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BACKGROUND: While several definitions exist for multimorbidity, frailty or polypharmacy, it is yet unclear to what extent single healthcare markers capture the complexity of health-related needs in older people in the community. We aimed to identify and characterise older people with complex health needs based on healthcare resource use (unplanned hospitalisations or polypharmacy) or frailty using large population-based linked records. METHODS: In this cohort study, data was extracted from UK primary care records (CPRD GOLD), with linked Hospital Episode Statistics inpatient data. People aged > 65 on 1st January 2010, registered in CPRD for ≥ 1 year were included. We identified complex health needs as the top quintile of unplanned hospitalisations, number of prescribed medicines, and electronic frailty index. We characterised all three cohorts, and quantified point-prevalence and incidence rates of preventive medicines use. RESULTS: Overall, 90,597, 110,225 and 116,076 individuals were included in the hospitalisation, frailty, and polypharmacy cohorts respectively; 28,259 (5.9%) were in all three cohorts, while 277,332 (58.3%) were not in any (background population). Frailty and polypharmacy cohorts had the highest bi-directional overlap. Most comorbidities such as diabetes and chronic kidney disease were more common in the frailty and polypharmacy cohorts compared to the hospitalisation cohort. Generally, prevalence of preventive medicines use was highest in the polypharmacy cohort compared to the other two cohorts: For instance, one-year point-prevalence of statins was 64.2% in the polypharmacy cohort vs. 60.5% in the frailty cohort. CONCLUSIONS: Three distinct groups of older people with complex health needs were identified. Compared to the hospitalisation cohort, frailty and polypharmacy cohorts had more comorbidities and higher preventive therapies use. Research is needed into the benefit-risk of different definitions of complex health needs and use of preventive therapies in the older population.
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Fragilidade , Humanos , Idoso , Estudos de Coortes , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Web Semântica , Hospitais , Atenção Primária à Saúde , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma. METHODS/DESIGN: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom. TRIAL REGISTRATION: ISRCTN84434175. Registered 12 November 2018.
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Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Ipilimumab/administração & dosagem , Temozolomida/administração & dosagem , Adulto , Idoso , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Quimiorradioterapia , Procedimentos Cirúrgicos de Citorredução , Feminino , Glioblastoma/radioterapia , Glioblastoma/cirurgia , Humanos , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Temozolomida/uso terapêutico , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
OBJECTIVES: Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of deterioration. The objective of this study was to evaluate the application of joint latent class model in identifying trajectories of frailty progression over time and their group-specific risk of death in older people. STUDY DESIGN AND SETTING: The primary care records of UK patients, aged over 65 as of January 1, 2010, included in the Clinical Practice Research Datalink: GOLD and AURUM databases, were analyzed and linked to mortality data. The electronic frailty index (eFI) scores were calculated at baseline and annually in subsequent years (2010-2013). Joint latent class model was used to divide the population into clusters with different trajectories and associated mortality hazard ratios. The model was built in GOLD and validated in AURUM. RESULTS: Five trajectory clusters were identified and characterized based on baseline and speed of progression: low-slow, low-moderate, low-rapid, high-slow, and high-rapid. The high-rapid cluster had the highest average starting eFI score; 7.9, while the low-rapid cluster had the steepest rate of eFI progression; 1.7. Taking the low-slow cluster as reference, low-rapid and high-rapid had the highest hazard ratios: 3.73 (95% CI 3.71, 3.76) and 3.63 (3.57-3.69), respectively. Good validation was found in the AURUM population. CONCLUSION: Our research found that there are vulnerable subgroups of the older population who are currently frail or have rapid frailty progression. Such groups may be targeted for greater healthcare monitoring.
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Objectives: This study aimed to investigate the anti-PD-1 inhibitor pembrolizumab as a potential agent for use in non-muscle-invasive bladder cancer (NMIBC) by conducting a Phase 1 safety run-in study to assess the safety and tolerability of intravesical pembrolizumab after transurethral resection of the bladder tumour (TURBT). Patients and methods: Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 and adequate end-organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of six doses. Intra-patient dose escalation was performed in three paired patient cohorts with doses starting at 50 mg and increasing through 100 mg to a maximum of 200 mg. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug-related, Grade 4 haematological or Grade 3 or higher non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results: Six patients were treated with no DLTs seen during dose escalation. Drug-related AEs were of low grade and included dysuria and fatigue. All patients completed six doses of treatment as planned. Pharmacokinetic and pharmacodynamic assays did not detect any pembrolizumab in the serum following repeated intravesical administration, and no changes in peripheral immune cell populations were observed. Conclusions: Administration of intravesical pembrolizumab was well tolerated and did not raise any safety concerns in patients with NMIBC following TURBT. There was no evidence of systemic absorption or systemic immune effects following intravesical administration. Further studies are required to assess whether intravesical administration has anti-tumour activity.
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BACKGROUND: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects. OBJECTIVES: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time. DESIGN: This was a new-user cohort study design with propensity score matching. SETTING AND DATA SOURCES: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4. PARTICIPANTS: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4. INTERVENTIONS/EXPOSURE: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure. MAIN OUTCOME MEASURES: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change. RESULTS: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users. LIMITATIONS: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively. CONCLUSIONS: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness. FUTURE WORK: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data. STUDY REGISTRATION: This study is registered as EUPAS10029. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.
RATIONALE AND AIMS: Bisphosphonates are used to prevent fractures in people with fragile bones. People with chronic kidney disease have a high risk of fracturing, but the safety and effectiveness of bisphosphonates in severe chronic kidney disease is unclear. The aim of this study was to assess the benefits (e.g. bone strength improvement and fracture prevention) and the risks of unwanted effects associated with bisphosphonates for people with moderate to severe chronic kidney disease. METHODS: Anonymised primary and secondary care electronic medical records data from the UK NHS were used, as well as a Danish equivalent that included bone density scans. Anyone in these databases with a measure of reduced kidney function that suggested moderate to severe chronic kidney disease was eligible, which was > 220,000 people from the UK. Over 20,000 of them used bisphosphonates. Bisphosphonate users were matched to non-users with similar age, sex and other characteristics. RESULTS: Bisphosphonate users had a 12% higher risk of their chronic kidney disease getting worse than non-users. Their risks of other side effects, such as acute kidney injuries and gastrointestinal problems, did not change. Bisphosphonate users had a 25% higher risk of fractures than non-users in the UK database, probably because the matching methods did not create similar-enough groups of users and non-users. However, it was found that bisphosphonate improved bone density in the Danish database. Bone density is a proxy for bone strength, so better bone density should mean fewer fractures. CONCLUSIONS: These results suggest that bisphosphonate therapy may make moderate to severe chronic kidney disease worse. More studies are needed on how bisphosphonates affect milder chronic kidney disease. Bisphosphonates were associated with better bone strength, but it could not be demonstrated that they reduced fracture risk. More data are required, probably from a placebo-controlled trial, to determine whether or not bisphosphonates prevent fractures in people with moderate to severe chronic kidney disease and whether or not this is worth the risk of their chronic kidney disease worsening.
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Fraturas Ósseas , Insuficiência Renal Crônica , Estudos de Coortes , Difosfonatos/efeitos adversos , Fraturas Ósseas/epidemiologia , Humanos , Pontuação de Propensão , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologiaRESUMO
Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Osteoporose , Insuficiência Renal Crônica , Estudos de Coortes , Difosfonatos/efeitos adversos , Taxa de Filtração Glomerular , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Fatores de RiscoRESUMO
INTRODUCTION: A full blood count (FBC) blood test includes 20 components. We systematically reviewed studies that assessed the association of the FBC and diagnosis of colorectal cancer to identify components as risk factors. We reviewed FBC-based prediction models for colorectal cancer risk. METHODS: MEDLINE, EMBASE, CINAHL, and Web of Science were searched until 3 September 2019. We meta-analysed the mean difference in FBC components between those with and without a diagnosis and critically appraised the development and validation of FBC-based prediction models. RESULTS: We included 53 eligible articles. Three of four meta-analysed components showed an association with diagnosis. In the remaining 16 with insufficient data for meta-analysis, three were associated with colorectal cancer. Thirteen FBC-based models were developed. Model performance was commonly assessed using the c-statistic (range 0.72-0.91) and calibration plots. Some models appeared to work well for early detection but good performance may be driven by early events. CONCLUSION: Red blood cells, haemoglobin, mean corpuscular volume, red blood cell distribution width, white blood cell count, and platelets are associated with diagnosis and could be used for referral. Existing FBC-based prediction models might not perform as well as expected and need further critical testing.
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BACKGROUND: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). METHODS: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. RESULTS: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III-IV AEs. Six-month PFS was 85% (90% CI: 66%-94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). CONCLUSION: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791).
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/administração & dosagem , Neoplasias Esofágicas/terapia , Oxaloacetatos/administração & dosagem , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Neoplasias Gástricas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Exantema/induzido quimicamente , Exantema/epidemiologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Masculino , Margens de Excisão , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Oxaloacetatos/efeitos adversos , Intervalo Livre de Progressão , Quinazolinas/efeitos adversos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Vômito/induzido quimicamente , Vômito/epidemiologiaRESUMO
Oral bisphosphonates (oBPs) have been associated with reduced fractures and mortality. However, their risks and benefits are unclear in patients with moderate-severe CKD. This study examined the association between oBPs and all-cause mortality in G3B-5D CKD. This is a population-based cohort study including all subjects with an estimated glomerular filtration rate (eGFR) <45/mL/min/1.73 m2 (G3B: eGFR <45/mL/min/1.73 m2 G4: eGFR 15-29/mL/min/1.73 m2 G5: eGFR <15/mL/min/1.73 m2 G5D: hemodialysis) aged 40+ years from the UK Clinical Practice Research Datalink (CPRD) and the Catalan Information System for Research in Primary Care (SIDIAP). Previous and current users of other anti-osteoporosis drugs were excluded. oBP use was modeled as a time-varying exposure to avoid immortal time bias. Treatment episodes in oBP users were created by concatenating prescriptions until patients switched or stopped therapy or were censored or died. A washout period of 180 days was added to (date of last prescription +180 days). Propensity scores (PSs) were calculated using prespecified predictors of mortality including age, gender, baseline eGFR, socioeconomic status, comorbidities, previous fracture, co-medications, and number of hospital admissions in the previous year. Cox models were used for PS adjustment before and after PS trimming (the first and last quintiles). In the CPRD, of 19,351 oBP users and 210,954 non-oBP users, 5234 (27%) and 85,105 (40%) deaths were recorded over 45,690 and 915,867 person-years of follow-up, respectively. oBP users had 8% lower mortality risk compared to non-oBP users (hazard ratio [HR] 0.92; 95% CI, 0.89 to 0.95). Following PS trimming, this became nonsignificant (HR 0.98; 95% CI, 0.94 to 1.04). In the SIDIAP, of 4146 oBP users and 86,127 non-oBP users, 1330 (32%) and 36,513 (42%) died, respectively. oBPs were not associated with mortality in PS adjustment and trimming (HR 1.04; 95% CI, 0.99 to 1.1 and HR 0.95; 95% CI, 0.89 to 1.01). In this observational, patient-based cohort study, oBPs were not associated with increased mortality among patients with moderate-severe CKD. However, further studies are needed on other effects of oBPs in CKD patients. © 2020 American Society for Bone and Mineral Research.
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Osteoporose , Insuficiência Renal Crônica , Estudos de Coortes , Difosfonatos/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologiaRESUMO
INTRODUCTION: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer-related deaths in the UK. The full blood count (FBC) is a blood test that may play a role in early detection of the disease. Previous studies have aimed to identify how levels of individual components, such as haemoglobin, can be used to assist the diagnosis. We aim to systematically review studies to identify whether components of the FBC are risk factors for diagnosis of colorectal cancer, critically appraise the methods used to assess the association and assess performance of the components. METHODS AND ANALYSIS: The MEDLINE (via OVID), EMBASE (via OVID), CINAHL (via EBSCOhost) and Web of Science databases will be searched to identify studies reporting the association between the levels of at least one FBC component and the risk of a future diagnosis of colorectal cancer in undiagnosed individuals. Clincialtrials.gov and the WHO registry will be searched to identify relevant ongoing research. Search terms will include relevant Medical Subject Headings and Emtree headings, and free-text terms relating to FBC, colorectal cancer and diagnosis. No date or language restrictions will be applied. Two reviewers will independently identify the studies for inclusion and perform data extraction. Time intervals between the blood tests and diagnosis will form the subgroups for analysis. ETHICS AND DISSEMINATION: There is no direct patient involvement and only published articles will be reviewed; no ethical approval is required. Results from this review will set a foundation for intended future work on developing a new risk score for early detection of colorectal cancer, derived using FBC data. This systematic review will also provide guidance on the analysis of time to diagnosis. The model will be freely available to UK primary care practices. PROSPERO REGISTRATION NUMBER: CRD42019134400.