Kathryn E. Mansfield

A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general population.

Abstract Chronic widespread pain (CWP) is common and associated with poor general health. There has been no attempt to derive a robust prevalence estimate of CWP or assess how this is influenced by sociodemographic factors. This study therefore aimed to determine, through a systematic review and meta-analysis, the prevalence of CWP in the adult general population and explore variation in prevalence by age, sex, geographical location, and criteria used to define CWP. MEDLINE, Embase, CINAHL, and AMED were searched using a search strategy combining key words and related database-specific subject terms to identify relevant cohort or cross-sectional studies published since 1990. Included articles were assessed for risk of bias. Prevalence figures for CWP (American College of Rheumatology criteria) were stratified according to geographical location, age, and sex. Potential sources of variation were investigated using subgroup analyses and meta-regression. Twenty-five articles met the eligibility criteria. Estimates for CWP prevalence ranged from 0% to 24%, with most estimates between 10% and 15%. The random-effects pooled prevalence was 10.6% (95% confidence intervals: 8.6-12.9). When only studies at low risk of bias were considered pooled, prevalence increased to 11.8% (95% confidence intervals: 10.3-13.3), with reduced but still high heterogeneity. Prevalence was higher in women and in those aged more than 40 years. There was some limited evidence of geographic variation and cultural differences. One in 10 adults in the general population report chronic widespread pain with possible sociocultural variation. The possibility of cultural differences in pain reporting should be considered in future research and the clinical assessment of painful conditions.

Quantification of risk factors for postherpetic neuralgia in herpes zoster patients: A cohort study

Objective: To investigate risk factors for postherpetic neuralgia, the neuropathic pain that commonly follows herpes zoster. Methods: Using primary care data from the Clinical Practice Research Datalink, we fitted multivariable logistic regression models to investigate potential risk factors for postherpetic neuralgia (defined as pain ≥90 days after zoster, based on diagnostic or prescription codes), including demographic characteristics, comorbidities, and characteristics of the acute zoster episode. We also assessed whether the effects were modified by antiviral use. Results: Of 119,413 zoster patients, 6,956 (5.8%) developed postherpetic neuralgia. Postherpetic neuralgia risk rose steeply with age, most sharply between 50 and 79 years (adjusted odds ratio [OR] for a 10-year increase, 1.70, 99% confidence interval 1.63–1.78). Postherpetic neuralgia risk was higher in women (6.3% vs 5.1% in men: OR 1.19, 1.10–1.27) and those with severely immunosuppressive conditions, including leukemia (13.7%: 2.07, 1.08–3.96) and lymphoma (12.7%: 2.45, 1.53–3.92); autoimmune conditions, including rheumatoid arthritis (9.1%: 1.20, 0.99–1.46); and other comorbidities, including asthma and diabetes. Current and ex-smokers, as well as underweight and obese individuals, were at increased risk of postherpetic neuralgia. Antiviral use was not associated with postherpetic neuralgia (OR 1.04, 0.97–1.11). However, the increased risk associated with severe immunosuppression appeared less pronounced in patients given antivirals. Conclusions: Postherpetic neuralgia risk was increased for a number of patient characteristics and comorbidities, notably with age and among those with severe immunosuppression. As zoster vaccination is contraindicated for patients with severe immunosuppression, strategies to prevent zoster in these patients, which could include the new subunit zoster vaccine, are an increasing priority.

Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

Objective To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. Design Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics. Setting UK primary care, 1997-2014. Participants Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363). Main outcome measures Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs. Results Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using <10% as reference). Results were consistent across calendar periods, across subgroups of patients, and among continuing users. Conclusions Increases in creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment.

Validity of estimated prevalence of decreased kidney function and renal replacement therapy from primary care electronic health records compared with national survey and registry data in the United Kingdom

Background Anonymous primary care records are an important resource for observational studies. However, their external validity is unknown in identifying the prevalence of decreased kidney function and renal replacement therapy (RRT). We thus compared the prevalence of decreased kidney function and RRT in the Clinical Practice Research Datalink (CPRD) with a nationally representative survey and national registry. Methods Among all people ≥25 years of age registered in the CPRD for ≥1 year on 31 March 2014, we identified patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, according to their most recent serum creatinine in the past 5 years using the Chronic Kidney Disease Epidemiology Collaboration equation and patients with recorded diagnoses of RRT. Denominators were the entire population in each age‐sex band irrespective of creatinine measurement. The prevalence of eGFR <60 mL/min/1.73 m2 was compared with that in the Health Survey for England (HSE) 2009/2010 and the prevalence of RRT was compared with that in the UK Renal Registry (UKRR) 2014. Results We analysed 2 761 755 people in CPRD [mean age 53 (SD 17) years, men 49%], of whom 189 581 (6.86%) had an eGFR <60 mL/min/1.73 m2 and 3293 (0.12%) were on RRT. The prevalence of eGFR <60 mL/min/1.73 m2 in CPRD was similar to that in the HSE and the prevalence of RRT was close to that in the UKRR across all age groups in men and women, although the small number of younger patients with an eGFR <60 mL/min/1.73 m2 in the HSE might have hampered precise comparison. Conclusions UK primary care data have good external validity for the prevalence of decreased kidney function and RRT.

Prescription of renin–angiotensin system blockers and risk of acute kidney injury: a population-based cohort study

Objective To investigate whether there is an association between use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) and risk of acute kidney injury (AKI). Study design We conducted a new-user cohort study of the rate of AKI among users of common antihypertensives. Setting UK primary care practices contributing to the Clinical Practice Research Datalink (CPRD) eligible for linkage to hospital records data from the Hospital Episode Statistics (HES) database between April 1997 and March 2014. Participants New users of antihypertensives: ACEI/ARB, β-blockers, calcium channel blockers and thiazide diuretics. Outcomes The outcome was first episode of AKI. We estimated incidence rate ratio (RR) for AKI during time exposed to ACEI/ARB compared to time unexposed, adjusting for age, sex, comorbidities, use of other antihypertensive drugs and calendar period using Poisson regression. Covariates were time updated. Results Among 570 445 participants, 303 761 were prescribed ACEI/ARB with a mean follow-up of 4.1 years. The adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 1.12 (95% CI 1.07 to 1.17). This relative risk varied depending on absolute risk of AKI, with lower or no increased relative risk from the drugs among those at greatest absolute risk. For example, among people with stage 4 chronic kidney disease (who had 6.69 (95% CI 5.57 to 8.03) times higher rate of AKI compared to those without chronic kidney disease), the adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 0.66 (95% CI 0.44 to 0.97) in contrast to 1.17 (95% CI 1.09 to 1.25) among people without chronic kidney disease. Conclusions Treatment with ACEI/ARB is associated with only a small increase in AKI risk while individual patient characteristics are much more strongly associated with the rate of AKI. The degree of increased risk varies between patient groups.

Adherence to guidelines for creatinine and potassium monitoring and discontinuation following renin-angiotensin system blockade: a UK general practice-based cohort study.

Objectives To examine adherence to serum creatinine and potassium monitoring and discontinuation guidelines following initiation of treatment with ACE inhibitors (ACEI) or angiotensin receptor blockers (ARBs); and whether high-risk patients are monitored. Design A general practice-based cohort study using electronic health records from the UK Clinical Practice Research Datalink and Hospital Episode Statistics. Setting UK primary care, 2004–2014. Subjects 223 814 new ACEI/ARB users. Main outcome measures Proportion of patients with renal function monitoring before and after ACEI/ARB initiation; creatinine increase ≥30% or potassium levels >6 mmol/L at first follow-up monitoring; and treatment discontinuation after such changes. Using logistic regression models, we also examined patient characteristics associated with these biochemical changes, and with follow-up monitoring within the guideline recommendation of 2 weeks after treatment initiation. Results 10% of patients had neither baseline nor follow-up monitoring of creatinine within 12 months before and 2 months after initiation of an ACEI/ARB, 28% had monitoring only at baseline, 15% only at follow-up, and 47% both at baseline and follow-up. The median period between the most recent baseline monitoring and drug initiation was 40 days (IQR 12–125 days). 34% of patients had baseline creatinine monitoring within 1 month before initiating therapy, but <10% also had the guideline-recommended follow-up test recorded within 2 weeks. Among patients experiencing a creatinine increase ≥30% (n=567, 1.2%) or potassium level >6 mmol/L (n=191, 0.4%), 80% continued treatment. Although patients with prior myocardial infarction, hypertension or baseline potassium >5 mmol/L were at high risk of ≥30% increase in creatinine after ACEI/ARB initiation, there was no evidence that they were more frequently monitored. Conclusions Only one-tenth of patients initiating ACEI/ARB therapy receive the guideline-recommended creatinine monitoring. Moreover, the vast majority of the patients fulfilling postinitiation discontinuation criteria for creatinine and potassium increases continue on treatment.

Partner Bereavement and Risk of Herpes Zoster: Results from Two Population-Based Case-Control Studies in Denmark and the United Kingdom

Summary Psychological stress is thought to be a risk factor for herpes zoster. However, 2 large population-based studies in Denmark and the United Kingdom found no consistent increase in risk of herpes zoster after partner bereavement.

Methodological challenges when carrying out research on CKD and AKI using routine electronic health records

Research regarding chronic kidney disease (CKD) and acute kidney injury (AKI) using routinely collected data presents particular challenges. The availability, consistency, and quality of renal data in electronic health records has changed over time with developments in policy, practice incentives, clinical knowledge, and associated guideline changes. Epidemiologic research may be affected by patchy data resulting in an unrepresentative sample, selection bias, misclassification, and confounding by factors associated with testing for and recognition of reduced kidney function. We systematically explore the issues that may arise in study design and interpretation when using routine data sources for CKD and AKI research. First, we discuss how access to health care and management of patients with CKD may have an impact on defining the target population for epidemiologic study. We then consider how testing and recognition of CKD and AKI may lead to biases and how to potentially mitigate against these. Illustrative examples from our own research within the UK are used to clarify key points. Any research using routine renal data has to consider the local clinical context to achieve meaningful interpretation of the study findings.

Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study

Abstract Objective To determine if trimethoprim use for urinary tract infection (UTI) is associated with an increased risk of acute kidney injury, hyperkalaemia, or sudden death in the general population. Design Cohort study. Setting UK electronic primary care records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. Participants Adults aged 65 and over with a prescription for trimethoprim, amoxicillin, cefalexin, ciprofloxacin, or nitrofurantoin prescribed up to three days after a primary care diagnosis of UTI between April 1997 and September 2015. Main outcome measures The outcomes were acute kidney injury, hyperkalaemia, and death within 14 days of a UTI treated with antibiotics. Results Among a cohort of 1 191 905 patients aged 65 and over, 178 238 individuals were identified with at least one UTI treated with antibiotics, comprising a total of 422 514 episodes of UTIs treated with antibiotics. The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57). The results suggest that, for 1000 UTIs treated with antibiotics among people 65 and over, treatment with trimethoprim instead of amoxicillin would result in one to two additional cases of hyperkalaemia and two admissions with acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury. Conclusion Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups.

Comparative effectiveness of fourth-line anti-hypertensive agents in resistant hypertension: A systematic review and meta-analysis

Aim We assessed the effectiveness of fourth-line mineralocorticoid receptor antagonists in comparison with other fourth-line anti-hypertensive agents in resistant hypertension. Methods and results We systematically searched Medline, EMBASE and the Cochrane library from database inception until January 2016. We included randomised and non-randomised studies that compared mineralocorticoid receptor antagonists with other fourth-line anti-hypertensive agents in patients with resistant hypertension. The outcome was change in systolic blood pressure, measured in the office, at home or by ambulatory blood pressure monitoring. Secondary outcomes were changes in serum potassium and occurrence of hyperkalaemia. We used random effects models and assessed statistical heterogeneity using the I2 test and corresponding 95% confidence intervals. From 2,506 records, 5 studies met our inclusion criteria with 755 included patients. Two studies were randomised and three were non-randomised. Comparative fourth-line agents included bisoprolol, doxazosin, furosemide and additional blockade of the renin angiotensin-aldosterone system. Using data from randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 7.4 mmHg (95%CI 3.2 – 11.6) more than the active comparator. When limited to non-randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 11.9 mmHg (95% CI 9.3 – 14.4) more than the active comparator. Conclusion On the basis of this meta-analysis, mineralocorticoid receptor antagonists reduce blood pressure more effectively than other fourth-line agents in resistant hypertension. Effectiveness stratified by ethnicity and comorbidities, in addition to information on clinical outcomes such as myocardial infarction and stroke, now needs to be determined.