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BackgroundIt remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients.MethodsCohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019.FindingsConsultations for cancer clinical features decreased by 24.19% (95% CI: 24.04–24.34%) between 2019 and 2020, particularly in the 6–12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82–11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years.ConclusionDue to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.

AbstractObjectivesTo report reliable estimates of short term and long term survival rates for people with a diagnosis of heart failure and to assess trends over time by year of diagnosis, hospital admission, and socioeconomic group.DesignPopulation based cohort study.SettingPrimary care, United Kingdom.ParticipantsPrimary care data for 55 959 patients aged 45 and overwith a new diagnosis of heart failure and 278 679 age and sex matched controls in the Clinical Practice Research Datalink from 1 January 2000 to 31 December 2017 and linked to inpatient Hospital Episode Statistics and Office for National Statistics mortality data.Main outcome measuresSurvival rates at one, five, and 10 years and cause of death for people with and without heart failure; and temporal trends in survival by year of diagnosis, hospital admission, and socioeconomic group.ResultsOverall, one, five, and 10 year survival rates increased by 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2000 to 48.2% in 2012), and 6.4% (from 19.8% in 2000 to 26.2% in 2007), respectively. There were 30 906 deaths in the heart failure group over the study period. Heart failure was listed on the death certificate in 13 093 (42.4%) of these patients, and in 2237 (7.2%) it was the primary cause of death. Improvement in survival was greater for patients not requiring admission to hospital around the time of diagnosis (median difference 2.4 years; 5.3 v 2.9 years, P<0.001). There was a deprivation gap in median survival of 0.5 years between people who were least deprived and those who were most deprived (4.6 v 4.1 years, P<0.001).ConclusionsSurvival after a diagnosis of heart failure has shown only modest improvement in the 21st century and lags behind other serious conditions, such as cancer. New strategies to achieve timely diagnosis and treatment initiation in primary care for all socioeconomic groups should be a priority for future research and policy.

AbstractObjectiveTo examine the association between antihypertensive treatment and specific adverse events.DesignSystematic review and meta-analysis.Eligibility criteriaRandomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.Information sourcesSearches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.Main outcome measuresThe primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2).ResultsOf 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.ConclusionsThis meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.RegistrationPROSPERO CRD42018116860.

Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data. This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out. Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.

This retrospective analysis of the Cancer Analysis System registry in England describes the characteristics, systemic anti-cancer therapy (SACT) use, and survival outcomes of patients with multiple myeloma (MM), overall, by therapy line (L), and by autologous stem cell therapy (ASCT) status. Of 20,240 patients not on Cancer Drugs Fund therapies between January 2014 and December 2019, 12,095 had ≥ 1 SACT record and 3,419 received ASCT. Overall, regimens were aligned with national recommendations, but treatment sequencing differed by ASCT status, with 99.3% of ASCT patients subsequently receiving bortezomib-based regimens vs. 83.5% of non-ASCT patients. Time to next treatment or death decreased from 17.3 months at 1 L to 5.6 at 4 L, and was 47.4 months in patients receiving ASCT vs. 13.4 in non-ASCT patients at 1 L. Median overall survival also decreased by line of therapy, from 44.5 months at 1 L to 11.5 at 4 L. Approximately 77% of patients receiving ASCT survived > 60 months vs. 28% of non-ASCT patients. This study describes the real-world treatment landscape and survival outcomes for patients with MM on NHS funded treatments in England, highlighting differences between patients receiving ASCT and those not receiving it. It also demonstrates important data limitations and considerations for improvement.

ObjectiveHeart failure (HF) is a malignant condition requiring urgent treatment. Guidelines recommend natriuretic peptide (NP) testing in primary care to prioritise referral for specialist diagnostic assessment. We aimed to assess association of baseline NP with hospitalisation and mortality in people with newly diagnosed HF.MethodsPopulation-based cohort study of 40 007 patients in the Clinical Practice Research Datalink in England with a new HF diagnosis (48% men, mean age 78.5 years). We used linked primary and secondary care data between 1 January 2004 and 31 December 2018 to report one-year hospitalisation and 1-year, 5-year and 10-year mortality by NP level.Results22 085 (55%) participants were hospitalised in the year following diagnosis. Adjusted odds of HF-related hospitalisation in those with a high NP (NT-proBNP >2000 pg/mL) were twofold greater (OR 2.26 95% CI 1.98 to 2.59) than a moderate NP (NT-proBNP 400–2000 pg/mL). All-cause mortality rates in the high NP group were 27%, 62% and 82% at 1, 5 and 10 years, compared with 19%, 50% and 77%, respectively, in the moderate NP group and, in a competing risks model, risk of HF-related death was 50% higher at each timepoint. Median time between NP test and HF diagnosis was 101 days (IQR 19–581).ConclusionsHigh baseline NP is associated with increased HF-related hospitalisation and poor survival. While healthcare systems remain under pressure from the impact of COVID-19, research to test novel strategies to prevent hospitalisation and improve outcomes—such as a mandatory two-week HF diagnosis pathway—is urgently needed.

•There are limited real-world studies of advanced HER2m NSCLC in Europe.•Patients with advanced HER2m NSCLC had a median age of 66 years and 64% were female.•The most common first-line treatment for advanced HER2m NSCLC was chemotherapy.•Median overall survival from advanced HER2m NSCLC diagnosis date was <1.5 years.•Routine HER2 testing and HER2-directed therapies for advanced HER2m NSCLC are needed. Human epidermal growth factor receptor 2 (HER2 [ERBB2]) gene mutations occur in ∼3–5% of non-small cell lung cancer (NSCLC) cases and are associated with poor prognosis. However, real-world data on patients with HER2-mutant (HER2m) NSCLC are needed. This retrospective, observational study evaluated characteristics, treatment patterns, and clinical outcomes of patients with advanced nonsquamous HER2m NSCLC from the Institut Curie (France) and Thoraxklinik Heidelberg (Germany) between 2011 and 2022. Of the 55 patients (Curie: n = 17; Heidelberg: n = 38) included in the study, median age at diagnosis was 66 years (range, 22–90), 63.6% were female, and 50.9% had no history of smoking. Forty-eight (87.3%) patients received ≥1 line of therapy, 29 (52.7%) received ≥2 lines of therapy, and 19 (34.5%) received ≥3 lines of therapy. The most common first-line treatment was platinum-based and non-platinum-based chemotherapy (54.2%, n/n = 26/48); treatment patterns in the second- and third-line settings were more diverse than in the first-line setting. Median overall survival was 14.2 months (95% confidence interval [CI] 11.2, 23.2; n = 55) from the diagnosis of advanced disease and 16.5 months (12.3, 29.8; n = 48) from the start of first-line treatment. Median progression-free survival was 5.1 months (95% CI 3.5, 8.5; n = 48) and 4.0 months (2.4, 6.3; n = 29) from the start of first- and second-line treatment, respectively. Patients with advanced HER2m NSCLC had a poor prognosis despite treatment with standard-of-care regimens available during the study period. These findings highlight the need for novel therapeutic options to improve clinical outcomes for patients with HER2m NSCLC.

[This corrects the article DOI: 10.1371/journal.pmed.1004223.].

The balance of benefits and risks associated with lowering blood pressure levels in individuals with dementia remains controversial with a lack of evidence for possible harms associated with antihypertensive treatment. We examined the association between antihypertensive medication and serious adverse events in individuals with dementia compared to those without dementia. This was a retrospective analysis using nationally representative UK general practice population between 1998 and 2018, from electronic health records (Clinical Practice Research Datalink, CPRD, GOLD). Eligible individuals were aged ≥40 years, with a systolic blood pressure 130-179 mmHg, and not previously prescribed antihypertensive treatment. The diagnosis of dementia was based on clinical codes in the electronic health record. Individuals were allocated to the exposure group if they were prescribed at least one antihypertensive medication during a 12-month exposure period. Those who were not prescribed any antihypertensive medication during the exposure period were allocated to the control group. The primary outcome was the first hospitalisation or death from a fall within 10 years of the follow-up period. Secondary outcomes were first hospitalisation or death from hypotension, syncope, and fracture. In a population of 1,219,732 individuals, 23,510 had dementia. Antihypertensive medications were newly prescribed in 4,062/23,510 (17.3%) individuals with dementia and 142,385/1,196,222 (11.9%) individuals without dementia in the 12-month exposure period. In the primary analyses, which adjusted for the propensity score and a previous history of the outcome of interest, antihypertensive treatments were associated with a small increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.15, 95% confidence interval [CI] 1.08, 1.22), hypotension (aHR 1.51, 95%CI 1.29, 1.78), syncope (aHR 1.34, 95%CI 1.11, 1.61), but not fracture (aHR 1.05, 95%CI 0.96, 1.15), in individuals with dementia. These findings were consistent across different analytic approaches, including multivariable adjustment, propensity score matching, and inverse probability treatment weighting. In individuals without dementia, the association between antihypertensive treatment and serious adverse events was similar, with a small increased risk of hospitalisation or death from falls (aHR 1.07, 95%CI 1.05, 1.10). However, the absolute fall risk associated with antihypertensive treatment was significantly higher in individuals with dementia (47 per 10,000 individuals per year, 95%CI 26, 70) compared to those without (14 per 10,000 individuals per year, 95%CI 10, 18). The absolute risks of hypotension and syncope with antihypertensive treatment were also higher in the individuals with dementia compared to those without. The main limitation is the possibility of unmeasured confounding, and heterogeneity in dementia diagnoses based on coded entries in the electronic health record. Antihypertensive treatment was associated with increased risk of serious adverse events in individuals with and without dementia, however, the absolute risk of harm was more than double in individuals with dementia. These data suggest that clinicians, patients, and their carers should consider these risks before starting new antihypertensive medications, particularly in the context of dementia.

Background: Treatment for advanced non-small-cell lung cancer (NSCLC) has evolved substantially over the past decade, necessitating evaluation of real-world treatment patterns and effectiveness before and after the introduction of newer therapies. Methods: This retrospective cohort study included adult patients initiating a non-curative first-line therapy for advanced NSCLC between 2014 and 2021 at the IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), with follow-up through 2022. Overall survival (OS) and real-world progression-free survival from the start date of the first line of therapy for advanced NSCLC were estimated using Kaplan–Meier methods. Results: Overall, 910 patients were included; at diagnosis, 83% had a de novo diagnosis and 17% had recurrent disease. During the study, 41% of patients received platinum-based chemotherapy alone; 22% received non-platinum-based chemotherapy alone; 21% received anti-programmed death (PD)-(ligand [L])1 immune checkpoint inhibitors (ICIs), alone or with chemotherapy; and 16% received targeted therapy (single-agent tyrosine kinase inhibitors) as first-line therapy for advanced disease. From 2014 to 2021, the proportion of patients receiving first-line anti-PD-(L)1 ICIs increased from 0% to 58% and the proportion of those receiving first-line platinum-based chemotherapy decreased from 65% to 6%. Median (95% CI) OS was 8.2 (7.5–9.2) months; the minimum-to-maximum range of median OS was 6.0–7.4 months from 2014 to 2017 and 8.4–15.9 months from 2018 to 2021. Median OS was numerically longer in patients with recurrent disease versus a de novo diagnosis, first-line targeted versus other therapy, high versus low PD-L1 expression, and non-squamous/other versus squamous histology. Conclusions: This study provides real-world data further supporting (i) the benefits of precision targeted therapy for patients with advanced NSCLC and actionable genomic alterations and (ii) the positive impact of immunotherapy approvals on the treatment paradigm for advanced NSCLC.