Target trial emulation has drastically improved the quality of observational studies investigating the effects of interventions. Its ability to prevent avoidable biases that have plagued many ...observational analyses has contributed to its recent popularity. This review explains what target trial emulation is, why it should be the standard approach for causal observational studies that investigate interventions, and how to do a target trial emulation analysis. We discuss the merits of target trial emulation compared with often used, but biased analyses, as well as potential caveats, and provide clinicians and researchers with the tools to better interpret results from observational studies investigating the effects of interventions.
ABSTRACT
In this article we introduce the concept of inverse probability of treatment weighting (IPTW) and describe how this method can be applied to adjust for measured confounding in observational ...research, illustrated by a clinical example from nephrology. IPTW involves two main steps. First, the probability—or propensity—of being exposed to the risk factor or intervention of interest is calculated, given an individual’s characteristics (i.e. propensity score). Second, weights are calculated as the inverse of the propensity score. The application of these weights to the study population creates a pseudopopulation in which confounders are equally distributed across exposed and unexposed groups. We also elaborate on how weighting can be applied in longitudinal studies to deal with informative censoring and time-dependent confounding in the setting of treatment-confounder feedback.
Limited information exists regarding the safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD treated in routine care. We evaluated the safety of SGLT2i in patients with ...CKD and type 2 diabetes treated in US routine practice.
Using claims data from Medicare and two large US commercial databases (April 2013-December 2021), we included 96,128 adults with CKD stages 3-4 and type 2 diabetes who newly filled prescriptions for SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA). Safety outcomes included diabetic ketoacidosis (DKA), lower limb amputations, nonvertebral fractures, genital infections, hypovolemia, AKI, hypoglycemia, and severe urinary tract infections (UTIs). Hazard ratios (HRs) and incidence rate differences per 1000 person-years were estimated after 1:1 propensity score matching, adjusted for >120 baseline characteristics.
Compared with GLP-1RA, SGLT2i initiators had a higher risk of nonvertebral fractures (HR, 1.30; 95% confidence interval CI, 1.03 to 1.65; incidence rate difference, 2.13 95% CI, 0.28 to 3.97), lower limb amputations (HR, 1.65 95% CI, 1.22 to 2.23; incidence rate difference, 2.46 95% CI, 1.00 to 3.92), and genital infections (HR, 3.08 95% CI, 2.73 to 3.48; incidence rate difference, 41.26 95% CI, 37.06 to 45.46). Similar risks of DKA (HR, 1.07 95% CI, 0.74 to 1.54; incidence rate difference, 0.29 95% CI, -0.89 to 1.46), hypovolemia (HR, 0.99 95% CI, 0.86 to 1.14; incidence rate difference, 0.20 95% CI, -2.85 to 3.25), hypoglycemia (HR, 1.08 95% CI, 0.92 to 1.26; incidence rate difference, 1.46 95% CI, -1.31 to 4.23), and severe UTI (HR, 1.02 95% CI, 0.87 to 1.19; incidence rate difference, 0.35 95% CI, -2.51 to 3.21) were observed. SGLT2i had lower risk for AKI (HR, 0.93 95% CI, 0.87 to 0.99; incidence rate difference, -6.75 95% CI, -13.69 to 0.20).
In US patients with CKD and type 2 diabetes receiving routine care, SGLT2i use was associated with higher risks of genital infections and potentially lower limb amputations and nonvertebral fractures.
It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes.
We studied patients referred to nephrologist care, listed on the ...Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m
) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT).
Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m
, 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m
. Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model.
In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.
The novel nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to reduce the risk of kidney and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney ...disease. In this issue of Kidney International, Bakris et al. present new data on the kidney efficacy of finerenone across subgroups of estimated glomerular filtration rate and urinary albumin–to–creatinine ratio, as well as safety data. We attempt to place these results in context by discussing the benefits and risks of finerenone, as well as the generalizability of the study findings to routine care settings.
AbstractObjectiveTo identify the optimal estimated glomerular filtration rate (eGFR) at which to initiate dialysis in people with advanced chronic kidney disease.DesignNationwide observational cohort ...study.SettingNational Swedish Renal Registry of patients referred to nephrologists.ParticipantsPatients had a baseline eGFR between 10 and 20 mL/min/1.73 m2 and were included between 1 January 2007 and 31 December 2016, with follow-up until 1 June 2017.Main outcome measuresThe strict design criteria of a clinical trial were mimicked by using the cloning, censoring, and weighting method to eliminate immortal time bias, lead time bias, and survivor bias. A dynamic marginal structural model was used to estimate adjusted hazard ratios and absolute risks for five year all cause mortality and major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) for 15 dialysis initiation strategies with eGFR values between 4 and 19 mL/min/1.73 m2 in increments of 1 mL/min/1.73 m2. An eGFR between 6 and 7 mL/min/1.73 m2 (eGFR6-7) was taken as the reference.ResultsAmong 10 290 incident patients with advanced chronic kidney disease (median age 73 years; 3739 (36%) women; median eGFR 16.8 mL/min/1.73 m2), 3822 started dialysis, 4160 died, and 2446 had a major adverse cardiovascular event. A parabolic relation was observed for mortality, with the lowest risk for eGFR15-16. Compared with dialysis initiation at eGFR6-7, initiation at eGFR15-16 was associated with a 5.1% (95% confidence interval 2.5% to 6.9%) lower absolute five year mortality risk and 2.9% (0.2% to 5.5%) lower risk of a major adverse cardiovascular event, corresponding to hazard ratios of 0.89 (95% confidence interval 0.87 to 0.92) and 0.94 (0.91 to 0.98), respectively. This 5.1% absolute risk difference corresponded to a mean postponement of death of 1.6 months over five years of follow-up. However, dialysis would need to be started four years earlier. When emulating the intended strategies of the Initiating Dialysis Early and Late (IDEAL) trial (eGFR10-14v eGFR5-7) and the achieved eGFRs in IDEAL (eGFR7-10v eGFR5-7), hazard ratios for all cause mortality were 0.96 (0.94 to 0.99) and 0.97 (0.94 to 1.00), respectively, which are congruent with the findings of the randomised IDEAL trial.ConclusionsVery early initiation of dialysis was associated with a modest reduction in mortality and cardiovascular events. For most patients, such a reduction may not outweigh the burden of a substantially longer period spent on dialysis.
Chronic kidney disease (CKD) and atrial fibrillation (AF) are both risk factors for bleeding, stroke and mortality. The aim of our study was to investigate the interaction between CKD and atrial ...fibrillation and outcomes.
We included 12,394 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2018 for an out-patient visit (Utrecht Cardiovascular Cohort Second Manifestation of Arterial disease cohort). Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding, ischemic stroke or mortality were calculated with Cox proportional hazard analyses. Presence of interaction between AF and CKD was examined by calculating the relative excess risk due to interaction (RERI), the attributable proportion (AP) due to interaction and the synergy index (S).
Of the 12,394 patients, 699 patients had AF, 2,752 patients had CKD and 325 patients had both AF and CKD. Patients with both CKD and AF had a 3.0-fold (95% CI 2.0-4.4) increased risk for bleeding, a 4.2-fold (95% CI 3.0-6.0) increased ischemic stroke risk and a 2.2-fold (95% CI 1.9-2.6) increased mortality risk after adjustment as compared with subjects without atrial fibrillation and CKD. We did not find interaction between AF and CKD for bleeding and mortality. However, we found interaction between AF and CKD for ischemic stroke risk (RERI 1.88 (95% CI 0.31-3.46), AP 0.45 (95% CI 0.17-0.72) and S 2.40 (95% CI 1.08-5.32)).
AF and CKD are both associated with bleeding, ischemic stroke and mortality. There is a positive interaction between AF and CKD for ischemic stroke risk, but not for bleeding or mortality.
Management of the global crisis of the coronavirus disease 2019 pandemic requires detailed appraisal of evidence to support clear, actionable, and consistent public health messaging. The use of cloth ...masks for general public use is being debated, and is in flux. We searched the MEDLINE and EMBASE databases and Google for articles reporting the filtration properties of flat cloth or cloth masks. We reviewed the reference lists of relevant articles to identify further articles and identified articles through social and conventional news media. We found 25 articles. Study of protection for the wearer used healthy volunteers, or used a manikin wearing a mask, with airflow to simulate different breathing rates. Studies of protection of the environment, also known as source control, used convenience samples of healthy volunteers. The design and execution of the studies was generally rigorously described. Many descriptions of cloth lacked the detail required for reproducibility; no study provided all the expected details of material, thread count, weave, and weight. Some of the homemade mask designs were reproducible. Successful masks were made of muslin at 100 threads per inch (TPI) in 3 to 4 layers (4-layer muslin or a muslin-flannel-muslin sandwich), tea towels (also known as dish towels), made using 1 layer (2 layers would be expected to be better), and good-quality cotton T-shirts in 2 layers (with a stitched edge to prevent stretching). In flat-cloth experiments, linen tea towels, 600-TPI cotton in 2 layers, and 600-TPI cotton with 90-TPI flannel performed well but 80-TPI cotton in 2 layers did not. We therefore recommend cotton or flannel at least 100 TPI, at least 2 layers. More layers, 3 or 4, will provide increased filtration but there is a trade-off in that more layers increases the resistance to breathing. Although this is not a systematic review, we included all the articles that we identified in an unbiased way. We did not include gray literature or preprints. A plain language summary of these data and recommendations, as well as information on making, wearing and cleaning cloth masks is available at www.clothmasks.ca.
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