A systematic review of observational studies of the association between pioglitazone use and bladder cancer.

AIM: To conduct a systematic review of all observational studies on the effect of pioglitazone on the risk of bladder cancer. METHODS: The MEDLINE and EMBASE databases were queried for papers published between 1 January 2000 and 30 October 2017. We took into consideration observational studies (both retrospective and prospective) that included participants with Type 2 diabetes prescribed anti-hyperglycaemic drugs. RESULTS: While some studies reported an association, others did not, and meta-analyses of these studies showed a significantly increased risk; however, while meta-analysis is a powerful and practical statistical tool, its results should be considered with caution when applied to widely heterogeneous studies. We describe how many of these studies are affected by different types of bias, most notably time-related biases, which should preclude a pooled analysis that would result in biased estimation of the risk. CONCLUSIONS: Given existing data, it is not appropriate to pool the outcomes of highly heterogeneous studies and further rigorously conducted observational research is needed to clarify the role of pioglitazone use on the incidence of bladder cancer.

Drospirenone-containing oral contraceptive pills and the risk of venous thromboembolism: a systematic review of observational studies.

BACKGROUND: The effects of fourth-generation drospirenone-containing combined oral contraceptives (COCs) on the risk of venous thromboembolism (VTE) are controversial. OBJECTIVES: To assess the methodological strengths and limitations of the evidence on the VTE risk of these COCs. SEARCH STRATEGY: We searched CINAHL, the Cochrane Library, EMBASE, HealthStar, Medline, and the Science Citation Index. SELECTION CRITERIA: Studies were included if they were cohort and case-control studies, reported a venous thrombotic outcome, had a comparator group, reported an effect measure of the association of interest, and were published in English or French. DATA COLLECTION AND ANALYSIS: We assessed study quality using the ROBINS-I tool and assessed the presence of four common sources of bias: prevalent user bias, inappropriate choice of comparator, VTE misclassification, and confounding. MAIN RESULTS: Our systematic review included 17 studies. The relative risks of VTE associated with drospirenone- versus second-generation levonorgestrel-containing COCs ranged from 1.0 to 3.3. Based on ROBINS-I, three studies had a moderate risk, ten had a serious risk, and four had a critical risk. Nine studies included prevalent users, four included inappropriate comparators, four had VTE misclassification, and five did not account for two or more important confounding factors. The three highest quality studies had relative risks ranging from 1.0 to 1.57. AUTHOR'S CONCLUSIONS: As a result of the methodological limitations of the individual studies, the VTE risk of drospirenone-containing COCs remains unknown. The highest quality studies suggest there are no or slightly increased harmful effects, but their confidence limits do not rule out an almost doubling of the risk. TWEETABLE ABSTRACT: Systematic review of drospirenone: best studies show no or slightly increased VTE risk (versus levonorgestrel).

Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. Patients and methods: We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. Results: A total of 19 RCTs were included in the meta-analysis (n = 62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07-1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85-1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45-0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77-1.07). Conclusions: The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Drospirenone-containing combined oral contraceptives and the risk of arterial thrombosis: a population-based nested case-control study.

OBJECTIVE: To compare the rate of arterial thromboembolism (ATE) of drospirenone-containing COCs to that of levonorgestrel-containing COCs. DESIGN: Population-based cohort study. SETTING: United Kingdom's Clinical Practice Research Datalink (CPRD), which contains clinical records for >11 million patients. POPULATION: Women aged 16-45 years prescribed a drospirenone- or levonorgestrel-containing COC between May 2002 and June 2012. METHODS: We conducted nested case-control analyses using risk set sampling to randomly select up to 10 controls for each ATE case, matched on age, cohort entry year, CPRD registration year, COC user type (first-time ever, new, switcher, or prevalent users), duration of COC use, duration of progestin-only or implantable contraceptive use, pre-cohort entry duration of drospirenone and levonorgestrel use, and duration of follow up. MAIN OUTCOME MEASURES: We used conditional logistic regression to estimate hazard ratios and 95% confidence intervals (CIs), adjusted for high-dimensional propensity scores. RESULTS: Our cohort included 339 743 women followed over a mean 4.4 years, during which 228 ATE cases occurred: 37 myocardial infarctions, 170 strokes, and 21 other ATEs; overall rate: 1.5 events per 10 000 person-years (PYs). After adjusting for potential confounders, the hazard ratio for ATE with current use of drospirenone-containing COCs versus current use of levonorgestrel-containing COCs was 0.89 (95% CI 0.35, 2.28), corresponding to a rate difference of -0.16 events per 10 000 PYs. CONCLUSIONS: The overall rate of ATE in this population is low regardless of which COC was taken. We found little evidence of a difference in the rate of ATE with drospirenone- versus levonorgestrel-containing COCs. TWEETABLE ABSTRACT: Little evidence was found of a greater incidence of arterial thrombosis with drospirenone versus levonorgestrel contraceptives.

NNT, number needed to treat: does it have any real value?

Clinical trials usually use the relative risk (rate ratio or hazard ratio) to compare the effects of one treatment modality with others. However, the numbers needed to treat/harm (NNT/NNH) are sometimes used as another way of presenting an estimate of the effect of a medical intervention, pointing at the number of patients needed to be exposed over a certain period of time in order to achieve one beneficial or adverse event. For clinicians and patients, this is a very simple and clear tool to demonstrate the consequences of a specific intervention. Epidemiologists and statisticians are more cautious with interpretations of data of that sort. This article brings the relevant perspectives of a clinician, an epidemiologist and a statistician in regard to the value of NNT/NNH.

Long-term effects of insulin glargine on the risk of breast cancer.

AIMS/HYPOTHESIS: There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer. METHODS: We used the UK's General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002-2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer. RESULTS: The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7-1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8-4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1-6.5). CONCLUSIONS/INTERPRETATION: The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine.

Use of tamoxifen and aromatase inhibitors in a large population-based cohort of women with breast cancer.

BACKGROUND: Non-compliance with oral treatment in oncology is an emerging health issue. For breast cancer (BC) patients, few data are available on compliance and persistence to tamoxifen in younger women and to aromatase inhibitors (AIs) as compared with tamoxifen in older women. METHODS: We constituted a cohort of 13,479 women with BC who received at least one prescription of tamoxifen or AI between 1998 and 2008, in the United Kingdom General Practice Research Database. Days covered by medication and treatment discontinuation were studied. Time to treatment discontinuation was calculated using Kaplan-Meier estimates. RESULTS: Overall, 18.9% (95% CI: 15.1-23.0) of women on AIs as compared with 31.0% (95% CI: 29.6-32.2) of women on tamoxifen had discontinued their treatments within the first 5 years (P<0.001). This rate raised to 50.7% (95% CI: 43.0-57.9) among the 416 women under 40 years receiving tamoxifen as initial hormonal therapy. Among older women, treatment discontinuation was less frequent for AIs as compared with tamoxifen (P<0.001). Among women on AI therapy, 14% of them (n=374) had switched treatments. CONCLUSION: Among older women, the real-life patterns of use of AI show high rates of compliance. In younger women, tamoxifen is prematurely discontinued for half of patients.

The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case-control study.

BACKGROUND: Glucocorticoid therapy is strongly associated with an elevated risk of serious infections in patients with rheumatoid arthritis (RA). The association between glucocorticoids and common non-serious infections (NSI) is not well studied. METHODS: A cohort of 16 207 patients with RA aged over 65 years was assembled using administrative data from Quebec. Glucocorticoid and disease-modifying antirheumatic drug (DMARD) therapy were identified from drug dispensing records. NSI cases were defined as first occurrence of a community physician billing code for infection or community-dispensed anti-infectives. A nested case-control analysis was performed considering drugs dispensed within 45 days of the index date, adjusting for age, sex, markers of disease severity, DMARD and comorbidity. RESULTS: For 13 634 subjects, a NSI occurred during 28 695 person-years of follow-up, generating an incidence rate of 47.5/100 person-years. The crude rate of NSI in glucocorticoid-exposed and unexposed person time was 52.4 and 38.8/100 person-years, respectively. Glucocorticoid therapy was associated with an adjusted RR of 1.20 (95% CI 1.15 to 1.25). A dose response was seen, the adjusted RR increasing from 1.10 (<5 mg prednisolone/day) to 1.85 for doses greater than 20 mg/day. All glucocorticoid risk estimates (including <5 mg/day) were higher than that seen for methotrexate (adjusted RR 1.00; 0.95 to 1.04). CONCLUSION: Glucocorticoid therapy is associated with an increased risk of NSI. The magnitude of risk increases with dose, and is higher than that seen with methotrexate, although residual confounding may exist. While the RR is low at 1.20, the absolute risk is high with one additional infection seen for every 13 patients treated with glucocorticoids for 1 year.

The relationship of retinal vessel diameter to changes in diabetic nephropathy structural variables in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. METHODS: Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. RESULTS: While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv((Int/cortex))] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. CONCLUSIONS/INTERPRETATION: Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv((Int/cortex),) a measure of interstitial expansion in persons with type 1 diabetes mellitus.

Hormone replacement therapy and the risk of venous thromboembolism: a population-based study.

SUMMARY BACKGROUND: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. METHODS: Among the United Kingdom's General Practice Research Database, we identified the cohort of all women aged 50-79 between 1 January 1987 and 1 March 2008. Using a nested case-control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. RESULTS: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89-1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77-1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77-1.10), relative to non-use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37-1.63) and oral estrogen-progestogen (RR 1.54; 95% CI, 1.44-1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. CONCLUSION: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.

Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials.

The safety of long-acting beta(2)-agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or all-cause mortality and morbidity were increased with formoterol use. The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol. There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterol-randomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (>90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 microg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABA-treated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant. There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting beta(2)-agonist-randomised patients. However, despite data on >68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment.

OBJECTIVE: To provide context for the malignancy experience in the rheumatoid arthritis (RA) abatacept clinical development programme (CDP) by performing comparisons with similar RA patients and the general population. METHODS: Malignancy outcomes included total malignancy (excluding non-melanoma skin cancer (NMSC)), breast, colorectal, lung cancers and lymphoma. Comparisons were made between the observed incidence in patients within the abatacept CDP and RA patients on disease-modifying antirheumatic drugs (DMARD) identified from five data sources: the population-based British Columbia RA Cohort, the Norfolk Arthritis Register, the National Data Bank for Rheumatic Diseases, the Sweden Early RA Register and the General Practice Research Database. Age and sex-adjusted incidence rates (IR) and standardised incidence ratios (SIR) were used to compare events in the abatacept trials with the RA DMARD cohorts and the general population. RESULTS: A total of 4134 RA patients treated with abatacept in seven trials and 41,529 DMARD-treated RA patients in the five observational cohorts was identified for study inclusion. In the abatacept-treated patients, the 51 malignancies (excluding NMSC), seven cases of breast, two cases of colorectal, 13 cases of lung cancer and five cases of lymphoma observed were not greater than the range of expected cases from the five RA cohorts. The SIR comparing RA patients with the general population were consistent with those reported in the literature. CONCLUSIONS: The IR of total malignancy (excluding NMSC), breast, colorectal, lung cancers and lymphoma in the abatacept CDP were consistent with those in a comparable RA population. These data suggest no new safety signals with respect to malignancies, which will continue to be monitored.