Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. ...We investigated this question in a randomized trial.
We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization.
We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients 26.5% and 225 patients 27.7%, respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life.
Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program a Medical Research Council and National Institute of Health Research partnership and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).
Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy.
To ...estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection.
Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009.
Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study.
Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 95% confidence interval (CI) 0.16 to 0.31}, to absence of clinically important benefit, as in the large Chingleput trial rate ratio 1.05 (95% CI 0.88 to 1.25) and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials.
Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing.
The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies.
BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination.
The National Institute for Health Research Health Technology Assessment programme.
The conventional reporting of composite endpoints in clinical trials has an inherent limitation in that it emphasizes each patient's first event, which is often the outcome of lesser clinical ...importance. To overcome this problem, we introduce the concept of the win ratio for reporting composite endpoints. Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. Consider a primary composite endpoint, e.g. cardiovascular (CV) death and heart failure hospitalization (HF hosp) in heart failure trials. For each matched pair, the new treatment patient is labelled a 'winner' or a 'loser' depending on who had a CV death first. If that is not known, only then they are labelled a 'winner' or 'loser' depending on who had a HF hosp first. Otherwise they are considered tied. The win ratio is the total number of winners divided by the total numbers of losers. A 95% confidence interval and P-value for the win ratio are readily obtained. If formation of matched pairs is impractical then an alternative win ratio can be obtained by comparing all possible unmatched pairs. This method is illustrated by re-analyses of the EMPHASIS-HF, PARTNER B, and CHARM trials. The win ratio is a new method for reporting composite endpoints, which is easy to use and gives appropriate priority to the more clinically important event, e.g. mortality. We encourage its use in future trial reports.
In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We ...sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)).
A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups.
BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35.
In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).
Background Conventional composite outcomes in heart failure (HF) trials, for example, time to cardiovascular death or first HF hospitalization, have recognized limitations. We propose an alternative ...outcome, days alive and out of hospital (DAOH), which incorporates mortality and all hospitalizations into a single measure. A refinement, the patient journey, also uses functional status (New York Heart Association NYHA class) measured during follow-up. The CHARM program is used to illustrate the methodology. Methods CHARM randomized 7,599 patients with symptomatic HF to placebo or candesartan, with median follow-up of 38 months. We related DAOH and percent DAOH (ie, percentage of time spent alive and out of hospital) to treatment using linear regression adjusting for follow-up time. Results Mean increase in DAOH for patients on candesartan versus placebo was 24.1 days (95% CI 9.8-38.3 days, P < .001). The corresponding mean increase in percent DAOH was 2.0% (95% CI 0.8%-3.1%, P < .001). These findings were dominated by reduced mortality (23 days) but enhanced by reduced time in hospital (1 day). Percent time spent in hospital because of HF was reduced by 0.10% (95% CI 0.04%-0.14%, P < .001). The patient journey analysis showed that patients in the candesartan group spent more follow-up time in NYHA classes I and II and less in NYHA class IV. Conclusions Days alive and out of hospital, especially percent DAOH, provide a valuable tool for summarizing the overall absolute treatment effect on mortality and morbidity. In future HF trials, percent DAOH can provide a useful alternative perspective on the effects of treatment.
Background: Oral corticosteroids (OCS) are often prescribed for chronic obstructive pulmonary disease (COPD) exacerbations. Methods: This observational, individually matched historical cohort study ...used electronic medical records (1987-2019) from the UK Clinical Practice Research Datalink linked to English Hospital Episode Statistics (HES) to evaluate adverse outcomes in patients with COPD who used OCS (OCS cohort) and those not exposed to OCS (non-OCS cohort). Risk of 17 adverse outcomes was estimated using proportional hazard regression. Results: Of 323,722 patients, 106,775 (33.0%) had COPD-related OCS prescriptions. Of the 106,775 patients in the overall cohort, 58,955 had HES linkage and were eligible for inclusion in the OCS cohort. The individual matching process identified 53,299 pairs of patients to form the OCS and non-OCS cohorts. Median follow-up post-index was 6.9 years (OCS cohort) and 5.4 years (non-OCS cohort). Adjusted risk of multiple adverse outcomes was higher for the OCS cohort versus the non-OCS cohort, including osteoporosis with/without fractures (adjusted hazard ratio aHR 1.80; 95% confidence interval CI 1.70-1.92), type 2 diabetes mellitus (aHR 1.44; 95% CI 1.37-1.51), cardiovascular/cerebrovascular disease (aHR 1.26; 95% CI 1.21-1.30), and all-cause mortality (aHR 1.04; 95% CI 1.02-1.07). In the OCS cohort, risk of most adverse outcomes increased with increasing categorized cumulative OCS dose. For example, risk of cardiovascular/cerebrovascular disease was 34% higher in the 1.0-<2.5 g group versus the <0.5 g group (HR 1.34; 95% CI 1.26-1.42). Conclusion: Any OCS use was associated with higher risk of adverse outcomes in patients with COPD, with risk generally increasing with greater cumulative OCS dose. Plain Language Summary: Many patients with chronic obstructive pulmonary disease (COPD) have occasions when their symptoms suddenly worsen, called flare-ups or exacerbations. To treat flare-ups, doctors might prescribe a course of steroid tablets (oral corticosteroids or OCS for short). Doctors might also prescribe "rescue packs" containing OCS and antibiotics, to keep at home and start taking when needed. While OCS may speed up recovery from flare-ups, repeated use may have negative health effects. We studied effects of OCS use in patients with COPD, using anonymized electronic patient medical records in England. These databases are made available following a high-quality research proposal to research and ethics committees. Of 323,722 patients with COPD, around one-third received OCS for flare-ups. We studied 17 outcomes including important medical diagnoses and death. We grouped patients into 53,299 pairs so that every patient who used OCS matched a similar patient (eg, the same age and sex) who never used OCS. The patients were followed for an average of 6.9 years (used OCS) and 5.4 years (never used OCS). Most diagnoses, including diabetes, osteoporosis, cardiovascular/cerebrovascular disease, and death, were more likely in patients who used OCS than those who never used OCS. Patients using larger amounts of OCS over time were generally more likely to experience diagnoses or die. These results show risks of using OCS, even occasionally, in patients with COPD. Flare-up prevention is important, for example with appropriate daily "maintenance" medication, vaccinations for infections, and quitting smoking, thereby reducing health effects from OCS use for flare-ups. Keywords: chronic obstructive pulmonary disease, cohort study, COPD, corticosteroids, observational, primary care
Purpose: Oral corticosteroid (OCS) use for asthma is associated with considerable healthcare resource utilization (HCRU) and costs. However, no study has investigated this in relation to patterns of ...intermittent OCS prescription. Methods: This historical UK cohort study used primary care medical records, linked to Hospital Episode Statistics, from 2008 to 2019, of patients (greater than or equal to4 years old) with asthma prescribed intermittent OCS. Patients were categorized by OCS prescribing pattern (one-off single, less frequent greater than or equal to90-day gap and frequent <90-day gap) and matched 1:1 (by sex, age and index date) with people never prescribed OCS with/without asthma. HCRU (reported as episodes, except for length of hospital stay days and any prescription records) and associated costs were compared between intermittent OCS and non-OCS cohorts, and among intermittent OCS prescribing patterns. Results: Of 149,191 eligible patients, 50.3% had one-off, 27.4% less frequent, and 22.3% frequent intermittent OCS prescribing patterns. Annualized non-respiratory HCRU rates were greater in the intermittent OCS versus non-OCS cohorts for GP visits (5.93 vs 4.70 episodes, p < 0.0001), hospital admissions (0.24 vs 0.16 episodes, p < 0.0001), and length of stay (1.87 vs 1.58 days, p < 0.0001). In the intermittent OCS cohort, rates were highest in the frequent prescribing group for GP visits (7.49 episodes; p < 0.0001 vs one-off), length of stay (2.15 days; p < 0.0001) and any prescription including OCS (25.22 prescriptions; p < 0.0001). Mean per-patient non-respiratory related and all-cause HCRU-related costs were higher with intermittent OCS than no OCS (pounds sterling3902 vs pounds sterling2722 and pounds sterling8623 vs pounds sterling4929, respectively), as were mean annualized costs (pounds sterling565 vs pounds sterling313 and pounds sterling1526 vs pounds sterling634, respectively). A dose-response relationship existed; HCRU-related costs were highest in the frequent prescribing cohort (p < 0.0001). Conclusion: Intermittent OCS use and more frequent intermittent OCS prescription patterns were associated with increased HCRU and associated costs. Improved asthma management is needed to reduce reliance on intermittent OCS in primary care. Keywords: asthma, costs, healthcare resource utilization, intermittent, oral corticosteroids
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