Association of lipid-regulating drugs with dementia and related conditions: an observational study of data from the Clinical Practice Research Datalink

Background: There is some evidence that circulating blood lipids play a role in the development of Alzheimer's disease (AD) and dementia. These modifiable risk factors could be targeted by existing lipid-regulating agents, including statins, for dementia prevention. Here, we test the association between lipid-regulating agents and incidence of dementia and related conditions in the Clinical Practice Research Datalink (CPRD), an United Kingdom-based electronic health record database. Methods: A retrospective cohort study was performed using routinely collected CPRD data (January 1995 and March 2016). Multivariable Cox proportional hazard models, allowing for a time-varying treatment indicator, were used to estimate the association between seven lipid-regulating drug classes (vs. no drug) and five dementia outcomes (all-cause, vascular and other dementias, and probable and possible Alzheimer's disease). Results: We analyzed 1,684,564 participants with a total follow-up of 10,835,685 patient-years (median: 5.9 years (IQR:2.7-9.7)). We found little evidence that lipid-regulating agents were associated with incidence of Alzheimer's disease (probable HR:0.98, 95%CI:0.94-1.01; possible HR:0.97, 95%CI:0.93-1.01), but there was evidence of an increased risk of all-cause (HR:1.17, 95%CI:1.14-1.19), vascular (HR:1.81, 95%CI:1.73-1.89) and other dementias (HR:1.19, 95%CI:1.15-1.24). Evidence from a number of control outcomes indicated the presence of substantial residual confounding by indication (ischaemic heart disease HR: 1.62, 95%CI: 1.59-1.64; backpain HR: 1.04, 95%CI: 1.03-1.05; and Type 2 diabetes HR: 1.50, 95%CI: 1.48-1.51). Conclusion: Lipid-regulating agents were not associated with reduced Alzheimer's disease risk. There was some evidence of an increased the risk of all-cause, vascular and other dementias, likely due to residual confounding by indication.

Association between the use of exchange devices for peritoneal dialysis fluids and peritonitis incidence: A nationwide cohort study

Background: The use of exchange devices for peritoneal dialysis (PD) fluids is a common practice in Japan. Evidence on the effectiveness of exchange devices in preventing PD-related peritonitis is scarce. We evaluated the association between the use of exchange devices for PD fluids and peritonitis incidence. Methods: We retrospectively enrolled 3845 patients, aged ≥20 years, receiving PD for ≥3 months, with available data on the exchange procedure for PD fluids and peritonitis incidence that was obtained from the Japan Renal Data Registry, a nationwide annual survey. The patients were grouped according to whether the manual or device PD fluid exchange method was used. The onset of peritonitis was defined as a leukocyte count of >100/µL (neutrophils ≥50%) in PD effluents. We applied quasi-Poisson regression analyses to estimate the incidence rate ratio (IRR). Age, sex, PD vintage, body mass index, automated PD use, residual kidney function, comorbidities, haemoglobin and serum albumin were adjusted as potential confounders. Results: Older age, automated PD use, diabetes as comorbidity and lower haemoglobin levels were associated with the use of exchange devices for PD fluids. Patients using devices for PD fluid exchange (69.2%) had an increased risk of peritonitis of 37% (IRR: 1.37, 95% confidence interval (CI): 1.07–1.75) and 28% (IRR: 1.28, 95% CI: 1.00–1.63) in the crude and multivariate adjustment models, respectively. Conclusions: The use of exchange devices for PD fluids and peritonitis incidence showed no favourable association. There may remain possible residual confounding by indication.

Does biologic therapy impact the development of PsA among patients with psoriasis?

ObjectiveTo examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis.MethodsA retrospective cohort study was conducted in the OptumInsights Electronic Health Record Database between 2006 and 2017 among patients with psoriasis between the ages of 16 and 90 initiating a therapy for psoriasis (oral, biologic or phototherapy). The incidence of PsA was calculated within each therapy group. Multivariable Cox models were used to calculate the HR for biologic versus oral or phototherapy using biologics as a time-varying exposure and next in a propensity score-matched cohort.ResultsAmong 1 93 709 patients with psoriasis without PsA, 14 569 biologic and 20 321 cumulative oral therapy and phototherapy initiations were identified. Mean age was lower among biologic initiators compared with oral/phototherapy initiators (45.9 vs 49.8). The incidence of PsA regardless of therapy exposure was 9.75 per 1000 person-years compared with 77.26 among biologic users, 61.99 among oral therapy users, 26.11 among phototherapy users and 5.85 among those without a prescription for one of the target therapies. Using a multivariable adjustment approach with time-varying exposure, adjusted HR (95% CI) for biologic users was 4.48 (4.23 to 4.75) compared with oral or phototherapy users. After propensity score matching, the HR (95% CI) was 2.14 (2.00 to 2.28).ConclusionsIn this retrospective cohort study, biologic use was associated with the development of PsA among patients with psoriasis. This may be related to confounding by indication and protopathic bias. Prospective studies are needed to address this important question.

Effectiveness of topical vancomycin in the prevention of spinal surgical site infections: a retrospective cohort study

Background The risk of surgical site infections (SSIs), particularly methicillin-resistant Staphylococcus aureus (MRSA) SSIs, after spinal surgeries is one of the most daunting experiences to patients and surgeons. Some authors suggest applying vancomycin powder on the wound before skin closure to minimize the risk of SSIs; however, this practice is not supported by well-established evidence. This study sought to assess the effectiveness of topical (i.e. intra-wound) vancomycin in minimizing the risk of SSIs in patients who underwent spinal surgeries at a Saudi hospital. Methods A retrospective cohort study was conducted using the hospital database. Patients who underwent spinal surgeries from the period of 09/2013 to 09/2019 were included and followed up (observed from the time of the surgery) to 30 days (surgeries without implants) or 90 days (with implants). The odds ratio (OR) of the primary outcome between vancomycin treated versus non-treated patients was estimated using a logistic regression model adjusting for the measured confounders. A sensitivity analysis was conducted using propensity score analysis (inverse probability of treatment weighting [IPTW] with stabilized weights) to control for confounding by indication. All study analyses were completed using RStudio Version 1.2.5033. Results We included 81 vancomycin treated vs. 375 untreated patients with 28 infections (8/81 vs. 20/375; respectively). The adjusted OR of SSIs between the two groups was 0.40 (95% confidence interval [CI] 0.11 to 1.34). The result of the propensity score analysis was consistent (OR: 0.97 [95% CI 0.35 to 2.68]). Conclusions We could not find a lower association of SSIs with intra-wound vancomycin in patients who underwent spinal surgeries. Further studies are needed to assess benefits of using topical vancomycin for this indication vs. the risk of antimicrobial resistance.

Metformin Reduces the Risk of Diverticula of Intestine in Taiwanese Patients with Type 2 Diabetes Mellitus

Aim: To investigate the risk of diverticula of intestine associated with metformin use.Methods: This retrospective cohort study used the Taiwan’s National Health Insurance database to enroll 307,548 ever users and 18,839 never users of metformin. The patients were followed up starting on January 1, 2006 and ending on a date up to December 31, 2011. To address confounding by indication, hazard ratios were derived from Cox regression based on the inverse probability of treatment weighting using propensity score.Results: During follow-up, newly diagnosed cases of diverticula were identified in 1,828 ever users (incidence rate: 125.59 per 100,000 person-years) and 223 never users (incidence rate: 268.17 per 100,000 person-years). Ever users had an approximately 54% lower risk, as shown by the overall hazard ratio of 0.464 (95% confidence interval 0.404–0.534). While patients categorized in each tertile of cumulative duration of metformin therapy were compared to never users, a dose-response pattern was observed with hazard ratios of 0.847 (0.730–0.983), 0.455 (0.391–0.531) and 0.216 (0.183–0.255) for the first (<27.37 months), second (27.37–59.70 months) and third (>59.70 months) tertiles, respectively. The findings were similar when the diagnosis of diverticula was restricted to the small intestine or to the colon. Subgroup analyses suggested that the lower risk of diverticula of intestine associated with metformin use was significant in all age groups of <50, 50–64 and ≥65 years, but the magnitude of risk reduction attenuated with increasing age.Conclusion: Metformin treatment is associated with a significantly reduced risk of diverticula of intestine.

647Use of menopausal hormone therapy before and after ovarian cancer diagnosis and ovarian cancer survival

Background Menopausal hormone therapy (MHT) use before ovarian cancer (OvCa) diagnosis has been suggested to improve survival but data on type, duration and use after treatment for OvCa are scarce. Methods We investigated MHT use and OvCa survival among participants with newly diagnosed OvCA in the Ovarian cancer Prognosis And Lifestyle (OPAL) Study. Analysis of pre-diagnosis use was restricted to 661 post-menopausal women and analysis of post-diagnosis use included 254 women aged ≤55-years. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between MHT and OvCa-specific survival. We used propensity score-based approaches to account for potential bias due to confounding by indication. Results Approximately 14% of post-menopausal women were current/recent users of oestrogen-only (7%) or oestrogen-progestin/unknown MHT (E-P=7%) at the time of diagnosis. In the pre-diagnosis analysis, E-P use was associated with better survival (HR = 0.60, 95%CI=0.37-0.98; HR = 0.93, 95%CI=0.79-1.09 per 5-years/use). The association between oestrogen-only MHT and survival was weaker and non-significant (HR = 0.74, 95%CI=0.47-1.16). Among women ≤55-years at diagnosis, the HR was 0.91 (95%CI=0.50-1.67) for new use after diagnosis regardless of type; and 0.89 (95%CI 0.51-1.54) for any use post-diagnosis compared to never users. Propensity-score-based methods showed similar estimates. Conclusions Pre-diagnosis MHT use is associated with better ovarian cancer survival. Post-diagnosis MHT use might also improve survival for women younger than 55-years, even after accounting for bias due to confounding by indication. Key messages Menopausal hormone therapy may be considered to manage menopausal symptoms in women with ovarian cancer.

Impact of arteriovenous fistulas versus arteriovenous grafts on vascular access performance in haemodialysis patients: A systematic review and meta-analysis

Background Controversy exists regarding the best-performing vascular access type for patients undergoing haemodialysis. We aimed to compare outcomes of starting dialysis on arteriovenous fistulas (AVFs) versus arteriovenous grafts (AVGs) in haemodialysis patients. Methods We conducted a systematic search of multiple electronic information sources and bibliographic reference lists. The following outcome parameters were evaluated at 1, 2 and 5 years: primary failure, defined as access never used for dialysis; primary patency, defined as intervention-free access survival; primary-assisted patency, defined as uninterrupted access survival with interventions; and secondary patency, defined as cumulative access survival. Results We identified 15 comparative studies reporting a total of 118,434 patients who initiated haemodialysis with AVF ( n = 95,143) or AVG ( n = 23,291). Our analysis demonstrated that AVF was associated with significantly higher primary failure rate (OR: 2.05, p = .0005) but significantly higher rate of primary patency at 1 year (OR: 1.91, p < .00001), at 2 years (OR: 2.52, p < .00001) and at 5 years (OR: 2.59, p < .00001); and primary-assisted patency at 1 year (OR: 1.71, p < .00001), at 2 years (OR: 2.13, p < .00001) and 5 years (OR: 2.79, p < .00001). There was no significant difference in secondary patency at 1 year (OR: 1.08, p < .00001) but AVF had better secondary patency at 2 years (OR: 1.26, p < .00001) and 5 years (OR: 1.60, p < .00001) than AVG. Conclusions The meta-analysis of best available comparative evidence (Level 2) demonstrated that AVFs may be associated with significantly higher primary failure rate but higher primary patency, primary-assisted patency and secondary patency at 1, 2 and 5 years compared to AVGs. However, the available evidence is subject to significant selection bias and confounding by indication.

The Association Between Gut Microbiome Affecting Concomitant Medication and The Related Effectiveness of Immunotherapy in Patients With Stage IV NSCLC

Objectives This historically matched cohort study investigated the influence of microbiome-affecting-medication on the effectiveness of immunotherapy in patients with stage IV non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is mediated by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. Methods Immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. Results A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. Conclusion The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding by indication rather than disturbing the composition of the microbiome.