Validity of Routine Health Data To Identify Safety Outcomes of Interest For Covid-19 Vaccines and Therapeutics in the Context of the Emerging Pandemic: A Comprehensive Literature Review.

Introduction: Regulatory guidance encourages transparent reporting of information on the quality and validity of electronic health record data being used to generate real-world benefit-risk evidence for vaccines and therapeutics. We aimed to provide an overview of the availability of validated diagnostic algorithms for selected safety endpoints for Coronavirus disease 2019 (COVID-19) vaccines and therapeutics in the context of the emerging pandemic prior to December 2020. Methods: We reviewed the literature up to December 2020 to identify validation studies for various safety events of interest, including myocardial infarction, arrhythmia, myocarditis, acute cardiac injury, vasculitis/vasculopathy, venous thromboembolism, stroke, respiratory distress syndrome (RDS), pneumonitis, cytokine release syndrome (CRS), multiple organ dysfunction syndrome, and renal failure. We included studies published between 2015 and 2020 that were considered high quality assessed with QUADAS and that reported positive predictive values (PPVs). Results: Out of 43 identified studies, we found that diagnostic algorithms for cardiovascular outcomes were supported by the highest number of validation studies (n=17). Accurate algorithms are available for myocardial infarction (median PPV 80%; IQR 22%), arrhythmia (PPV range >70%), venous thromboembolism (median PPV: 73%) and ischaemic stroke (PPV range ≥85%). We found a lack of validation studies for less common respiratory and cardiac safety outcomes of interest (eg, pneumonitis and myocarditis), as well as for COVID-specific complications (CRS, RDS). Conclusion: There is a need for better understanding of barriers to conducting validation studies, including data governance restrictions. Regulatory guidance should promote embedding validation within real-world EHR research used for decision-making.

Real world safety of methoxyflurane analgesia in the emergency setting: a comparative hybrid prospective-retrospective post-authorisation safety study.

BACKGROUND: Low-dose analgesic methoxyflurane (Penthrox®) was approved in Europe for emergency relief of moderate to severe pain in conscious adults with trauma in 2015. A comparative post-authorisation safety study (PASS) was conducted to assess the risk of hepatotoxicity and nephrotoxicity with methoxyflurane during routine clinical practice. METHODS: This was a comparative hybrid prospective-retrospective cohort study. The comparative cohorts consisted of adults who were given methoxyflurane (methoxyflurane cohort) or another analgesic (concurrent cohort) routinely used for moderate to severe trauma and associated pain in the emergency setting (ambulance and Emergency Department) in the UK between December 2016 and November 2018. Hepatic and renal events were captured in the ensuing 12 weeks. A blinded clinical adjudication committee assessed events. A historical comparator cohort (non-concurrent cohort) was identified from patients with fractures in the English Hospital Episode Statistics (HES) accident and emergency database from November 2013 and November 2015 (before commercial launch of methoxyflurane). Hepatic and renal events were captured in the ensuing 12 weeks via linkage with the Clinical Practice Research Datalink (CPRD) and HES hospital admissions databases. RESULTS: Overall, 1,236, 1,101 and 45,112 patients were analysed in the methoxyflurane, concurrent and non-concurrent comparator cohorts respectively. There was no significant difference in hepatic events between the methoxyflurane and concurrent cohorts (1.9% vs. 3.0%, P = 0.079) or between the methoxyflurane and non-concurrent cohorts (1.9% vs. 2.5%, P = 0.192). Renal events were significantly less common in the methoxyflurane cohort than in the concurrent cohort (2.3% vs. 5.6%, P < 0.001). For methoxyflurane versus non-concurrent cohort the lower occurrence of renal events (2.3% vs. 3.2%, P = 0.070) was not statistically significant. Multivariable adjustment did not change these associations. CONCLUSIONS: Methoxyflurane administration was not associated with an increased risk of hepatotoxicity or nephrotoxicity compared with other routinely administered analgesics and was associated with a reduced risk of nephrotoxicity compared with other routinely administered analgesics. TRIAL REGISTRATION: Study registered in the EU PAS Register (ENCEPP/SDPP/13040).

Totality of evidence of the effectiveness of repurposed therapies for COVID-19: Can we use real-world studies alongside randomized controlled trials?

Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational "real-world studies" (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID-19) pandemic. Comparing results between them offers a unique opportunity to determine the potential value and contribution of each. A learning review of these parallel evidence channels in COVID-19, based on quantitative modeling, can help improve speed and reliability in the evaluation of repurposed therapeutics in a future pandemic. Analysis of all-cause mortality data from 249 observational RWS and RCTs across eight treatment regimens for COVID-19 showed that RWS yield more heterogeneous results, and generally overestimate the effect size subsequently seen in RCTs. This is explained in part by a few study factors: the presence of RWS that are imbalanced for age, gender, and disease severity, and those reporting mortality at 2 weeks or less. Smaller studies of either type contributed negligibly. Analysis of evidence generated sequentially during the pandemic indicated that larger RCTs drive our ability to make conclusive decisions regarding clinical benefit of each treatment, with limited inference drawn from RWS. These results suggest that when evaluating therapies in future pandemics, (1) large RCTs, especially platform studies, be deployed early; (2) any RWS should be large and should have adequate matching of known confounders and long follow-up; (3) reporting standards and data standards for primary endpoints, explanatory factors, and key subgroups should be improved; in addition, (4) appropriate incentives should be in place to enable access to patient-level data; and (5) an overall aggregate view of all available results should be available at any given time.

Malignancy rates in Crohn's disease patients with perianal fistula: A German retrospective cohort study.

BACKGROUND: Patients with inflammatory bowel disease are at increased risk of colorectal and extra-intestinal cancer. However, the overall cancer risk in patients with Crohn's disease (CD) with perianal fistulas (PF) (CPF) and those with CD without PF (non-PF CD) is unclear. OBJECTIVE: To describe the prevalence and incidence of cancer in patients with CPF and non-PF CD, and to estimate incidence rate ratio (IRR) of cancer between CPF and non-PF CD groups. METHODS: A retrospective cohort study was conducted using the German InGef (Institute for Applied Health Research Berlin) research database. Patients with a CD record and PF from 1 January 2013 to 31 December 2014 were identified and followed up from 1 January 2015 until the first occurrence of cancer, end of health insurance contributing data, death, or end of study period (31 December 2020). Prevalence of any type of cancer including patients with CD diagnosed with cancer in the selection period and incidence of cancer excluding patients with CD diagnosed with cancer in the selection period were calculated. RESULTS: In total, 10,208 patients with CD were identified. Of 824 patients with CPF (8.1%), 67 had had a malignancy (6-year period crude malignancy prevalence 8.13% [95% confidence interval (CI) 6.36%-10.21%]), which was lower than patients with non-PF CD (19.8% [95% CI 19%-20.6%]). Incidence (per 100,000 person-years) in patients with CPF was 1184 (95% CI 879-1561) and in non-PF CD was 2365 (95% CI 2219-2519). There was no significant difference in the adjusted IRR of cancer for the CPF group compared with the non-PF CD group (0.83 [95% CI 0.62-1.10]; p = 0.219). CONCLUSION: There was no significant difference in the incidence of any cancer in patients with CPF compared with non-PF CD. However, patients with CPF had a higher numerical risk of cancer than the general German population.

Healthcare resource utilisation and cost of pneumococcal disease from 2003 to 2019 in children ≤17 years in England.

OBJECTIVE: To estimate healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003-2019. METHODS: A retrospective study in children aged ≤17 years was conducted using the Clinical Practice Research Datalink Gold primary care database and Hospital Episodes Statistics Admitted Patient Care database from 2003-2019. Episodes of invasive pneumococcal disease (IPD) were identified in hospital, pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) episodes in primary care and in hospital, and acute otitis media (AOM) episodes in primary care. General practitioner (GP) visits and inpatient admission yearly rates were calculated per 1,000 persons. The average inpatient and primary care cost per episode were calculated. The Mann-Kendall test was used to assess monotonic time trends. RESULTS: 1,500,686 children were followed from 2003-2019. The highest average inpatient cost per episode [£34,255 (95%CI 27,222-41,288)] was in IPD, followed by ACP [£3,549 (95%CI 3,405-3,693)] and PP [£1,498 (95%CI 1,153-1,843)]. The highest primary care costs per episode were in AOM [£48.7 (95%CI 48.7-48.7)], followed by PP [£38.4 (95%CI 37.0-39.7)] and ACP [£28.6 (95%CI 28.2-29.1)]. The highest inpatient admission and GP visits yearly rates were observed in children aged <2 years. Across years, a significant decrease in GP visits yearly rates was observed for PP, ACP and AOM in children overall (p-value<0.001). A decrease in primary care costs was observed for ACP (p-value<0.001). There was an increasing trend in AOM primary care costs (p-value<0.001). No significant trends were observed in inpatient admission yearly rates in PP, ACP or IPD and inpatient costs per episode in PP, ACP and IPD. CONCLUSION: From 2003-2019, primary care HCRU and costs decreased (except for PP cost), but no trends in inpatient HCRU and costs were observed. The economic burden of pneumonia, IPD and AOM remains substantial in children aged ≤17 years in England.

Healthcare resource utilization and cost of pneumococcal disease in children in Germany, 2014-2019: a retrospective cohort study.

BACKGROUND: Since the introduction of higher valency pneumococcal conjugate vaccines in 2009, recent estimates on the economic burden of pediatric pneumococcal disease (PD) in Germany have been lacking. This study estimates healthcare resource utilization (HCRU) and medical cost associated with PDs in children < 16 years old in Germany from 2014-2019. METHODS: A nationally representative sample from the Institute for Applied Health Research (InGef) German claims database was used, covering approximately 5% of the total German population. Episodes of pneumococcal pneumonia (PP), all-cause pneumonia (ACP), invasive pneumococcal disease (IPD), and acute otitis media (AOM) in children aged < 16 years were identified using ICD-10-GM codes. HCRU was estimated from annual rates of outpatient visits, outpatient antibiotic prescriptions and inpatient admissions, divided by person-years (PY) at-risk. Average direct medical costs per episode were estimated as the total cost of all HCRU, divided by the total number of episodes. The Mann-Kendall test was used to assess monotonic time trends from 2014-2019. RESULTS:  During 2014-2019, 916,805 children aged < 16 years were followed up for a total of 3,608,716 PY. The average costs per episode for out-versus inpatient care associated with PP and ACP were €67 (95% CI 58-76) versus €2,606 (95% CI 1,338-3,873), and €63 (95% CI 62-63) versus €620 (95% CI 598-641), respectively. For IPD, the average medical cost per episode for out-versus inpatients were €30 (95% CI 19-42) versus €6,051 (95% CI 3,323-8,779), respectively. There were no significant trends in HCRU or costs for IPD or pneumonia over the study period, except for a significant reduction in ACP outpatient visits. A significant decrease in rate of outpatient visits and antibiotic prescribing for recurrent AOM was observed, in addition to an increase in rates of hospital admissions for simple AOM. This was paralleled by a significant increase in inpatient costs per episode for treating AOM overall, and simple AOM, over the study period. CONCLUSIONS:  The HCRU and cost per episode of pneumonia and IPD did not vary significantly from 2014-2019, but increased for AOM. The economic burden of pneumonia, IPD, and AOM remains substantial in Germany.

Incidence of pneumococcal disease from 2003 to 2019 in children ≤17 years in England.

BACKGROUND: Pneumococcal disease is a leading cause of communicable disease morbidity and mortality globally. We aimed to estimate invasive pneumococcal disease (IPD), pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) incidence rates (IRs) in children aged 0-17 years in England from 2003 to 2019. METHODS: A retrospective study in children ≤17 years old from 2003 to 2019 using the Clinical Practice Research Datalink (CPRD) Gold and Hospital Episodes Statistics Admitted Patient Care (HES APC) databases. IPD episodes were identified in hospital records (HES APC). PP (caused by Streptococcus pneumoniae only) and ACP episodes (caused by any pathogen) were identified in primary care (CPRD) and in hospital records (HES APC). Annual IRs by age-group were calculated as the number of episodes/person-years (PY) at risk, with 95% confidence intervals (95% CI). Interrupted time series analyses were conducted to assess changes in IRs across the post-PCV7 (2007-2009), early post-PCV13 (2011-2014) and late post-PCV13 (2015-2019) periods compared to the pre-PCV7 period (2003-2005) using generalized linear models. RESULTS: 170 IPD episodes, 769 PP episodes and 12,142 ACP episodes were identified in 1,500,686 children in 2003-2019. The overall IPD, PP and ACP IRs (per 100,000 PY) were 2.29 (95% CI 1.96-2.66), 10.34 (95% CI 9.62-11.10) and 163.37 (95% CI 160.47-166.30), respectively. The highest IPD, PP and ACP IRs were observed in children aged < 2 years compared to older children (2-4 and 5-17 years). IPD IRs decreased between the pre-PCV7 period and the late post-PCV13 period from 3.28 (95% CI 2.42-4.33) to 1.41 (95% CI 0.80-2.29), IRR 0.28 (95% CI 0.09-0.90), p-value 0.033. PP IRs declined between the pre-PCV7 period and the late post-PCV13 period from 14.65 (95% CI 12.77-16.72) to 3.87 (95% CI 2.81-5.20), IRR 0.19 (95% CI 0.09-0.38), p-value < 0.001. ACP IRs declined between the pre-PCV7 period and the late post-PCV13 period from 167.28 (95% CI 160.78-173.96) to 124.96 (95% CI 118.54-131.63), IRR 0.77 (95% CI 0.66-0.88), p-value < 0.001. CONCLUSIONS: The clinical burden of IPD, PP and ACP declined in children in England aged 0-17 years between 2003 and 2019, especially in the late post-PCV13 period. This study highlights the importance of PCV vaccination in reducing the burden of PD and ACP in children in England.

Incidence of acute otitis media from 2003 to 2019 in children ≤ 17 years in England.

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2006 and the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 in the UK. PCVs are active immunization for the prevention of invasive disease, pneumonia and acute otitis media (AOM) caused by Streptococcus pneumoniae in children. The aim of this observational study was to estimate incidence rates (IRs) of AOM in children ≤17 years from 2003 to 2019 in England, before and after the introduction of pneumococcal conjugate vaccines (PCVs). METHODS: AOM episodes were identified using Read diagnosis codes in children aged ≤17 years in the Clinical Practice Research Datalink (CPRD) Gold database from 2003 to 2019. Annual IRs with 95% confidence intervals (CI) by age group were calculated as the number of episodes/person-years (PY) at risk. Interrupted time series analyses were conducted to estimate incidence rate ratios (IRR) across post-PCV7 (2007-2009), early post-PCV13 (2011-2014) and late post-PCV13 (2015-2019) periods compared to the pre-PCV7 period (2003-2005) using generalized linear models. RESULTS: From 2003 to 2019, 274,008 all-cause AOM episodes were identified in 1,500,686 children. The overall AOM IR was 3690.9 (95% CI 3677.1-3704.8) per 100,000 PY. AOM IRs were highest in children aged < 5 years and decreased by age; < 2 years: 8286.7 (95% CI 8216.8-8357.1); 2-4 years: 7951.8 (95% CI 7902.5-8001.4); 5-17 years: 2184.4 (95% CI 2172.1-2196.8) (per 100,000 PY). Overall AOM IRs declined by 40.3% between the pre-PCV7 period and the late-PCV13 period from 4451.9 (95% CI 4418.1-4485.9) to 2658.5 (95% CI 2628.6-2688.7) per 100,000 PY, and across all age groups. IRRs indicated a significant decrease in AOM IRs in all the post-vaccination periods, compared to the pre-PCV7 period: post-PCV7 0.87 (95% CI 0.85-0.89), early post-PCV13 0.88 (95% CI 0.86-0.91), and late post-PCV13 0.75 (95% CI 0.73-0.78). CONCLUSIONS: The AOM IRs declined during the 2003-2019 period; however, the clinical burden of AOM remains substantial among children ≤17 years in England.

Clinical and economic burden of pneumococcal disease among individuals aged 16 years and older in Germany.

This study assessed the incidence rate of all-cause pneumonia (ACP) and invasive pneumococcal disease (IPD) and associated medical costs among individuals aged ≥16 in the German InGef database from 2016 to 2019. Incidence rate was expressed as the number of episodes per 100 000 person-years (PY). Healthcare resource utilisation was investigated by age group and by risk group (healthy, at-risk, high-risk). Direct medical costs per ACP/IPD episode were estimated as the total costs of all inpatient and outpatient visits. The overall incidence rate of ACP was 1345 (95% CI 1339-1352) and 8.25 (95% CI 7.76-8.77) per 100 000 PY for IPD. For both ACP and IPD, incidence rates increased with age and were higher in the high-risk and at-risk groups, in comparison to the healthy group. ACP inpatient admission rate increased with age but remained steady across age-groups for IPD. The mean direct medical costs per episode were €8075 (95% CI 7121-9028) for IPD and €1454 (95% CI 1426-1482) for ACP. The aggregate direct medical costs for IPD and ACP episodes were estimated to be €8.5 million and €248.9 million respectively. The clinical and economic burden of IPD and ACP among German adults is substantial regardless of age.

Pneumococcal vaccination coverage in individuals (16-59 years) with a newly diagnosed risk condition in Germany.

BACKGROUND: Despite recommendations from the German Standing Committee on Vaccination (STIKO), pneumococcal vaccination coverage remains low in vulnerable populations. This study estimated the pneumococcal vaccination coverage rate (VCR) and timing among individuals aged 16-59 years in Germany who were recommended to receive pneumococcal vaccination, according to STIKO. METHODS: A retrospective cohort analysis was conducted using the German InGef database. Individuals aged 16 to 59 years diagnosed with at least one "at-risk" (chronic disease) or "high-risk" (e.g., immunocompromising) condition considered to be at-risk of pneumococcal infection were identified at the time of first diagnosis, between January 1, 2016 and December 31, 2018, and followed up until December 31, 2019. The percentage of cumulative pneumococcal VCR with 95% confidence interval (CI) was reported for each calendar year of follow-up. RESULTS: There were 334,292 individuals followed for a median of 2.38 (interquartile range (IQR) 1.63-3.13) person years. For individuals aged 16-59 years diagnosed with an incident risk condition in 2016, pneumococcal VCR increased from 0.44% (95% CI 0.41-0.48) in 2016 to 1.24% (95% CI 1.18-1.30) in 2019. In 2019, VCRs were higher in individuals with high-risk conditions compared with at-risk conditions (2.24% (95% CI 2.09-2.40) vs. 0.90% (95% CI 0.85-0.96)). In 2019, VCRs were higher in individuals aged 50 to 59 years compared with individuals aged 16 to 49 years (2.25% (95% CI 2.10-2.41) vs. 0.90% (95% CI 0.84-0.96)). Similar trends were observed in individuals with newly diagnosed risk conditions identified in 2017 and in 2018. Older age, influenza vaccination and increasing number of risk conditions increased the likelihood of pneumococcal vaccination. Median time to vaccination from diagnosis of the risk condition was shorter for high-risk conditions (369.5 days (IQR 155.8-702.0)) compared to at-risk conditions (435.5 days (IQR 196.3-758.8)). CONCLUSION: Despite recommendations from STIKO, pneumococcal vaccination coverage remains very low and with long delays in vulnerable individuals aged 16-59 in Germany. Further efforts are required to increase immunization levels and shorten time to vaccination among individuals 16-59 years of age developing conditions with higher susceptibility to pneumococcal infection.

Incidence of acute otitis media in children < 16 years old in Germany during 2014-2019.

BACKGROUND: Acute otitis media (AOM) remains a common infection in children despite the introduction of pneumococcal conjugate vaccines. This study estimated AOM incidence rates (IRs) over time in children < 16 years old in Germany following PCV13 introduction. METHODS: AOM episodes were identified in the InGef healthcare claims database from 2014-2019 in children aged < 16 years. Each AOM episode was classified as either simple or recurrent. Recurrent AOM was defined as 3 or more episodes identified within a 6-month period; or 4 or more episodes within a 12-month period with at least one episode in the prior 6 months. AOM-related surgical procedures within 12 months and complications within 21 days of an AOM episode were also identified. Annual IRs were calculated as number of episodes/child-years (CY) at risk. 95% Confidence intervals (95%CI) were calculated using the Wilson method. The Mann-Kendall test was used to assess trends over time. RESULTS: Between 2014 and 2019, the study population comprised 916,805 children with 327,726 AOM episodes, of which 15% (49,011) of all episodes were identified as recurrent AOM and 85% (278,715) as simple AOM. There were significant declines in AOM (p = 0.003) in the study population overall and in all age groups over the study period; from 101 (95%CI 101-102)/1000 CY to 79 (95%CI 78-80)/1000 CY in the total study population, from 209 (95%CI 206-212)/1000 CY to 147 (95%CI 145-150)/1000 CY in < 2-year-olds, from 239 (95%CI 237-242) to 179 (95%CI 177-182)/1000 CY in 2-4-year-olds, and from 50 (95%CI 49-50) to 38 (95%CI 37-39)/1000 CY in 5-15-year-olds. No significant trends were identified for AOM-related surgical procedures over the study period; however, AOM-related complications overall increased (p = 0.003). CONCLUSION: Between 2014 and 2019, AOM incidence overall declined in children aged 0-15 years in Germany. Over the study period, the incidence of complicated AOM cases increased, however the incidence of AOM-related surgical procedures remained constant. Despite the impact of PCV13, the burden associated with AOM in Germany remains substantial.

Antipsychotic treatment patterns in Alzheimer's disease patients with agitation: a cohort study using the UK clinical practice research datalink.

OBJECTIVES: There is a lack of robust epidemiological evidence on antipsychotic (AP) use in patients with agitation in Alzheimer's disease (AD). Authors studied AP use in patients with AD and agitation and compared their use with patients with other or no neuropsychiatric symptoms (NPS). METHODS: A retrospective cohort study in the UK Clinical Practice Research Datalink, included patients with AD between January 1st, 2015, and December 31st, 2017. AP use was compared between patients with agitation, other types of NPS and no NPS. RESULTS: There were 24,464 patients with AD, median follow-up of 1.1 years (interquartile range [IQR] 0.5-2.1), and median age 83 years (78-88). A larger percentage of patients with agitation (n = 2432) were prescribed APs (38.2%) than other NPS (n = 13,076, 20.4%) and no NPS (n = 11,816, 12.2%). Compared to patients with no NPS, adjusted hazard ratios for AP use were 3.45 (95% CI 2.86-4.17) for patients with agitation and 1.31 (95% CI 1.19-1.44) for patients with other NPS. Among users of APs, the treatment discontinuation rate at six months was 44.8% in patients with agitation (other NPS 57.1%; no NPS 63.5%). CONCLUSIONS: Patients with AD and agitation were frequently prescribed APs and for long periods in routine clinical practice in the UK. The high real-life usage of APs suggests that physicians prefer using APs for the treatment of agitation despite recommendations against their long-term use. These data support a need for AP therapies that better address known safety concerns with currently used APs to treat agitation in elderly patients with AD.

Effectiveness of Additional Risk Minimization Measures for Atezolizumab in the European Union.

BACKGROUND: A Guide for Healthcare Professionals (HCP Guide) and patient alert card (PAC) for atezolizumab as additional risk minimization measures for physicians were distributed to raise awareness and help in the detection and management of immune-related adverse drug reactions. OBJECTIVES: The main objective of this study was to assess the receipt, knowledge, and behaviors of physicians regarding the atezolizumab HCP Guide and PAC. METHODS: A multi-country, one-wave, observational, cross-sectional, web-based, self-reported physician survey was conducted to assess the level of knowledge of key messages related to immune-related adverse drug reactions summarized in the atezolizumab HCP Guide and PAC among physicians (oncologists, pulmonologists, and urologists) prescribing atezolizumab in six European countries (Denmark, Germany, Italy, Spain, Sweden, and the UK). Responses regarding the receipt, understanding and use of the materials, and knowledge and behavior related to the HCP Guide and PAC are presented as percentages and continuous scores scaled out of 100 points, with corresponding 95% confidence intervals (CIs). RESULTS: Among 313 physicians (255 oncologists, 30 pulmonologists, and 28 urologists), 77.4% received the HCP Guide and 74.2% the PAC. The HCP Guide was read by 71.3% of the 267 physicians who received the materials, and the mean usage score was 69.5 (95% CI 66.0-72.9), and 57.1% of physicians had scores ≥ 70. The HCP Guide was completely understood by 85.4% of physicians who had read it. Mean knowledge scores were 63.9 (95% CI 62.1-65.7) and 39.4% of physicians had correct knowledge scores ≥ 70. Mean knowledge scores were 66.8 (95% CI 64.9-68.7) for receipt of both the HCP Guide and PAC, 59.4 (95% CI 55.5-63.4) for one of the materials, and 60.8 (95% CI 55.4-66.2) for having received none of the materials. Mean behavior scores were 78.9 (95% CI 76.8-81.0), and 74.8% of physicians had behavior scores ≥ 70. The mean behavior score was 79.0 (95% CI 76.5-81.5) for those who received both the HCP Guide and PAC, 76.9 (95% CI 72.2-81.5) for receipt of one of the materials, and 81.5 (95% CI 75.0-88.0) for those who received none of the materials. CONCLUSIONS: The study assessed the effectiveness of the atezolizumab additional risk minimization educational materials among physicians in six European countries, using process indicators. The educational materials reached over 70% of target physicians, 57.1% of whom reported using them. Knowledge and behavior related to immune-related adverse drug reactions for atezolizumab were no better in those who received the additional risk minimization educational materials. The results support the safe use of atezolizumab by these physician groups and contributed to the European Medicines Agency permitting removal of the HCP Guide.

A Prospective Open-Label Observational Study of a Buffered Soluble 70 mg Alendronate Effervescent Tablet on Upper Gastrointestinal Safety and Medication Errors: The GastroPASS Study.

Upper gastrointestinal (GI) side effects are a main reason for discontinuing bisphosphonate treatment, an important therapeutic option for osteoporosis patients. Consequently, the development of novel formulations with improved tolerability is warranted. In this multicenter prospective, observational, postauthorization safety study conducted in Italy and Spain, postmenopausal women (PMW) with osteoporosis (naïve to bisphosphonates) were treated weekly with a buffered soluble alendronate 70 mg effervescent (ALN-EFF) tablet (Binosto®) and followed for 12 ± 3 months. Information was collected on adverse events (AEs), medication errors, persistence, and compliance using the Morisky-Green questionnaire. Patients (N = 1028) aged 67 ± 9 years (mean ± SD) received ALN-EFF weekly. The cumulative incidence of upper GI AEs (oesophageal toxicity, gastritis, gastric ulcers, and duodenitis) related to ALN-EFF (primary endpoint) was 9.6% (95% confidence interval [CI] 7.9-11.6%), the vast majority being of mild intensity. The most frequently occurring upper GI AEs related to ALN-EFF were dyspepsia (2.7%), gastroesophageal reflux disease (2.4%), and nausea (2.2%). None of the relevant upper GI AEs listed in the primary endpoint and no serious AEs were reported. At least one medication error occurred in 29.9% (95% CI 27.1-32.8%) of patients. However, the majority of medication errors were associated with administration instructions applicable to any oral bisphosphonate and only seven medication errors were associated with the ALN-EFF formulation. ALN-EFF was discontinued in 209 of 1028 (20.3%) patients. The most frequent reasons for discontinuation were AEs related to ALN-EFF (46.9%) and patients' decision (42.6%). Compliance with ALN-EFF was high, reflected by a mean Morisky-Green score of 92.8 ± 18.6. PMW with osteoporosis treated with ALN-EFF in a real-world setting experienced few upper GI AEs. In addition, they had a low discontinuation and high compliance compared with other formulations, suggesting that ALN-EFF may increase patient satisfaction and therefore long-term adherence and efficacy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study.

BACKGROUND: Uncertainty remains concerning the association of blood cholesterol with the risk of subsequent dementia. Using data from people with lipid measurements in the UK Clinical Practice Research Datalink (CPRD), we examined the association between blood lipid levels and dementia (both vascular and non-vascular, including Alzheimer's disease) by age at first measurement of blood lipids and duration of follow-up. METHODS: We studied a cohort from the UK CPRD of people aged 40 years or older with a first total cholesterol recording between Jan 1, 1992, and Dec 31, 2009. Follow-up was until the first record of dementia, the last data collection date, patient death or transfer out of the practice, or Jan 5, 2015, whichever was earliest. We excluded individuals with a record of dementia before the total cholesterol measurement. We used Poisson regression to examine the association between baseline total cholesterol, LDL cholesterol and HDL cholesterol, and triglycerides and incident dementia diagnosis. Analyses were stratified by age at first measurement (<65 years or ≥65 years) and duration of follow-up (<10 years or ≥10 years). Our primary focus was LDL cholesterol. We adjusted for age, sex, calendar year, country within the UK, socioeconomic status, ethnicity, smoking, alcohol, body-mass index, comorbidities, and prescriptions. FINDINGS: 1 853 954 people had a first total cholesterol recording (dementia diagnosis in 49 416 [2·7%] people), including 953 635 [51·4%] people with LDL cholesterol values for analysis (dementia diagnosis in 21 602 [2·3%] people). Overall, we found a modest positive association between LDL cholesterol and dementia, with an adjusted rate ratio (RR) of 1·05 (95% CI 1·03-1·06) per SD increase in LDL cholesterol (1·01 mmol/L or 39 mg/dL increase). Adjusted RRs per 1-SD increase in LDL cholesterol in people younger than 65 years at baseline (n=636 262) were 1·10 (95% 1·04-1·15) for dementia diagnosed in the first 10 years after measurement and 1·17 (1·08-1·27) for dementia diagnosed more than 10 years after measurement. Associations for LDL cholesterol in people aged 65 years or older at baseline (n=317 373) were weaker compared with people younger than 65 years (RR 1·03 [95% CI 1·01-1·05] for dementia diagnosed during the first 10 years of follow-up and 1·07 [1·03-1·13] for dementia diagnosed after 10 years). We observed a weaker association between total cholesterol and dementia incidence and no consistent associations for HDL cholesterol and triglycerides. INTERPRETATION: LDL cholesterol measured in mid-life (<65 years) is modestly associated with dementia risk more than 10 years later. LDL cholesterol should be added to the list of modifiable risk factors for dementia. FUNDING: The Alzheimer's Society.

Localised neuropathic pain in the primary care setting: a cross-sectional study of prevalence, clinical characteristics, treatment patterns, quality of life and sleep performance.

BACKGROUND: Localised Neuropathic Pain (LNP) is challenging to diagnose and manage in primary care. OBJECTIVE: To describe clinical characteristics, treatment patterns, quality of life and sleep performance of patients with LNP and estimate its prevalence in primary care. METHODS: Cross-sectional study in 4 European countries. Patients were identified using a screening tool for LNP. Patients completed the EQ-5D VAS score and Chronic Pain Sleep Inventory (CPSI). RESULTS: There were 1030 LNP patients for analysis. They presented a median pain intensity of 6.0 (IQR 4.0-7.0) with a median duration of 30.9 months (IQR 12.0-75.3), despite 97% receiving pain treatment. Main sites affected were the limbs (62% upper/58% lower) and spine (41%). Main aetiologies were neuropathic low back pain (47%), post-surgical neuropathic pain (17%), and diabetic poly-neuropathy (12%). Thirty percent received a single analgesic (2% topical), while combinations comprised 43% systemic-systemic, 24% topical-systemic, 1% topical-topical. Medications included NSAIDs (45%), anticonvulsants (38%), WHO step 2 opioids (35%), and topical analgesics (27%). In the previous 6 months, 40% had switched treatment. The mean (SD) EQ-5D VAS score was 58 (22.3) and the mean (SD) EQ-5D summary score (UK tariff) was 0.62 (0.25). Patients had a CPSI mean index of 41/100, and sleeping pills were used by 33% of patients. The standardized prevalence of LNP by age and sex was 2.01% in the general population and 43.3% among chronic pain patients. CONCLUSIONS: Many LNP patients reported pain intensities of six on a ten-point scale in average for durations longer than 2.5 years, with quality of life and sleep performance affected, with frequent treatment combinations and switches, suggesting suboptimal pain management.

Risk Minimisation Evaluation with Process Indicators and Behavioural or Health Outcomes in Europe: Systematic Review.

BACKGROUND: European Pharmacovigilance regulatory guidance recommends the evaluation of additional risk minimisation measures (aRMMs) with process indicators and outcomes. Evaluation of both measures within the same evaluation helps to establish the relationship between the implementation of aRMMs (across process indicators) and the impact on drug safety-related outcomes. The term risk minimisation evaluation (RMEv) was used to describe a study or group of studies that assesses the effectiveness of aRMMs for one specific product. OBJECTIVES: The objective of this systematic review was to describe the characteristics and results of RMEv that include both process indicators and outcomes as well as those of studies that conform the RMEv in Europe. METHODS: We conducted a systematic search in the European Union Register of Post-Authorization Studies, PubMed and grey literature (Google and abstracts of the International Conference on Pharmacoepidemiology and Therapeutic Risk Management) to identify studies that assessed the effectiveness of aRMMs including at least one European country, from 1 January, 2011 to 12 October, 2019. Identified studies linked to one product were considered part of the product RMEv. Only RMEv that included both process indicators and outcomes (behavioural and/or health/safety outcomes) were eligible. Data were abstracted from reports, manuscripts and abstracts. RESULTS: Eighteen of 102 (18%) RMEv had both process indicators and outcomes, and were included in this review. Of the 18 RMEv, ten consisted of one study only, five of two studies, and three of three or more studies. A total of 30 studies were included within the 18 RMEv. The designs of the studies were: 19 (63%) cross-sectional surveys (47% targeted patients and 89% healthcare professionals), 17 (57%) retrospective studies (47% using pre/post approach) and 3 (10%) prospective studies. Nineteen studies included process indicators that were receipt (n = 14), use (n = 12), knowledge (n = 17) and self-reported behaviour (n = 15). Regarding outcomes, 67% of the 18 RMEv evaluated behavioural outcomes and 50% health/safety outcomes. Three of the 18 RMEv evaluated both behavioural and health/safety outcomes. For five RMEv, correlations between process indicators and outcomes were performed, two at the patient level. Results were available for 14 of the 18 RMEv. In healthcare professional surveys, the median percentage was 57% for receipt, 92% for reading, 80% for use, 77% for knowledge and 74% for behaviour. In patient surveys, the median percentage was 56% for receipt, 87% for reading, 65% for use, 47% for knowledge and 69% for behaviour. Knowledge was better in healthcare professionals than patients (p < 0.05). Of the three RMEv with a correlation analysis, only one found a positive trend for a lower occurrence of outcomes as process indicators improved, though this was not statistically significant. CONCLUSIONS: A minority of RMEv assessed both process indicators and outcomes. More RMEv require approaches that correlate process indicators and outcomes at the patient level to evaluate more comprehensively the implementation of aRMMs.

Linking process indicators and clinical/safety outcomes to assess the effectiveness of abatacept (ORENCIA) patient alert cards in patients with rheumatoid arthritis.

PURPOSE: Patient alert cards (PACs) for abatacept (ORENCIA) inform patients and healthcare professionals (HCPs) about the risk of infections and allergic reactions. The study evaluates the effectiveness of the PACs in rheumatoid arthritis patients and HCPs, using process indicators (awareness, receipt, utility, knowledge, behaviour) and outcomes. METHODS: Surveys of patients and HCPs in five European countries. A retrospective chart review permitted linking clinical and safety outcomes with survey responses. RESULTS: Data on 190 patients and 79 HCPs (50 physicians and 29 nurses) were analysed. Sixty percent of patients were aware of the PAC, of whom 95% had received it. Knowledge of risk of infection was higher among patients who had received the PAC vs those who had not (64% vs 46%; P = .013). Infections leading to hospitalisation increased with decreasing patient survey global scores: scores of ≥67%, 34%-67% and ≤ 33% were associated with hospitalisation rates of 2.5%, 5.2% and 8.4%, respectively (P = .4). Among HCPs 90% were aware and 68% had accessed the PAC. More nurses than physicians were aware (93% vs 88%), had accessed (78% vs 74%), read (90% vs 59%), distributed (81% vs 66%) and explained the content (94% vs 43%) of the PAC. Knowledge of risk of infection was higher among HCPs who had (91%) vs those who had not (73%) accessed the PAC (P = .053). CONCLUSIONS: PACs were effective in improving knowledge of key safety messages in patients and HCPs. This novel study design bridges the gap of linking process indicators with outcomes in the same patients, thereby strengthening the clinical relevance of patient surveys.

Burden of disease from shingles and post-herpetic neuralgia in the over 80 year olds in the UK.

BACKGROUND: The current UK vaccination programme for herpes zoster (HZ) excludes people aged ≥80 years. This study aimed to quantify the number of individuals ≥80 years who missed HZ vaccination and the consequent epidemiological and economic burden of HZ and post-herpetic neuralgia (PHN). METHODS: Immunocompetent individuals aged ≥80 years between 1st September 2013 and 31st December 2017 in the Clinical Practice Research Datalink were selected and linked to Hospital Episodes Statistics, where available. Rates of HZ and PHN and healthcare resource utilisation were investigated for the overall study population and by age group (80-84, 85-89, ≥90 years old) and the burden of HZ and PHN was projected to the UK population. RESULTS: 4,858 HZ episodes and 464 PHN cases were identified in 255,165 individuals over 576,421 person-years (PY). Rates of HZ and PHN were 8.43 (95% confidence interval [CI] 8.19-8.66) and 0.80 (0.73-0.87) per 1,000 PY respectively and lowest in those aged ≥90 (HZ rate 7.37/1,000 PY; PHN rate 0.56/1,000 PY). Within HZ episodes, 10.27% of GP visits, 5.82% of prescribed medications and 21.65% of hospitalisations were related to HZ/PHN. Median length of hospitalisation increased from 7.0 days for all-cause to 10.5 days for HZ/PHN related hospitalisations. Individuals ≥90 stayed in hospital a median of 3-4 days longer than younger groups. Approximately 2.23 million individuals in the UK missed HZ vaccination since 2013 (1.86 million had never been eligible and 365,000 lost eligibility for HZ vaccination), resulting in an estimated 43,149 HZ episodes. CONCLUSION: This study highlights the impact of the 80-year upper age limit policy on the health system. Our study estimates that 2.23 million individuals in the UK may have lost the opportunity to be vaccinated and that their burden of HZ and PHN remains high, especially among the very elderly.

Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia.

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.