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Background: Evidence on a possible association between newer hormonal contraceptives (HC) and risk of breast cancer remains inconclusive, especially as concerns progestogen-only methods., Methods: In this nationwide prospective cohort study, all Swedish women aged 15-34 at study start on January 1 st 2005, or who turned 15 years during the study period, were followed until December 31 st 2017. Using information from seven National Registers, we assessed the risk ratio of developing breast cancer and breast cancer in situ in relation to different HC using Poisson regression. We adjusted the analyses for several known confounders of breast cancer., Findings: This cohort included 1.5 million women providing more than 14 million person-years. During the study period, 3842 women were diagnosed with breast cancer. Compared with never users of any HC, we found no increased risk of developing breast cancer among current users of any combined HC, IRR 1.03 (0.91-1.16), whereas current users of progestogen-only methods had an increased risk of developing breast cancer, IRR 1.32 (1.20-1.45). Across all types of HC, the risk of developing breast cancer appeared to be highest the first five years of use (combined HC IRR 1.39 (1.14-1.69); progestogen-only methods IRR 1.74 (1.44-2.10). The risk disappeared ten years after the women stopped using HC. The absolute risk of breast cancer per 100,000 women-years was 22.4 for never users, 10.9 for current users of combined HC, and 29.8 for current users of progestogen-only methods., Interpretation: Current use of progestogen-only methods is associated with a small increased risk of developing breast cancer, whereas we could only detect an increased risk among users of combined HC during the first five years of use. This may partly be explained by a selective prescription of progestogen-only methods to women with risk factors for breast cancer, like smoking or obesity. As the absolute risk of breast cancer was small, the many health benefits associated with HC must also be taken into account in contraceptive counselling., Funding: This study was funded by the Swedish Cancer Society and by the Uppsala County Council, the Faculty of Medicine at Uppsala University., Competing Interests: Jenny Niemeyer Hultstrand has received funding from the Family Planning Fund, Uppsala University, and travel grants from the Swedish Society of Medicine. Kristina Gemzell-Danielsson has acted as consultant for Bayer, Gedeon Richter, Exeltis, Natural Cycles, Daisy, Medincell, Cirqle, ObsEva, Mithra, Vifor. She has received lecture fees from Bayer, Gedeon Richter, Exeltis, Nordic Pharma, Natural Cycles, Mithra, and Organon. Helena Kopp Kallner has received lecture fees from: Actavis, Bayer, Gedeon Richter Exeltis, Nordic Pharma, Natural Cycles, Mithra, Teva, Merck, Ferring, Consilient Health, and acted as consultant for Bayer, Evolan, Gedeon Richter, Exeltis, Merck, Teva, TV4, Natural Cycles, Pharmiva, Dynamic Code, Ellen, Estercare, Leia and Essity. Henrik Lindman has received lecture fees from Lilly, AstraZeneca, Novartis, and Daiichi Sankyo. Per Wikman reports no conflicts of interest. Inger Sundström Poromaa has served occasionally on advisory boards or acted as invited speaker at scientific meetings for Bayer Health Care, Gedeon Richter, Peptonics, Shire/Takeda, and Sandoz. ISP is supported by grants from the Swedish Research Council 2020-01801 and the Swedish Cancer Society., (© 2022 The Authors.)

Background: Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results., Objectives: This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort., Methods: Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates., Results: The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those <70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53)., Conclusions: HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states., Competing Interests: This research was supported by the Italian Ministry of Health (GR-2018-12365661 - CHANGE Study, principal investigator Pietro Ameri) and is part of the work covered by the 2015-2020 Collaboration between the Regional Healthcare Agency of Puglia Region (AReSS Puglia) and the Istituto di Ricerche Farmacologiche Mario Negri IRCCS. Dr Maack was supported by the Barth Syndrome Foundation, the German Research Foundation (Ma 2528/7-1, SFB 894, TRR-219), and the German Federal Agency for Education and Research (01EO1504). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: The disease course of inflammatory bowel disease (IBD) following treatment with glucagon-like peptide (GLP)-1 based therapies is unclear. The aim of this study was to examine the disease course of IBD in patients treated with GLP-1 based therapies compared with treatment with other antidiabetics., Methods: Using nationwide Danish registries, we identified patients with IBD and type 2 diabetes who received antidiabetic treatment between 1 January 2007 and 31 March 2019. The primary outcome was a composite of the need for oral corticosteroids, tumour necrosis factor-α inhibitors, IBD-related hospitalisation, or IBD-related surgery. In the setting of a new-user active comparator design, we used Poisson regression to estimate incidence rate ratios (IRR) comparing treatment with GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors with other antidiabetic therapies. The analyses were adjusted for age, sex, calendar year, IBD severity, and metformin use., Findings: We identified 3751 patients with a diagnosis of IBD and type 2 diabetes and with a prescription of an antidiabetic drug (GLP-1 receptor agonists/DPP-4 inhibitors: 982 patients; other antidiabetic treatment: 2769 patients). The adjusted IRR of the composite outcome was 0·52 (95% CI: 0·42-0·65) for patients exposed to GLP-1 receptor agonists/DPP-4 inhibitors compared with patients exposed to other antidiabetics., Interpretation: In patients with IBD and type 2 diabetes, we observed a lower risk of adverse clinical events amongst patients treated with GLP-1 based therapies compared with treatment with other antidiabetics. These findings suggest that treatment with GLP-1 based therapies may improve the disease course of IBD., Competing Interests: EJS is co-author of studies sponsored by pharmaceutical companies; Eli Lilly, Amgen, UCB, Novartis and Janssen. EJS has not personally received any economic compensation from any pharmaceutical company in the last 36 months. MV, ABS, KHA, TJ have no conflicts of interest to disclose., (© 2021 The Authors.)

Background: Approximately 12-20% of those with osteoarthritis (OA) in Australia who undergo total knee replacement (TKR) surgery do not report any clinical improvement. There is a need to develop prediction tools for use in general practice that allow early identification of patients likely to undergo TKR and those unlikely to benefit from the surgery. First-line treatment strategies can then be implemented and optimised to delay or prevent the need for TKR. The identification of potential non-responders to TKR may provide the opportunity for new treatment strategies to be developed and help ensure surgery is reserved for those most likely to benefit. This statistical analysis plan (SAP) details the statistical methodology used to develop such prediction tools., Objective: To describe in detail the statistical methods used to develop and validate prediction models for TKR surgery in Australian patients with OA for use in general practice., Methods: This SAP contains a brief justification for the need for prediction models for TKR surgery in general practice. A description of the data sources that will be linked and used to develop the models, and estimated sample sizes is provided. The planned methodologies for candidate predictor selection, model development, measuring model performance and internal model validation are described in detail. Intended table layouts for presentation of model results are provided., Conclusion: Consistent with best practice guidelines, the statistical methodologies outlined in this SAP have been pre-specified prior to data pre-processing and model development., (© 2020 The Authors.)

Cardiovascular disease remains a leading cause of death, but stakeholders have recently raised concerns about the pace of innovation and investment in developing new therapeutics. Here, the authors characterized temporal trends in cardiovascular research and development over the past 2 decades and the likelihood of successful completion of pre-approval clinical trials. The authors also evaluated the reasons for discontinuation, novelty, and rates of trial results publication for cardiovascular therapies in late-stage development. Between 1990 and 2012, the number of new cardiovascular drugs entering clinical trials declined across all stages of development (p < 0.001 for linear trends). There was no evidence for a difference in probability of successful progression to the next stage of development between cardiovascular and noncardiovascular drugs. Small and medium-sized companies sponsored 43%, 38%, and 31% of new Phase 1, Phase 2, and Phase 3 trials, respectively. Roughly one-half of the drugs in Phase 3 trials were categorized as targeting a novel biological pathway. The number of cardiovascular trials sponsored by small and medium-sized companies and the number of novel drugs entering Phase 3 trials increased over time. Most drugs were discontinued in Phase 3 due to inadequate efficacy (44%) or safety issues (24%), but the Phase 3 trial results for only one-half of the discontinued drugs were published in peer-reviewed journals. These results shed light on important shifts in research and development activity and confirm the perceived challenges in cardiovascular translational research.

Purpose: Evaluate the potential Drug-Drug Interactions (pDDI) found in prescription orders of adult Intensive Care Unit (ICU) of a Brazilian public health system hospital; quantify and qualify the pDDI regarding their severity and risks to the critical patient, using the database from Micromedex®., Methods: Prospective study (January-December of 2011) collecting and evaluating 369 prescription orders (convenient sampling), one per patient., Results: During the study 1844 pDDIs were identified and distributed in 405 pairs (medication A × medication B combination). There was an average of 5.00 ± 5.06 pDDIs per prescription order, the most prevalent being moderate and important interactions, present in 74% and 67% of prescription orders, respectively. In total, there were 9 contraindicated, 129 important and 204 moderate pDDIs. Among them 52 had as management recommendation to "avoid concomitant use" or "suspension of medication", while 306 had as recommendation "continuous and adequate monitoring"., Conclusion: The high number of pDDIs found in the study combined with the evaluation of the clinical relevancy of the most frequent pDDIs in the ICU shows that moderate and important interactions are highly incident. As the majority of them demand monitoring and adequate management, being aware of these interactions is major information for the safe and individualized risk management.