ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway.

BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

Detectable High-Sensitivity Cardiac Troponin within the Population Reference Interval Conveys High 5-Year Cardiovascular Risk: An Observational Study.

BACKGROUND: Increased cardiac troponin I or T detected by high-sensitivity assays (hs-cTnI or hs-cTnT) confers an increased risk of adverse prognosis. We determined whether patients presenting with putatively normal, detectable cTn concentrations [> limit of detection and < upper reference limit (URL)] have increased risk of major adverse cardiovascular events (MACE) or all-cause mortality. METHODS: A prospective 5-year follow-up of patients recruited in the emergency department with possible acute coronary syndrome (ACS) and cTn concentrations measured with hs-cTnI (Abbott) and hs-cTnT (Roche) assays. Cox regression models were generated with adjustment for covariates in those without MACE on presentation. Hazard ratios (HRs) for hs-cTn were calculated relative to the HRs at the median concentration. RESULTS: Of 1113 patients, 836 were without presentation MACE. Of these, 138 incurred a MACE and 169 died during a median 5.8-year follow-up. HRs for MACE at the URLs were 2.3 (95% CI, 1.7-3.2) for hs-cTnI and 1.8 (95% CI, 1.3-2.4) for hs-cTnT. Corresponding HRs for mortality were 1.7 (95% CI, 1.2-2.2) for hs-cTnI and 2.3 (95 % CI, 1.7-3.1) for hs-cTnT. The HR for MACE increased with increasing hs-cTn concentration similarly for both assays, but the HR for mortality increased at approximately twice the rate for hs-cTnT than hs-cTnI. Patients with hs-cTnI ≥10 ng/L or hs-cTnT ≥16 ng/L had the same percentage of MACE at 5-year follow-up (33%) as patients with presentation MACE. CONCLUSIONS: Many patients with ACS ruled out and putatively normal but detectable hs-cTnI concentrations are at similar long-term risk as those with MACE. hs-cTnT concentrations are more strongly associated with 5-year mortality than hs-cTnI.

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.

Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Primary Funding Source: Emergency Care Foundation.

The performance of contemporary cystatin C-based GFR equations in predicting gentamicin clearance.

AIMS: We aimed to compare the performances of contemporary cystatin C (Cys)-based GFR equations, and the creatinine only Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for predicting gentamicin clearance. METHODS: The bias and imprecision of the CKD-EPI, CKD-EPI_Cys and creatinine-cystatin C CKD-EPI (CKD-EPI_CrCys) equations for predicting gentamicin clearances, were assessed in 260 patients treated with gentamicin during 2012-2013. The creatinine-cystatin C Berlin Initiative Study equation (BIS_CrCys) was examined in the ≥70 year subgroup. The reference gentamicin clearance was calculated using post-dose plasma concentrations. RESULTS: The CKD-EPI_CrCys equation had the highest percentage of estimates within 30% of the reference gentamicin clearance (70%, P = 0.003) and lowest root mean square error (95% CI) of 29 (25, 23) ml min(-1) of the three equations for the entire cohort. There was no significant improvement in the performances of the equations with the exclusion of 41 patients with abnormal thyroid function tests or steroid co-prescription at the time of the index gentamicin dose. Of the remaining 219 patients, adjustment for individual BSA improved the performances of all GFR equations (P ≤ 0.003) in those with body mass indices (BMI) <18.5 or ≥30 kg m(-2) , but not those with BMI 18.5-29.9 kg m(-2) . There was no advantage of the BIS_CrCys over the CKD-EPI_CrCys equation in the ≥70 year subgroup. CONCLUSIONS: The CKD-EPI_CrCys equation provided the best estimate of gentamicin clearance. If used for guiding gentamicin dosing, the results from GFR equations should be adjusted for individual BSA at the extremes of body size.

Plasma glucose measurement in diabetes: impact and implications of variations in sample collection procedures with a focus on the first hour after sample collection.

BACKGROUND: Previous studies of participants with plasma glucose concentrations at or near the glucose reference range demonstrate glucose loss following delayed separation and extraction of plasma from the cellular components of blood, of ≤7% per hour. We aimed to assess pre-analytical glucose loss in diabetic subjects, focusing on the first hour after sample collection. METHODS: Venous blood was collected from diabetes clinic attendees, into a series of lithium heparin PST™ (plasma separator tube) and fluoride oxalate Vacutainers™. Baseline (reference) plasma glucose measurements were undertaken on samples prepared under refrigerated conditions. The remaining samples underwent a series of controlled pre-analytical delays in sample preparation, at room temperature. Plasma glucose was measured using the hexokinase method. RESULTS: Median baseline glucose (mmol/L) for the 62 participants was 10.6 (range 3.4-31.1). Using lithium heparin PST™ tubes, mean glucose loss (95% CI) was 0.16 (0.09-0.23) after 30 min delay in plasma preparation and 0.28 (0.21-0.34) after 60 min delay. Glucose loss was independent of both baseline glucose and also individual cellular count. Fluoride failed to inhibit glucose loss within the first hour after sample collection. Immediate plasma centrifugation of PST™ tubes, followed by delayed plasma extraction (median delay 92 min), produced a mean glucose loss of 0.02 mmol/L (-0.05-0.09). CONCLUSIONS: Samples collected into lithium heparin PST™ tubes show pre-analytical glucose loss at 1 h that is independent of baseline glucose and cellular count. Furthermore, immediate plasma separation using these tubes attenuates glucose loss across a wide range of glucose concentrations.

Pharmacokinetic comparison of a generic coenzyme Q10 solubilizate and a formulation with soybean phytosterols.

Coenzyme Q10 (CoQ10) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ10 solubilized in low-dose soybean phytosterols (SterolQ10) with a generic CoQ10 solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ10, as SterolQ10 or generic CoQ10, with a two-week washout between treatments. Plasma CoQ10 was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ10 or SterolQ10 for 4 weeks. Fasting plasma CoQ10 levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80-0.96), respectively. Four-weeks of CoQ10 resulted in a comparable twofold increase in CoQ10 levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ10 and phytosterol formulation, SterolQ10, showed bioequivalence to the generic CoQ10 following a single CoQ10 dose, and demonstrated comparable bioavailability following multiple dose administration.

Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.

CONTEXT: Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive. OBJECTIVE: To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand. INTERVENTION: Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months. MAIN OUTCOME MEASURES: The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes. RESULTS: The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels. CONCLUSION: In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609000486224.

Reducing Patient Risk and Enhancing Care Through the Development and Implementation of a New Chest Pain Pathway, Expedited by and for the COVID-19 Era.

The COVID-19 pandemic raised major concerns relating to hospital capacity and cross-infection patients and staff in the Emergency Department (ED) of a metropolitan hospital servicing a population of ~500,000. We determined to reduce length of stay and admissions in patients presenting with symptoms of possible myocardial infarction; the most common presentation group. After establishing stakeholder consensus, the existing accelerated diagnostic pathway (ADP) based on the ED Assessment of Chest-pain Score (EDACS), electrocardiogram, and troponin measurements with a high-sensitivity assay (hs-cTn) on presentation and two hours later (EDACS-ADP) was modified to stream patients following an initial troponin measure as follows: (i) to a very-low risk group who could be discharged home without follow-up or further testing, and (ii) to a low-risk group who could be discharged with next-day follow-up community troponin testing. Simulations were run in an extensive research database to determine appropriate hs-cTnI and EDACS thresholds for risk classification. This COVID-ADP was developed in ~2-weeks and was implemented in the ED within a further 3-weeks. A comparison of all chest pain presentations for the 3 months prior to implementation of the COVID-ADP to 3 months following implementation showed that there was a 64.7% increase in patients having only one troponin test in the ED, a 30-minute reduction of mean length of stay of people discharged home from the ED, and a 24.3% reduction in hospital admissions of patients ultimately diagnosed with non-cardiac chest pain.

Effect of genetic factors on the response to vitamin D3 supplementation in the VIDARIS randomized controlled trial.

OBJECTIVES: Supplementation provides the best means of improving vitamin D status; however, individual responses vary partly owing to genetics. The aim of this study was to determine whether 28 single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were associated with differences in response to supplementation. METHODS: Participants (N = 313; n = 160 vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections Study), a double-blind, randomized controlled trial involving oral monthly supplementation of either vitamin D3 (200 000 IU each for the first 2 mo, thereafter 100 000 IU monthly) or placebo for 18 mo. Circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline and 2, 6, 12, and 18 mo, and vitamin D binding protein (Gc-globulin) and calculated free 25(OH)D concentrations at baseline and 2 mo were obtained. Multiple regression was used to model associations between genetic variants and 25(OH)D, Gc-globulin, and free 25(OH)D concentrations. RESULTS: SNPs within GC, CYP2 R1, and CYP27 B1 were associated with 25(OH)D concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than 2 mo of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations; however, there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25(OH)D concentrations in the supplemented arm. CONCLUSION: Only variants of GC were associated with 25(OH)D concentrations after supplementation. This effect was modest and disappeared after >2 mo of supplementation, suggesting it may be time/dose-dependent and saturable.

A patient with pseudo-Addison's disease and falsely elevated thyroxine due to interference in serum cortisol and free thyroxine immunoassays by two different mechanisms.

Interference in immunoassays is a widely recognized problem, which could potentially lead to unnecessary investigations and treatment. We describe a case where interference in a cortisol immunoassay led to a falsely low serum cortisol concentration and interference in the free thyroxine assay led to falsely elevated serum thyroxine concentrations, in the same patient. A 42-year-old woman with documented hypothyroidism underwent a synacthen test for suspected adrenal insufficiency. Previous thyroid function tests had been discordant and difficult to interpret, with elevated thyroxine and non-suppressed thyroid-stimulating hormone. The synacthen test showed a subnormal cortisol response and she was commenced on cortisol replacement. Clinically, it was doubted whether she had true adrenal insufficiency and it was thought that the cortisol results might be artefactually low due to assay interference. Cortisol was measured by an alternative immunoassay, before and after incubation in an antibody blocking tube ('Scantibodies'), after heat treatment and also after treatment with Protein A. The results supported assay interference and cortisol 'replacement' was stopped. Thyroxine had been discontinued although thyroid function tests (TFTs) were significantly different between analytical platforms, also consistent with interference. Thyroxine replacement was restarted and once on a stable dose, the discrepancy in TFTs was also investigated by similar procedures as for cortisol. Good clinician-laboratory interface and laboratory work-up of patients with results that are discordant from the clinical findings can reduce unnecessary investigation and inappropriate treatment.

Comparative aspects of the care of familial hypercholesterolemia in the "Ten Countries Study".

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH). OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere. METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark. RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (Ï° = 0.667, P < .05). Opportunistic and systematic screening methods, and the Dutch Lipid Clinic Network criteria were most commonly used to detect FH; genetic testing was infrequently used. Noninvasive imaging of coronary calcium and/or carotid plaques was underutilized in risk assessment. Patients with FH were generally not adequately treated, with <30% of patients achieving guideline recommended low-density lipoprotein cholesterol targets on conventional therapies. Treatment gaps included suboptimal availability and use of lipoprotein apheresis and proprotein convertase subtilsin-kexin type 9 inhibitors. A deficit of FH registries, training programs, and publications were identified in less economically developed countries. The demonstration of cost-effectiveness for cascade screening, genetic testing, and specialized treatments were significantly associated with the availability of subsidies from the health care system (Ï° = 0.571-0.800, P < .05). CONCLUSION: We identified important gaps across the continuum of care for FH, particularly in less economically developed countries. Wider implementation of primary and pediatric care, telehealth services, patient support groups, education/training programs, research activities, and health technology assessments are needed to improve the care of patients with FH in these countries.

Effect of atorvastatin on plasma levels of asymmetric dimethylarginine in patients with non-ischaemic heart failure.

BACKGROUND: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endothelial nitric oxide synthase (eNOS) inhibitor, may contribute to endothelial dysfunction in chronic heart failure (CHF). Since statins upregulate eNOS and ameliorate endothelial dysfunction in non-ischaemic CHF, we hypothesized that this may be in part through modification of ADMA. AIM: To evaluate the effect of atorvastatin on the relationship between ADMA and endothelial function in non-ischaemic CHF. METHODS: Twenty-four patients with CHF (ejection fraction <40%, New York Heart Association Functional Classes II and III) were randomised to atorvastatin treatment (40 mg) or placebo once daily for 6 weeks in a double-blinded, placebo-controlled crossover study. Plasma ADMA and l-arginine levels were measured by HPLC. Endothelial function was assessed by flow-mediated dilatation and invasive forearm plethysmography. RESULTS: Post-statin therapy, endothelial function was improved (p<0.05) independent of LDL-cholesterol reductions, but no changes were observed in ADMA levels or the l-arginine to ADMA ratio. There was a trend for ADMA to inversely correlate with endothelial function at baseline. CONCLUSIONS: Short-term atorvastatin treatment in non-ischaemic CHF improves endothelial function but has no effect on ADMA or the l-arginine to ADMA ratio. Our finding suggests that the observed statin-induced improvements in endothelial function are likely mediated via alternative pathways.

Comparison of the Mayo Clinic Quadratic Equation with the Modification of Diet in Renal Disease equation and radionuclide glomerular filtration rate in a clinical setting.

BACKGROUND: Recent guidelines recommend automatic reporting of estimated glomerular filtration rate (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) equation with every request for plasma creatinine. The Mayo Clinic Quadratic Equation (MCQE) has been put forwards as a potentially more accurate alternative. We therefore evaluated its accuracy compared with radionuclide GFR in a clinical setting. METHOD: Data were collected on 601 patients aged 16-85 years who had undergone radionuclide GFR, and eGFR was calculated using MCQE and MDRD. Calculations of bias, correlation coefficients and percentage estimates within 30% and 50% of radionuclide GFR were used in comparisons. RESULTS: The MCQE had a significant positive bias in the overall population but no significant bias in individuals with normal renal function defined as measured GFR > 90 mL/min per 1.73 m(2). There was no significant difference in the performance of MCQE and MDRD eGFR in patients with measured GFR > 90 mL/min per 1.73 m(2). However, in the overall group and in subjects with radionuclide GFR < 90 mL/min per 1.73 m(2), the accuracy of MDRD eGFR with respect to the proportion of patients within 30% and 50% of radionuclide GFR was better than MCQE. CONCLUSION: MCQE compared moderately well with radionuclide GFR, although its overall bias and accuracy were inferior when compared with the MDRD equation in a clinical setting.