Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants ...with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 33.9% cases with simvastatin plus ezetimibe versus 1084 34.6% cases with placebo; rate ratio, 0.97; 95% confidence interval 95% CI, 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 47.4% events with treatment versus 1513 48.3% events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 38.2% events with treatment versus 1257 40.2% events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.
Abstract Background Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced ...by understanding how the trial population may differ from the populations it aims to represent. Methods We compared baseline characteristics and mortality of RECOVERY participants recruited in England ( n = 38,510) with a reference population hospitalised with COVID-19 in England ( n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. Results Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age standard deviation: RECOVERY 62.6 15.3 vs reference 65.7 18.5 years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% 95% confidence interval: 23.3–24.1%; vs reference 24.8% 24.6–25.0%), except during the first pandemic wave in the UK (March–May 2020) when adjusted mortality was lower in RECOVERY. Conclusions Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. Trial registration ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.
Routinely collected data could substantially decrease the cost of conducting trials.
To assess the accuracy and completeness of UK routine data for ascertaining serious vascular events (SVEs) ...compared with adjudicated follow-up data.
This was a secondary analysis of a randomized clinical trial. From June 24, 2005, to July 28, 2011, the ASCEND (A Study of Cardiovascular Events in Diabetes) primary prevention trial used mail-based methods to randomize people with diabetes without evidence of atherosclerotic vascular disease using a 2 × 2 factorial design to aspirin and/or ω-fatty acids vs matching placebo in the UK. Direct participant mail-based follow-up was the main source of outcome data, with more than 90% of the primary outcome events undergoing adjudication. Follow-up was completed on July 31, 2017. In parallel, more than 99% of participants were linked to routinely collected hospital admission and death registry data (ie, routine data), enabling post hoc randomized comparisons of different sources of outcome data (conducted from September 1, 2018, to October 1, 2021).
Random allocation to 100 mg of aspirin once daily vs matching placebo and separately to 1 g of ω-3 fatty acids once daily vs placebo.
The primary outcome consisted of SVEs (a composite of nonfatal myocardial infarction, ischemic stroke, transient ischemic attack TIA, or vascular death, excluding hemorrhagic stroke).
A total of 15 480 participants were randomized (mean SD age, 63 9 years; 9684 62.6% men) and followed up for a mean (SD) of 7.4 (1.8) years. For SVEs, agreement between adjudicated direct follow-up and routine data sources was strong (1401 vs 1127 events; κ = 0.78 95% CI, 0.76-0.80; sensitivity, 72.0% 95% CI, 69.7%-74.4%; specificity, 99.2% 95% CI, 99.0%-99.3%), and sensitivity improved for SVEs excluding transient ischemic attack (1129 vs 1026 events; sensitivity, 80.6% 95% CI, 78.3%-82.9%). Rate ratios for the aspirin-randomized comparison for adjudicated direct follow-up vs follow-up solely through routine data alone were 0.88 (95% CI, 0.79-0.97) vs 0.91 (95% CI, 0.81-1.02) for the primary outcome and 0.92 (95% CI, 0.82-1.03) vs 0.91 (95% CI, 0.80-1.02) for SVEs excluding TIA. Results were similar for the ω-3 fatty acid comparison, and adjudication did not seem to markedly change rate ratios.
Post hoc analyses of the ASCEND trial suggest that routinely collected hospital admission and death registry data in the UK could be used as the sole method of follow-up for myocardial infarction, ischemic stroke resulting in hospitalization, vascular death, and arterial revascularization in primary prevention cardiovascular trials, without the need for verification by clinical adjudication.
Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. ...However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.
Background:
Meta-analyses of individual-level data from randomised trials are often required to detect clinically worthwhile effects. The Cholesterol Treatment Trialists’ Collaboration, which ...includes data from numerous large long-term statin trials, is conducting a review of the effects of statin therapy on all adverse events collected in those trials. This article describes the approaches used and challenges faced to systematically capture and categorise the data.
Methods:
Protocols, statistical analysis plans, case report forms, clinical study reports and datasets were obtained, reviewed and checked. Relevant baseline and follow-up data from each trial was then reorganised into standardised formats based upon the Clinical Data Interchange Standards Consortium Study Data Tabulation Model. Adverse event data were organised and coded (automatically or, where necessary, manually) according to a common medical dictionary based upon the Medical Dictionary for Regulatory Activities.
Results:
Data from 23 double-blind statin trials and 5 open-label statin trials were provided, either through direct data transfer or through online access platforms. Together, these trials provided 845 datasets containing over 38 million records relating to 30,495 study variables and 181,973 randomised participants. Of the 46 Clinical Data Interchange Standards Consortium Study Data Tabulation Model domains that could potentially have been used to organise the data, the 13 most relevant to the project were identified and utilised, including 6 domains related to post-randomisation adverse events. Nearly 1.2 million adverse events were extracted and mapped to over 45,000 unique adverse event terms. Of these adverse events, 99% were coded to a Medical Dictionary for Regulatory Activities ‘lower level term’, with the remainder coded to a ‘higher level term’ or, very rarely, only a ‘higher level group term’.
Conclusion:
In this meta-analysis of adverse event data from the large randomised trials of statins, approaches based on common standards for data organisation and classification have provided a resource capable of allowing reliable and rapid evaluation of any previously unknown benefits or hazards of statin therapy.
Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on ...vascular access patency is unclear.
The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access.
Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 29.7% for simvastatin/ezetimibe versus 388 33.5% for placebo; risk ratio RR, 0.87; 95% confidence interval 95% CI, 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent confirmation (vascular access occlusive events: 352 28.9% for rosuvastatin versus 337 27.6% for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin-based regimen on vascular access occlusive events was not statistically significant (707 29.3% with any LDL-C-lowering therapy versus 725 30.5% with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29).
Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of benefit in AURORA. Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest.
Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal.
To assess the effects of reducing homocysteine levels with ...folic acid and vitamin B(12) on vascular and nonvascular outcomes.
Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008.
2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo.
First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization.
Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio RR, 1.04; 95% confidence interval CI, 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 20.4%, vs placebo, 1185 19.6%; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 4.5%, vs placebo, 265 4.4%; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 3.0%, vs placebo, 152 2.5%; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 9.6%, vs placebo, 559 9.3%) or nonvascular causes (vitamins, 405 6.7%, vs placebo, 392 6.5%) or in the incidence of any cancer (vitamins, 678 11.2%, vs placebo, 639 10.6%).
Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence.
isrctn.org Identifier: ISRCTN74348595.
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