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Background Multimorbidity is associated with mortality and service use, with specific types of multimorbidity having differential effects. Additionally, multimorbidity is often negatively associated with participation in research cohorts. Therefore, we set out to identify clusters of multimorbidity patients and how they are differentially associated with mortality and service use across age groups in a population-representative sample. Methods Linked primary and secondary care electronic health records contributed by 382 general practices in England to the Clinical Practice Research Datalink (CPRD) were used. The study included a representative set of multimorbid adults (18 years old or more, N  = 113,211) with two or more long-term conditions (a total of 38 conditions were included). A random set of 80% of the multimorbid patients ( N  = 90,571) were stratified by age groups and clustered using latent class analysis. Consistency between obtained multimorbidity phenotypes, classification quality and associations with demographic characteristics and primary outcomes (GP consultations, hospitalisations, regular medications and mortality) was validated in the remaining 20% of multimorbid patients ( N  = 22,640). Results We identified 20 patient clusters across four age strata. The clusters with the highest mortality comprised psychoactive substance and alcohol misuse (aged 18–64); coronary heart disease, depression and pain (aged 65–84); and coronary heart disease, heart failure and atrial fibrillation (aged 85+). The clusters with the highest service use coincided with those with the highest mortality for people aged over 65. For people aged 18–64, the cluster with the highest service use comprised depression, anxiety and pain. The majority of 85+-year-old multimorbid patients belonged to the cluster with the lowest service use and mortality for that age range. Pain featured in 13 clusters. Conclusions This work has highlighted patterns of multimorbidity that have implications for health services. These include the importance of psychoactive substance and alcohol misuse in people under the age of 65, of co-morbid depression and coronary heart disease in people aged 65–84 and of cardiovascular disease in people aged 85+.

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.

Health services have failed to respond to the pressures of multimorbidity. Improved measures of multimorbidity are needed for conducting research, planning services and allocating resources. We modelled the association between 37 morbidities and 3 key outcomes (primary care consultations, unplanned hospital admission, death) at 1 and 5 years. We extracted development (n = 300 000) and validation (n = 150 000) samples from the UK Clinical Practice Research Datalink. We constructed a general-outcome multimorbidity score by averaging the standardized weights of the separate outcome scores. We compared performance with the Charlson Comorbidity Index. Models that included all 37 conditions were acceptable predictors of general practitioner consultations (C-index 0.732, 95% confidence interval [CI] 0.731–0.734), unplanned hospital admission (C-index 0.742, 95% CI 0.737–0.747) and death at 1 year (C-index 0.912, 95% CI 0.905–0.918). Models reduced to the 20 conditions with the greatest combined prevalence/weight showed similar predictive ability (C-indices 0.727, 95% CI 0.725–0.728; 0.738, 95% CI 0.732–0.743; and 0.910, 95% CI 0.904–0.917, respectively). They also predicted 5-year outcomes similarly for consultations and death (C-indices 0.735, 95% CI 0.734–0.736, and 0.889, 95% CI 0.885–0.892, respectively) but performed less well for admissions (C-index 0.708, 95% CI 0.705–0.712). The performance of the general-outcome score was similar to that of the outcome-specific models. These models performed significantly better than those based on the Charlson Comorbidity Index for consultations (C-index 0.691, 95% CI 0.690–0.693) and admissions (C-index 0.703, 95% CI 0.697–0.709) and similarly for mortality (C-index 0.907, 95% CI 0.900–0.914). The Cambridge Multimorbidity Score is robust and can be either tailored or not tailored to specific health outcomes. It will be valuable to those planning clinical services, policymakers allocating resources and researchers seeking to account for the effect of multimorbidity.

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.

IntroductionPolypharmacy and multimorbidity pose escalating challenges. Despite numerous attempts, interventions have yet to show consistent improvements in health outcomes. A key factor may be varied approaches to targeting patients for intervention.ObjectivesTo explore how patients are targeted for intervention by examining the literature with respect to: understanding how polypharmacy is defined; identifying problematic polypharmacy in practice; and addressing problematic polypharmacy through interventions.DesignWe performed a scoping review as defined by the Joanna Briggs Institute.SettingThe focus was on primary care settings.Data sourcesMedline, Embase, Cumulative Index to Nursing and Allied Health Literature and Cochrane along with ClinicalTrials.gov, Science.gov and WorldCat.org were searched from January 2004 to February 2024.Eligibility criteriaWe included all articles that had a focus on problematic polypharmacy in multimorbidity and primary care, incorporating multiple types of evidence, such as reviews, quantitative trials, qualitative studies and policy documents. Articles focussing on a single index disease or not written in English were excluded.Extraction and analysisWe performed a narrative synthesis, comparing themes and findings across the collective evidence to draw contextualised insights and conclusions.ResultsIn total, 157 articles were included. Case-finding methods often rely on basic medication counts (often five or more) without considering medical history or whether individual medications are clinically appropriate. Other approaches highlight specific drug indicators and interactions as potentially inappropriate prescribing, failing to capture a proportion of patients not fitting criteria. Different potentially inappropriate prescribing criteria also show significant inconsistencies in determining the appropriateness of medications, often neglecting to consider multimorbidity and underprescribing. This may hinder the identification of the precise population requiring intervention.ConclusionsImproved strategies are needed to target patients with polypharmacy, which should consider patient perspectives, individual factors and clinical appropriateness. The development of a cross-cutting measure of problematic polypharmacy that consistently incorporates adjustment for multimorbidity may be a valuable next step to address frequent confounding.

Background Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data. Methods This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies. Results Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9–58.3) per 100,000 person-years; n = 521, 85.8 (78.6–93.5) per 100,000 person-years; and n = 518, 99.3 (90.9–108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33–1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48–1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67–4.86), and unstable angina, aHR = 1.92 (1.33–2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49–7.19), and acute myocardial infarction, aHR = 2.46 (1.72–3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies. Conclusions Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.

Elevated levels of prenatal testosterone may increase the risk for autism spectrum conditions (autism). Given that polycystic ovary syndrome (PCOS) is also associated with elevated prenatal testosterone and its precursor sex steroids, a hypothesis from the prenatal sex steroid theory is that women with PCOS should have elevated autistic traits and a higher rate of autism among their children. Using electronic health records obtained from the Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2014, we conducted three matched case-control studies. Studies 1 and 2 examined the risk of PCOS in women with autism (n = 971) and the risk of autism in women with PCOS (n = 26,263), respectively, compared with matched controls. Study 3 examined the odds ratio (OR) of autism in first-born children of women with PCOS (n = 8588), matched to 41,127 controls. In Studies 1 and 2 we found increased prevalence of PCOS in women with autism (2.3% vs. 1.1%; unadjusted OR: 2.01, 95% CI: 1.22–3.30) and elevated rates of autism in women with PCOS (0.17% vs. 0.09%, unadjusted OR: 1.94 CI: 1.37–2.76). In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions (unadjusted OR: 1.60, 95% CI: 1.28–2.00; adjusted OR: 1.35, 95% CI: 1.06–1.73). These studies provide further evidence that women with PCOS and their children have a greater risk of autism.

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 Polypharmacy is an increasing challenge for primary care. Although sometimes clinically justified, polypharmacy can be inappropriate, leading to undesirable outcomes. Optimising care for polypharmacy necessitates effective targeting and monitoring of interventions. This requires a valid, reliable measure of polypharmacy, relevant for all patients, that considers clinical appropriateness and generic prescribing issues applicable across all medications. Whilst there are several existing measures of potentially inappropriate prescribing, these are not specifically designed with polypharmacy in mind, can require extensive clinical input to complete, and often cover a limited number of drugs. The aim of this study was to identify what experts consider to be the key elements of a measure of prescribing appropriateness in the context of polypharmacy. Methods Firstly, we conducted a systematic review to identify generic (not drug specific) prescribing indicators relevant to polypharmacy appropriateness. Indicators were subject to content analysis to enable categorisation. Secondly, we convened a panel of 10 clinical experts to review the identified indicators and assess their relative clinical importance. For each indicator category, a brief evidence summary was developed, based on relevant clinical and indicator literature, clinical guidance, and opinions obtained from a separate patient discussion panel. A two-stage RAND/UCLA Appropriateness Method was used to reach consensus amongst the panel on a core set of indicators of polypharmacy appropriateness. Results We identified 20,879 papers for title/abstract screening, obtaining 273 full papers. We extracted 189 generic indicators, and presented 160 to the panel grouped into 18 classifications (e.g. adherence, dosage, clinical efficacy). After two stages, during which the panel introduced 18 additional indicators, there was consensus that 134 indicators were of clinical importance. Following the application of decision rules and further panel consultation, 12 indicators were placed into the final selection. Panel members particularly valued indicators concerned with adverse drug reactions, contraindications, drug-drug interactions, and the conduct of medication reviews. Conclusions We have identified a set of 12 indicators of clinical importance considered relevant to polypharmacy appropriateness. Use of these indicators in clinical practice and informatics systems is dependent on their operationalisation and their utility (e.g. risk stratification, targeting and monitoring polypharmacy interventions) requires subsequent evaluation. Trial registration Registration number: PROSPERO ( CRD42016049176 ).

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