Accuracy of heart failure ascertainment using routinely collected healthcare data: a systematic review and meta-analysis.

BACKGROUND: Ascertainment of heart failure (HF) hospitalizations in cardiovascular trials is costly and complex, involving processes that could be streamlined by using routinely collected healthcare data (RCD). The utility of coded RCD for HF outcome ascertainment in randomized trials requires assessment. We systematically reviewed studies assessing RCD-based HF outcome ascertainment against "gold standard" (GS) methods to study the feasibility of using such methods in clinical trials. METHODS: Studies assessing International Classification of Disease (ICD) coded RCD-based HF outcome ascertainment against GS methods and reporting at least one agreement statistic were identified by searching MEDLINE and Embase from inception to May 2021. Data on study characteristics, details of RCD and GS data sources and definitions, and test statistics were reviewed. Summary sensitivities and specificities for studies ascertaining acute and prevalent HF were estimated using a bivariate random effects meta-analysis. Heterogeneity was evaluated using I2 statistics and hierarchical summary receiver operating characteristic (HSROC) curves. RESULTS: A total of 58 studies of 48,643 GS-adjudicated HF events were included in this review. Strategies used to improve case identification included the use of broader coding definitions, combining multiple data sources, and using machine learning algorithms to search free text data, but these methods were not always successful and at times reduced specificity in individual studies. Meta-analysis of 17 acute HF studies showed that RCD algorithms have high specificity (96.2%, 95% confidence interval [CI] 91.5-98.3), but lacked sensitivity (63.5%, 95% CI 51.3-74.1) with similar results for 21 prevalent HF studies. There was considerable heterogeneity between studies. CONCLUSIONS: RCD can correctly identify HF outcomes but may miss approximately one-third of events. Methods used to improve case identification should also focus on minimizing false positives.

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.

BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.

LDL-cholesterol reduction in chronic kidney disease: options beyond statins.

PURPOSE OF REVIEW: Individuals with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) events. LDL cholesterol (LDL-C) is a key modifiable cause of ASCVD and lowering LDL-C with statins reduces the risk of ASCVD events in a wide range of populations, including those with CKD. This review considers the utility of recently developed nonstatin LDL-C-lowering therapies in CKD. RECENT FINDINGS: The cholesterol absorption inhibitor, ezetimibe, reduces LDL-C by 15-20% and is well tolerated in CKD. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) reduce LDL-C by 50-60% and reduce the risk of ASCVD events. However, these agents require self-administration by subcutaneous injection every 2-4 weeks. The PCSK9 synthesis inhibitor, inclisiran, is administered approximately 6 monthly and may be more suitable for widespread use, although outcome trials are awaited. These PCSK9 targeting therapies require no dose adjustment in CKD and have no drug interactions. SUMMARY: Statins and ezetimibe are safe and reduce ASCVD risk in CKD populations. PCSK9 targeting agents may be useful in high-risk CKD patients, including those with prior ASCVD.

Streamlined mail-based methods for large randomised trials: lessons learnt from the ASCEND study.

Reliable assessment of the effects of an intervention usually requires large randomised trials but such studies are becoming increasingly complex and costly to run. 'Streamlined' trials are needed in which every aspect of the trial design and conduct is simplified, retaining only those elements needed to answer the research question and ensure the safety of the individual participants. In this review we discuss how the trial 'A Study of Cardiovascular Events iN Diabetes' (ASCEND) was streamlined. The study included a two-by-two factorial design: it assessed the effects of low-dose aspirin and, separately, supplementation with n-3 fatty acids on serious vascular events in 15,480 people with diabetes but no overt cardiovascular disease. Other key streamlined design features, such as mail-based recruitment and follow-up, mainly by post, with no in-person visits and use of a run-in period, are also described. We go on to discuss the success of the study and other studies that have employed a similar mail-based approach, and the type of clinical trials that are suitable for mail-based design. Finally, we consider the limitations of the study, and how these could be circumvented in future studies. ASCEND randomised large numbers of eligible participants, achieved good adherence rates and almost complete follow-up at a fraction of the cost of traditional clinic-based trials. Such studies are necessary if researchers are to address the important clinical questions most relevant to improving health.

Prognostic utility of estimated albumin excretion rate in chronic kidney disease: results from the Study of Heart and Renal Protection.

Background: Estimated albumin excretion rate (eAER) provides a better estimate of 24-h albuminuria than albumin:creatinine ratio (ACR). However, whether eAER is superior to ACR in predicting end-stage renal disease (ESRD), vascular events (VEs) or death is uncertain. Methods: The prognostic utility of ACR and eAER (estimated from ACR, sex, age and race) to predict mortality, ESRD and VEs was compared using Cox proportional hazards regression among 5552 participants with chronic kidney disease in the Study of Heart and Renal Protection, who were not on dialysis at baseline. Results: During a median follow-up of 4.8 years, 1959 participants developed ESRD, 1204 had a VE and 1130 died (641 from a non-vascular, 369 from a vascular and 120 from an unknown cause). After adjustment for age, sex and eGFR, both ACR and eAER were strongly and similarly associated with ESRD risk. The average relative risk (RR) per 10-fold higher level was 2.70 (95% confidence interval 2.45-2.98) for ACR and 2.67 (2.43-2.94) for eAER. Neither ACR nor eAER provided any additional prognostic information for ESRD risk over and above the other. For VEs, there were modest positive associations between both ACR and eAER and risk [adjusted RR per 10-fold higher level 1.37 (1.22-1.53) for ACR and 1.36 (1.22-1.52) for eAER]. Again, neither measure added prognostic information over and above the other. Similar results were observed when ACR and eAER were related to vascular mortality [RR per 10-fold higher level: 1.64 (1.33-2.03) and 1.62 (1.32-2.00), respectively] or to non-vascular mortality [1.53 (1.31-1.79) and 1.50 (1.29-1.76), respectively]. Conclusions: In this study, eAER did not improve risk prediction of ESRD, VEs or mortality.

A practical method of measuring glomerular filtration rate by iohexol clearance using dried capillary blood spots.

BACKGROUND: Exogenous tracer-based methods of measuring glomerular filtration rate (GFR) are difficult to perform, whilst creatinine-based estimation formulae are inaccurate. METHODS: We assessed a new technique of measuring iohexol clearance using timed dried capillary blood spots. A reference GFR was measured in 81 subjects (GFR 15-124 ml/min/1.73 m(2)) by iohexol clearance using three venous samples (2, 3 and 4 h after an intravenous bolus). GFR was estimated by six test methods; iohexol clearance using (i) 3 blood spots (2, 3, 4 h); (ii) 2 blood spots (2, 4 h) and (iii) 1 blood spot (4 h); (iv) the Modification of Diet in Renal Disease (MDRD) formula; (v) the Cockcroft-Gault formula, and (vi) a formula estimating GFR from serum cystatin C concentration. For each test method the bias and precision were calculated as the mean and standard deviation (SD) of the 'GFR differences' (test method GFR - reference GFR). RESULTS: The limits of agreement (bias +/-1.96 x SD; in ml/min/1.73 m(2)) were: (i) 1.1 +/- 15.1 for 3-spot iohexol clearance; (ii) 0.6 +/- 14.9 for 2-spot iohexol clearance; (iii) 4.5 +/- 21.2 for 1-spot iohexol clearance; (iv) -15.7 +/- 33.3 for the MDRD formula; (v) -9.6 +/- 32.9 for the Cockcroft-Gault formula, and (vi) -12.1 +/- 31.7 for the Cystatin C formula. The accuracy of all six test methods was similar among individuals with GFR <60 ml/min/ 1.73 m(2); however, in individuals with GFR > or =60 ml/min/ 1.73 m(2), the MDRD, Cockcroft-Gault and Cystatin C formulae were all imprecise and systematically underestimated GFR. CONCLUSIONS: Blood spot iohexol clearance provides a potentially practical method of estimating GFR accurately in large-scale epidemiological studies especially among individuals without established chronic kidney disease.