To compare the validity and robustness of five methods for handling missing characteristics when using cardiovascular disease risk prediction models for individual patients in a real-world clinical ...setting.
The performance of the missing data methods was assessed using data from the Swedish National Diabetes Registry (n = 419,533) with external validation using the Scottish Care Information ˗ diabetes database (n = 226,953). Five methods for handling missing data were compared. Two methods using submodels for each combination of available data, two imputation methods: conditional imputation and median imputation, and one alternative modeling method, called the naïve approach, based on hazard ratios and populations statistics of known risk factors only. The validity was compared using calibration plots and c-statistics.
C-statistics were similar across methods in both development and validation data sets, that is, 0.82 (95% CI 0.82–0.83) in the Swedish National Diabetes Registry and 0.74 (95% CI 0.74–0.75) in Scottish Care Information-diabetes database. Differences were only observed after random introduction of missing data in the most important predictor variable (i.e., age).
Validity and robustness of median imputation was not dissimilar to more complex methods for handling missing values, provided that the most important predictor variables, such as age, are not missing.
Life expectancy is increasing in some countries and declining in others.1 Age-standardised cardiovascular disease incidence and mortality are declining in many populations, with more marked declines ...in more developed countries.2 However, more people die each year from cardiovascular disease than any other cause, with 31% of global deaths attributed to cardiovascular disease, partly as a consequence of increasing population size and ageing.3 Risk factor prevalence and the strength of associations between risk factors and cardiovascular disease and mortality are reasonably well described in high-income countries (HICs), but data for middle-income countries (MICs) and low-income countries (LICs) are more scarce. The WHO “STEPwise approach to surveillance” facilitates collection of comparable information on risk factor prevalence across countries but does not investigate associations with outcomes.4 The Global Burden of Disease Study provides national, regional, and global estimates of the burden of cardiovascular disease by modelling available data from heterogeneous sources over a wide time frame.1,2 It uses extensive extrapolation to cover countries for which data are not available, and most of these countries are LICs and MICs. The findings from the PURE study5 that indicate a large proportion of cardiovascular disease events and mortality can be attributed to a small number of modifiable risk factors are consistent with and extend the findings from several other large studies, including the Global Burden of Disease,2 INTERSTROKE,6 and INTERHEART studies.7 Taken together, the findings highlight the potential for further improvements in prevention of cardiovascular disease and premature mortality across the globe, through reductions in modifiable risk factors.
Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has ...been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.
This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.
Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology ...is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013.
Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year.
Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973).
Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.
Although prescribing is the most common intervention provided by physicians, limited research has examined the role of physician sex and gender on prescribing practices. In this article, we briefly ...summarize research relating to differences in prescribing behaviors based on physician sex and gender. To identify articles, PubMed was searched for studies from the last 20 years reporting on prescribing differences by physician sex or gender for the general population and specifically for older adults. We describe major themes emerging from the studies, illustrate findings from key studies, and note the major gaps in the literature, notably the lack of evidence on prescribing for older adults. Given the paucity of research in this area, we also explore evidence on the impact of physician sex and gender on other aspects of healthcare delivery, such as communication within the patient‐physician relationship, and consider how these findings may also apply to prescribing behaviors. In general, we note that female physicians have been observed to engage in more careful and conservative healthcare provision including prescribing. A careful and conservative approach to prescribing may reduce the incidence of adverse drug events in older adults and be linked to a more patient‐centered approach to care. To what extent these differences in prescribing are important for patient health outcomes is unknown, and further research is required to identify optimal prescribing practices that minimize harms.
To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these ...relationships.
A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control.
In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease.
Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.
Abstract
Background
Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for ...COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods.
Methods
Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods.
Results
A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio HR, 0.70; 95% confidence interval, .62–.78) and 28 days (HR, 0.75; 95% CI, .68–.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods.
Conclusions
Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.
Immunocompromised patients are at high risk of mortality from coronavirus disease 2019 (COVID-19). Early initiation of remdesivir is associated with a significant reduction in 14- and 28-day mortality among immunocompromised patients hospitalized for COVID-19.
Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/remdesivir-reduced-mortality-in-immunocompromised-patients-hospitalized-for-covid-19-across-variant-waves-findings-from-routine-clinical-practice
Aims/hypothesis
An excess cancer incidence of 20–25% has been identified among persons with diabetes, most of whom have type 2 diabetes. We aimed to describe the association between type 1 diabetes ...and cancer incidence.
Methods
Persons with type 1 diabetes were identified from five nationwide diabetes registers: Australia (2000–2008), Denmark (1995–2014), Finland (1972–2012), Scotland (1995–2012) and Sweden (1987–2012). Linkage to national cancer registries provided the numbers of incident cancers in people with type 1 diabetes and in the general population. We used Poisson models with adjustment for age and date of follow up to estimate hazard ratios for total and site-specific cancers.
Results
A total of 9,149 cancers occurred among persons with type 1 diabetes in 3.9 million person-years. The median age at cancer diagnosis was 51.1 years (interquartile range 43.5–59.5). The hazard ratios (HRs) (95% CIs) associated with type 1 diabetes for all cancers combined were 1.01 (0.98, 1.04) among men and 1.07 (1.04, 1.10) among women. HRs were increased for cancer of the stomach (men, HR 1.23 1.04, 1.46; women, HR 1.78 1.49, 2.13), liver (men, HR 2.00 1.67, 2.40; women, HR 1.55 1.14, 2.10), pancreas (men, HR 1.53 1.30, 1.79; women, HR 1.25 1.02,1.53), endometrium (HR 1.42 1.27, 1.58) and kidney (men, HR 1.30 1.12, 1.49; women, HR 1.47 1.23, 1.77). Reduced HRs were found for cancer of the prostate (HR 0.56 0.51, 0.61) and breast (HR 0.90 0.85, 0.94). HRs declined with increasing diabetes duration.
Conclusion
Type 1 diabetes was associated with differences in the risk of several common cancers; the strength of these associations varied with the duration of diabetes.
Calcium channel blockers (CCBs) are commonly prescribed agents for hypertension that can cause peripheral edema. A prescribing cascade occurs when the edema is misinterpreted as a new medical ...condition and a diuretic is subsequently prescribed to treat the edema. The extent to which this prescribing cascade occurs at a population level is not well understood.
To measure the association between being newly dispensed a CCB and subsequent dispensing of a loop diuretic in older adults with hypertension.
A population-based cohort study was performed using linked health administrative databases of community-dwelling adults 66 years or older with hypertension and new prescription drug claims from September 30, 2011, to September 30, 2016, in Ontario, Canada. The dates of analysis were September 1, 2018, to May 30, 2019.
Individuals who were newly dispensed a CCB were compared with the following 2 groups: (1) individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and (2) individuals who were newly dispensed an unrelated medication.
Hazard ratios (HRs) with 95% CIs were estimated for individuals who were dispensed a loop diuretic within 90 days of follow-up using Cox proportional hazards regression models.
The cohort included 41 086 older adults (≥66 years) with hypertension who were newly dispensed a CCB, 66 494 individuals who were newly dispensed another antihypertensive medication, and 231 439 individuals who were newly dispensed an unrelated medication. At index (ie, the dispensing date), the mean (SD) age was 74.5 (6.9) years, and 191 685 (56.5%) were women. Individuals who were newly dispensed a CCB had a higher cumulative incidence at 90 days of being dispensed a loop diuretic than individuals in both control groups (1.4% vs 0.7% and 0.5%, P < .001). After adjustment, individuals who were newly dispensed a CCB had increased relative rates of being dispensed a loop diuretic compared with individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (HR, 1.68; 95% CI, 1.38-2.05 in the first 30 days after index days 1-30; 2.26; 95% CI, 1.76-2.92 in the subsequent 30 days days 31-60; and 2.40; 95% CI, 1.84-3.13 in the third month of follow-up days 61-90) and individuals who were newly dispensed unrelated medications (HR, 2.51; 95% CI, 2.13-2.96 for 1-30 days after index; 2.99; 95% CI, 2.43-3.69 for 31-60 days after index; and 3.89; 95% CI, 3.11-4.87 for 61-90 days after index). This association persisted, although slightly attenuated, from 90 days to up to 1 year of follow-up and when restricted to a subgroup of individuals who were newly dispensed amlodipine.
Many older adults with hypertension who are newly dispensed a CCB subsequently receive a loop diuretic. Given how widely CCBs are prescribed, interventions are needed to raise clinicians' awareness of this common prescribing cascade to reduce the prescribing of potentially unnecessary medications that may cause harm.
To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with ...type 2 diabetes mellitus (T2DM).
We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors.
A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality.
Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.
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