and similar for all other treatments, including apremilast, ranging from 1.8 to 3.8 per 1000 PY. IRs were similar for all treatments for both stroke (0.1-1.6 per 1000 PY) and revascularization (3.1-5.1 per 1000 PY). IRs for apremilast were 2.5 per 1000 PY for MI, 1.6 per 1000 PY for stroke and 3.3 per 1000 PY for revascularization. CONCLUSION: In patients with treated PsA, IRs of MI, stroke and revascularization were low for all systemic treatments evaluated. Although the number of events was small, apremilast exposure did not signal potential acute cardiovascular harm and was not associated with a material increase in the risk of these serious cardiac events.

CPRD Aurum database: Assessment of data quality and completeness of three important comorbidities.

PURPOSE: The Clinical Practice Research Datalink (CPRD) now provides a new medical record database, CPRD Aurum. This is the second of several studies being undertaken to assess the quality of CPRD Aurum data for research. METHODS: We included patients aged 20+, with at least one lab test result of any type from a random sample of 50 000 patients in CPRD Aurum. We assessed whether diagnosis codes for type 2 diabetes, hyperlipidemia, and iron deficiency or unspecified anemia were accompanied by supporting codes including lab results and treatments (correctness) and whether lab results, treatments, or other codes indicate a missing diagnosis record (completeness). RESULTS: Among 37 502 patients in CPRD Aurum, correctness of type 2 diabetes, hyperlipidemia, and anemia diagnoses was high (99%, 93%, and 97%, respectively). Completeness was only high for type 2 diabetes (94%-98%); completeness for hypercholesterolemia and anemia diagnoses was modest even when the presence of treatments and lab results indicated the conditions were likely present (51%-59% and 58%-70%, respectively). CONCLUSIONS: Our findings indicate that for studies of type 2 diabetes, hyperlipidemia, and iron deficiency or unspecified anemia, the diagnosis code is likely to be correct where present. However, a significant proportion of cases of hyperlipidemia or anemia will be missed if only diagnosis codes are used to select patients with these conditions. Researchers should consider using treatments, supporting codes, and, when available, lab data to supplement diagnosis codes and enhance case capture when including these conditions in studies using CPRD Aurum.

Quality and completeness of diagnoses recorded in the new CPRD Aurum Database: evaluation of pulmonary embolism.

PURPOSE: The Clinical Practice Research Datalink (CPRD) now provides a new medical record database, CPRD Aurum. This is the first of several studies being undertaken to assess the quality and completeness of CPRD Aurum data for research endeavors. METHODS: We identified patients with a pulmonary embolism (PE) diagnosis from a random sample of 50 000 patients in CPRD Aurum and compared the diagnoses using data from Hospital Episode Statistics (HES). We calculated the proportion of PE cases recorded in CPRD Aurum who also had a PE diagnosis recorded in HES. We also evaluated completeness by identifying all PE diagnoses in HES and calculating the proportion also present in CPRD Aurum. RESULTS: The study included 781 PE patients: 580 had a PE in CPRD Aurum, 632 had a PE in HES, and 431 had a PE in both. The proportion of patients with anticoagulated PE in CPRD Aurum confirmed by HES was 76.8%. The completeness of primary hospitalized PE HES events compared to CPRD Aurum was 79.1%. In most instances, there was a plausible explanation for the presence of a PE in only one of the two data sources. CONCLUSIONS: The results of this study are reassuring and suggest that the correctness (eg, quality, accuracy) and completeness of diagnosis information in CPRD Aurum are promising with respect to serious acute conditions that require medical attention. Evaluation of other data elements will provide additional insight into this new data resource and its utility for medical research.

Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis.

PURPOSE: Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014-2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments. MATERIALS AND METHODS: Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years. RESULTS: The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8-15.7]), CS-only (12.5 [10.4-14.1]), and TNF+DMARDs and/or CS (11.9 [10.6-13.4]), compared with DMARDs only (9.9 [8.7-11.2]). IRs were lowest for users of IL-only (6.7 [5.8-7.8]) and APR (7.0 [5.8-8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant. CONCLUSION: Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.

Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.

BACKGROUND: Results of some studies suggest that prenatal antidepressant exposure increases the risk of autism spectrum disorder (ASD) in offspring, while other studies suggest that depression independently increases the risk of having a child with ASD. Thus, confounding by indication is a concern. OBJECTIVE: The aim of this study was to estimate the risk of ASD in offspring of women who were exposed to antidepressants and/or had depression during pregnancy compared to unexposed women. MATERIALS AND METHODS: We conducted a cohort study with nested sibling case-control analysis. Using the UK Clinical Practice Research Datalink (CPRD), we identified mother- baby pairs where the mother had ≥12 months of history before the delivery date and the child had ≥3 years of follow-up. Exposures during pregnancy were classified as 1) depression treated with antidepressants, 2) untreated depression, 3) other indications for antidepressant use, and 4) 4:1 match of unexposed women with no history of depression or antidepressant use. We calculated the prevalence of ASD and relative risk (RR) with 95% CI. In the sibling analysis, we compared exposure among ASD cases to that of non-ASD siblings born to the same mother. We calculated ORs and 95% CIs for women with treated and untreated depression, compared to unexposed. RESULTS: We identified 2,154 offspring with ASD among 194,494 mother-baby pairs. Compared to unexposed, the RR of ASD was 1.72 (95% CI 1.54-1.93) for treated depression and 1.50 (95% CI 1.28-1.75) for untreated depression, while the RR was not elevated in women who received antidepressants for other indications (RR =0.73, 95% CI 0.41-1.29). Additional analyses to assess the effects of severity of depression suggest that the risk of ASD in offspring increases with increasing severity, not with the antidepressant treatment. The results of the sibling analysis were similar to the main analysis. CONCLUSION: Women with depression during pregnancy have an increased risk of having a child with ASD, regardless of antidepressant use.

Validation of autism spectrum disorder diagnoses recorded in the Clinical Practice Research Datalink, 1990-2014.

BACKGROUND: Prior studies have reported that the validity of autism spectrum disorder (ASD) diagnoses recorded in the Clinical Practice Research Datalink (CPRD) was high; however, diagnostic criteria and screening practices have changed since the last study was published in 2004. OBJECTIVES: 1) To calculate the positive predictive value (PPV) of ASD diagnoses recorded in the CPRD compared to original medical records and 2) to describe characteristics of cases and use of clinical codes that support the ASD diagnosis as recorded in the electronic data by general practitioners over time. METHODS: We identified children with a code for ASD (autism spectrum disorder, autism, Asperger's, or pervasive developmental disorder) in the CPRD from 1990 to 2014. We evaluated presence of codes in the electronic medical record indicating the presence of developmental delay, speech delay, behavioral problems, and other supporting clinical codes (e.g., therapy, referrals, etc.). We also evaluated changes in recording of these clinical codes over time. We compared the information present in the electronic medical record to original medical records for a sample of cases and calculated PPVs of ASD diagnoses recorded in the CPRD. RESULTS: We identified 2154 children with a code for ASD. The mean age at diagnosis was 5.8 years, and 84% of cases were male. The majority (78.4%) had 1 ASD diagnosis code in their electronic medical record. Approximately half of the cases had a code indicating behavioral problem, developmental delay, or speech delay, and 24.7% had a code indicating specialist referral or visit. After review of original medical records, the PPV of ASD diagnoses recorded in the CPRD was 91.9%. CONCLUSION: The results of this study suggest that ASD diagnoses recorded in the CPRD are reliable and can be used with confidence to study ASD.

Risk of Incident Antidepressant-Treated Depression Associated with Use of 5α-Reductase Inhibitors Compared with Use of α-Blockers in Men with Benign Prostatic Hyperplasia: A Population-Based Study Using the Clinical Practice Research Datalink.

STUDY OBJECTIVE: To estimate the risk of incident antidepressant-treated depression in men with benign prostatic hyperplasia (BPH) who were prescribed 5α-reductase inhibitors (5-ARIs) compared with those prescribed an active comparator, α-blockers (ABs). DESIGN: Retrospective cohort study with a nested case-control analysis. DATA SOURCE: United Kingdom's Clinical Practice Research Datalink. PATIENTS: A total of 77,732 men with a diagnosis of BPH who received a prescription for a 5-ARI only and/or AB between January 1, 1992, and December 31, 2013. Of these men, 2842 had a first-time (incident) diagnosis of depression and received a prescription for an antidepressant within 90 days of the depression diagnosis date (cases); 11,333 controls without a diagnosis of depression were matched to the cases for the case-control analysis. MEASUREMENTS AND MAIN RESULTS: Exposures were classified as 5-ARI only, 5ARI + AB, or AB only. We calculated incidence rates of antidepressant-treated depression and compared rates among users of 5-ARIs only and 5-ARIs + ABs with rates among users of ABs only (i.e., incidence rate ratios [IRRs]). We also calculated odds ratios (ORs) to estimate the risk of incident depression with use of 5-ARIs only and 5-ARIs + ABs compared with ABs only. In this population of men with BPH, the risk of depression was not increased with use of 5-ARIs only (IRR 0.94, 95% confidence interval [CI] 0.85-1.04) or 5-ARIs + ABs (IRR 1.04, 95% CI 0.89-1.21) compared with use of ABs only. In the case-control analysis, exposure to 5-ARIs only (adjusted OR 0.88, 95% CI 0.78-1.01) or 5-ARIs + ABs (adjusted OR 0.90, 95% CI 0.73-1.10) was not associated with the risk of treated depression compared with exposure to ABs only, and results remained null regardless of number of prescriptions or timing of exposure. The risk of incident antidepressant-treated depression increased with longer duration of BPH, independent of study drug exposure. CONCLUSION: In this population of men with treated BPH, use of 5-ARIs, alone or in combination with ABs, did not increase the risk of incident antidepressant-treated depression compared with use of ABs only. Risk of treated depression increased with longer duration of BPH.

Risk of gynecomastia and breast cancer associated with the use of 5-alpha reductase inhibitors for benign prostatic hyperplasia.

BACKGROUND: Clinical trial results suggest that 5-alpha reductase inhibitors (5ARIs) for the treatment of benign prostatic hyperplasia (BPH) may increase the risk of gynecomastia and male breast cancer, but epidemiological studies have been limited. PATIENTS AND METHODS: We conducted a cohort study with nested case-control analyses using the UK Clinical Practice Research Datalink. We identified men diagnosed with BPH who were free from Klinefelter syndrome, prostate, genital or urinary cancer, prostatectomy or orchiectomy, or evidence of gynecomastia or breast cancer. Patients entered the cohort at age ≥40 years and at least 3 years after the start of their electronic medical record. We classified exposure as 5ARIs (alone or in combination with alpha blockers [ABs]), AB only, or unexposed to 5ARIs and ABs. Cases were men who had a first-time diagnosis of gynecomastia or breast cancer. Incidence rates and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) in the gynecomastia analysis and crude and adjusted odds ratios (ORs) with 95% CIs in both analyses were calculated. RESULTS: Compared to no exposure, gynecomastia risk was elevated for users of 5ARIs (alone or in combination with ABs) in both the cohort (IRR=3.55, 95% CI 3.05-4.14) and case-control analyses (OR=3.31, 95% CI 2.66-4.10), whereas the risk was null for users of AB only. The increased risk of gynecomastia with the use of 5ARIs persisted regardless of the number of prescriptions, exposure timing, and presence or absence of concomitant prescriptions for drugs known to be associated with gynecomastia. The risk was higher for dutasteride than for finasteride. 5ARI users did not have an increased risk of breast cancer compared to unexposed men (OR=1.52, 95% CI 0.61-3.80). CONCLUSION: In men with BPH, 5ARIs significantly increased the risk of gynecomastia, but not breast cancer, compared to AB use and no exposure.

Risk of erectile dysfunction associated with use of 5-α reductase inhibitors for benign prostatic hyperplasia or alopecia: population based studies using the Clinical Practice Research Datalink.

OBJECTIVE:  To estimate the risk of erectile dysfunction in men who used 5-α reductase inhibitors to treat benign prostatic hyperplasia or alopecia. DESIGN:  Cohort studies with nested case-control analyses. SETTING:  UK Clinical Practice Research Datalink. POPULATION:  Two populations of men free of risk factors for erectile dysfunction and other sexual dysfunction or its treatment: men aged 40 or more with benign prostatic hyperplasia who received a prescription for a 5-α reductase inhibitor (finasteride or dutasteride) or α blocker, or both, and men aged 18-59 with alopecia. EXPOSURES:  In the benign prostatic hyperplasia study, exposures were classified as 5-α reductase inhibitors only, 5-α reductase inhibitors+α blockers, or α blockers only. In the alopecia study, exposures were finasteride 1 mg or no treatment. MAIN OUTCOME MEASURES:  Cases were men with a diagnosis of erectile dysfunction or treatment (procedure or prescription for a phosphodiesterase type 5 inhibitor) during follow-up. We calculated incidence rates and adjusted incidence rate ratios with 95% confidence intervals. We also conducted nested case-control analyses to control for major confounders, and calculated adjusted odds ratios with 95% confidence intervals. RESULTS:  In the population with benign prostatic hyperplasia (n=71 849), the risk of erectile dysfunction was not increased with use of 5-α reductase inhibitors only (incidence rate ratio 0.92, 95% confidence interval 0.85 to 0.99; odds ratio 0.94, 95% confidence interval 0.85 to 1.03) or 5-α reductase inhibitors+α blocker (1.09, 0.99 to 1.21, 0.92; 0.80 to 1.06) compared with α blockers only, and remained null regardless of number of prescriptions or timing of use. The risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia, regardless of exposure. For the alopecia population (n=12 346), the risk of erectile dysfunction was not increased for users of finasteride 1 mg compared with unexposed men with alopecia (1.03, 0.73 to 1.44; 0.95, 0.64 to 1.41). CONCLUSION:  5-α reductase inhibitors do not seem to significantly increase the risk of incident erectile dysfunction, regardless of indication for use. Risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia.

Associations of NSAID and paracetamol use with risk of primary liver cancer in the Clinical Practice Research Datalink.

Liver cancer incidence has been rising rapidly in Western countries. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely-used analgesics that may modulate the risk of liver cancer, but population-based evidence is limited. We conducted a case-control study (1195 primary liver cancer cases and 4640 matched controls) within the United Kingdom's Clinical Practice Research Datalink to examine the association between the use of prescription NSAIDs and paracetamol and development of liver cancer. Multivariable-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Overall, ever-use of NSAIDs was not associated with risk of liver cancer (aOR=1.05, 95% CI=0.88-1.24), regardless of recency and intensity of use. Use of paracetamol was associated with a slightly increased risk of liver cancer (aOR=1.18, 95% CI=1.00-1.39), particularly among individuals with body mass index<25kg/m(2) (aOR=1.56, 95% CI=1.17-2.09). Our results suggest that NSAID use was not associated with liver cancer risk in this population. Ever-use of paracetamol may be associated with slightly higher liver cancer risk, but results should be interpreted cautiously due to methodological limitations. Given that paracetamol is a widely-used analgesic, further examination of its relationship with liver cancer is warranted.