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Aims: Novel oral iron supplements may be associated with a reduced incidence of adverse drug reactions compared to standard treatments of iron deficiency anaemia. The aim was to establish their value‐based price under conditions of uncertainty surrounding their tolerability. Methods: A discrete‐time Markov model was developed to assess the value‐based price of oral iron preparations based on their incremental cost per quality‐adjusted life year (QALY) gained from the perspective of the NHS in the UK. Primary and secondary care resource use and health state occupancy probabilities were estimated from routine electronic health records; and unit costs and health state utilities were derived from published sources. Patients were pre‐menopausal women with iron deficiency anaemia who were prescribed oral iron supplementation between 2000 and 2014. Results: The model reflecting current use of iron salts yielded a mean total cost to the NHS of £779, and 0.84 QALYs over 12 months. If a new iron preparation were to reduce the risk of adverse drug reactions by 30–40%, then its value‐based price, based on a threshold of £20 000 per QALY, would be in the region of £10–£13 per month, or about 7–9 times the average price of basic iron salts. Conclusions: There are no adequate, direct comparisons of new oral iron supplements to ferrous iron salts, and therefore other approaches are needed to assess their value. Our modelling shows that they are potentially cost‐effective at prices that are an order of magnitude higher than existing iron salts.

OBJECTIVE: To develop and externally validate the STRAtifying Treatments In the multi-morbid Frail elderlY (STRATIFY)-Falls clinical prediction model to identify the risk of hospital admission or death from a fall in patients with an indication for antihypertensive treatment. DESIGN: Retrospective cohort study. SETTING: Primary care data from electronic health records contained within the UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Patients aged 40 years or older with at least one blood pressure measurement between 130 mm Hg and 179 mm Hg. MAIN OUTCOME MEASURE: First serious fall, defined as hospital admission or death with a primary diagnosis of a fall within 10 years of the index date (12 months after cohort entry). Model development was conducted using a Fine-Gray approach in data from CPRD GOLD, accounting for the competing risk of death from other causes, with subsequent recalibration at one, five, and 10 years using pseudo values. External validation was conducted using data from CPRD Aurum, with performance assessed through calibration curves and the observed to expected ratio, C statistic, and D statistic, pooled across general practices, and clinical utility using decision curve analysis at thresholds around 10%. RESULTS: Analysis included 1 772 600 patients (experiencing 62 691 serious falls) from CPRD GOLD used in model development, and 3 805 366 (experiencing 206 956 serious falls) from CPRD Aurum in the external validation. The final model consisted of 24 predictors, including age, sex, ethnicity, alcohol consumption, living in an area of high social deprivation, a history of falls, multiple sclerosis, and prescriptions of antihypertensives, antidepressants, hypnotics, and anxiolytics. Upon external validation, the recalibrated model showed good discrimination, with pooled C statistics of 0.833 (95% confidence interval 0.831 to 0.835) and 0.843 (0.841 to 0.844) at five and 10 years, respectively. Original model calibration was poor on visual inspection and although this was improved with recalibration, under-prediction of risk remained (observed to expected ratio at 10 years 1.839, 95% confidence interval 1.811 to 1.865). Nevertheless, decision curve analysis suggests potential clinical utility, with net benefit larger than other strategies. CONCLUSIONS: This prediction model uses commonly recorded clinical characteristics and distinguishes well between patients at high and low risk of falls in the next 1-10 years. Although miscalibration was evident on external validation, the model still had potential clinical utility around risk thresholds of 10% and so could be useful in routine clinical practice to help identify those at high risk of falls who might benefit from closer monitoring or early intervention to prevent future falls. Further studies are needed to explore the appropriate thresholds that maximise the model's clinical utility and cost effectiveness.

BackgroundAntihypertensives reduce the risk of cardiovascular disease but are also associated with harms including acute kidney injury (AKI). Few data exist to guide clinical decision making regarding these risks.AimTo develop a prediction model estimating the risk of AKI in people potentially indicated for antihypertensive treatment.Design and settingObservational cohort study using routine primary care data from the Clinical Practice Research Datalink (CPRD) in England.MethodPeople aged ≥40 years, with at least one blood pressure measurement between 130 mmHg and 179 mmHg were included. Outcomes were admission to hospital or death with AKI within 1, 5, and 10 years. The model was derived with data from CPRD GOLD (n= 1 772 618), using a Fine–Gray competing risks approach, with subsequent recalibration using pseudo-values. External validation used data from CPRD Aurum (n= 3 805 322).ResultsThe mean age of participants was 59.4 years and 52% were female. The final model consisted of 27 predictors and showed good discrimination at 1, 5, and 10 years (C-statistic for 10-year risk 0.821, 95% confidence interval [CI] = 0.818 to 0.823). There was some overprediction at the highest predicted probabilities (ratio of observed to expected event probability for 10-year risk 0.633, 95% CI = 0.621 to 0.645), affecting patients with the highest risk. Most patients (>95%) had a low 1- to 5-year risk of AKI, and at 10 years only 0.1% of the population had a high AKI and low CVD risk.ConclusionThis clinical prediction model enables GPs to accurately identify patients at high risk of AKI, which will aid treatment decisions. As the vast majority of patients were at low risk, such a model may provide useful reassurance that most antihypertensive treatment is safe and appropriate while flagging the few for whom this is not the case.

ObjectiveTo examine the concordance between dates of death recorded in UK primary care and national mortality records.MethodsUK primary care data from the Clinical Practice Research Datalink were linked to Office for National Statistics (ONS) data, for 118 571 patients who died between September 2010 and September 2015. Logistic regression was used to examine factors associated with discrepancy in death dates between data sets.ResultsDeath dates matched in 76.8% of cases with primary care dates preceding ONS date in 2.9%, and following in 20.3% of cases; 92.2% of cases differed by 4 weeks later than ONS in 1.5% of cases and occurred more frequently with deaths categorised as ‘external’ (15.8% vs 0.8% for cancer), and in younger patients (15.9% vs 1% for 18–29 and 80–89 years, respectively). General practices with the greatest discrepancies (97.5th percentile) had around 200 times higher odds of recording substantially discordant dates than practices with the lowest discrepancies (2.5th percentile).ConclusionDates of death in primary care records often disagree with national records and should be treated with caution. There is marked variation between practices, and studies involving young patients, unexplained deaths and where precise date of death is important are particularly vulnerable to these issues.

Objective To examine the association between antihypertensive treatment and specific adverse events. Design Systematic review and meta-analysis. Eligibility criteria Randomised 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 sources Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020. Main outcome measures The 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 (τ 2 ). Results Of 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, τ 2 =0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ 2 =0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ 2 =0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ 2 =0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ 2 =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. Conclusions This 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. Registration PROSPERO CRD42018116860.