A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

OBJECTIVES: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. METHODS: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. RESULTS: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. CONCLUSIONS: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

Prognostic value of 12 novel cardiological biomarkers in stable coronary artery disease. A 10-year follow-up of the placebo group of the Copenhagen CLARICOR trial.

OBJECTIVE: To assess if 12 novel circulating biomarkers, when added to 'standard predictors' available in general practice, could improve the 10-year prediction of cardiovascular events and mortality in patients with stable coronary heart disease. DESIGN: The patients participated as placebo receiving patients in the randomised clarithromycin for patients with stable coronary artery disease (CLARICOR) trial at a random time in their disease trajectory. SETTING: Five Copenhagen University cardiology departments and a coordinating centre. PARTICIPANTS: 1998 participants with stable coronary artery disease. OUTCOMES: Death and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death. RESULTS: When only 'standard predictors' were included, 83.4% of all-cause death predictions and 68.4% of composite outcome predictions were correct. Log(calprotectin) and log(cathepsin-S) were not associated (p≥0.01) with the outcomes, not even as single predictors. Adding the remaining 10 biomarkers (high-sensitive assay cardiac troponin T; neutrophil gelatinase-associated lipocalin; osteoprotegerin; N-terminal pro-B-type natriuretic peptide; tumour necrosis factor receptor 1 and 2; pregnancy-associated plasma protein A; endostatin; YKL40; cathepsin-B), which were all individually significantly associated with the prediction of the two outcomes, increased the figures to 84.7% and 69.7%. CONCLUSION: When 'standard predictors' routinely available in general practices are used for risk assessment in consecutively sampled patients with stable coronary artery disease, the addition of 10 novel biomarkers to the prediction model improved the correct prediction of all-cause death and the composite outcome by <1.5%. TRIAL REGISTRATION NUMBER: NCT00121550.

Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment: A CLARICOR trial 10-year follow-up substudy.

BACKGROUND AND AIMS: Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD). METHODS: We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years. RESULTS: OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001). CONCLUSIONS: Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.

Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease.

Background The inflammatory biomarker YKL-40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL-40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. We used Cox proportional hazards regression models adjusted for C-reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL-40 to the risk factors was calculated using the Cox-Breslow method and c-statistic. A total of 2200 patients were randomized to placebo, with a follow-up duration of 10 years. YKL-40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL-40) 1.13, 95% CI 1.03-1.24, P=0.013) and all-cause mortality (hazard ratio 1.32, 95% CI 1.17-1.49, P<0.0001). Considering whether a composite-outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL-40 was added as a predictor. Equivalent results were obtained with c-statistics. Conclusions Higher serum YKL-40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL-40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.

Pregnancy Associated Plasma Protein-A as a Cardiovascular Risk Marker in Patients with Stable Coronary Heart Disease During 10 Years Follow-Up-A CLARICOR Trial Sub-Study.

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0-14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25-9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24-1.70; replication HR 1.29, 95% CI 1.10-1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors.

Early Discharge from the Emergency Department Based on Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels: A TRIAGE III Substudy.

OBJECTIVE: Using biomarkers for early and accurate identification of patients at low risk of serious illness may improve the flow in the emergency department (ED) by classifying these patients as nonurgent or even suitable for discharge. A potential biomarker for this purpose is soluble urokinase plasminogen activator receptor (suPAR). We hypothesized that availability of suPAR might lead to a higher proportion of early discharges. DESIGN: A substudy of the interventional TRIAGE III trial, comparing patients with a valid suPAR measurement at admission to those without. The primary endpoint was the proportion of patients discharged alive from the ED within 24 hours. Secondary outcomes were length of hospital stay, readmissions, and mortality within 30 days. SETTING: EDs at two university hospitals in the Capital Region of Denmark. PARTICIPANTS: 16,801 acutely admitted patients were included. MEASUREMENTS AND MAIN RESULTS: The suPAR level was available in 7,905 patients (suPAR group), but not in 8,896 (control group). The proportion of patients who were discharged within 24 hours of admittance was significantly higher in the suPAR group compared to the control group (50.2% (3,966 patients) vs. 48.6% (4,317 patients), P = 0.04). Furthermore, the mean length of hospital stay in the suPAR group was significantly shorter compared to that in the control group (4.3 days (SD 7.4) vs. 4.6 days (SD 9.4), P = 0.04). In contrast, the readmission rate within 30 days was significantly higher in the suPAR group (10.6% (839 patients) vs. 8.8% (785 patients), P < 0.001). Among patients discharged within 24 hours, there was no significant difference in the readmission rate or mortality within 30 days. Readmission occurred in 8.5% (336 patients) vs. 7.7% (331 patients) (P = 0.18) and mortality in 1.3% (52 patients) vs. 1.8% (77 patients) (P = 0.08) for the suPAR group and control group, respectively. CONCLUSION: These post hoc analyses demonstrate that the availability of the prognostic biomarker suPAR was associated with a higher proportion of discharge within 24 hours and reduced length of stay, but more readmissions. In patients discharged within 24 hours, there was no difference in readmission or mortality. TRIAL REGISTRATION OF THE MAIN TRIAL: This trial is registered with NCT02643459.

Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study.

BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

Availability of suPAR in emergency departments may improve risk stratification: a secondary analysis of the TRIAGE III trial.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a prognostic and nonspecific biomarker associated with short-term mortality in emergency department (ED) patients. Therefore, the blood level of suPAR might be usable for identification of patients at high- and low risk, shortly after arrival at the ED. Here, we investigate the value of adding suPAR to triage and how this may impact on risk stratification regarding mortality. METHODS: The analyses were performed on the TRIAGE III cohort. Patients were triaged in four groups: Red, Orange, Yellow, and Green. Outcome was all-cause mortality within seven days. Discriminative abilities of triage and suPAR on mortality were assessed using the area under the curve (AUC) for receiver operating characteristics (ROC) curves. A suPAR cut-off value was generated using the Youden's index. Patients were subsequently reclassified one triage level up if the suPAR level was above this cut-off and one level down if the suPAR level was below that value. RESULTS: The study included 4420 patients with an available triage category and suPAR measurement. suPAR was significantly better in predicting mortality than triage; AUC (95% confidence interval): 0.85 (0.80-0.89) vs. 0.71 (0.64-0.78), P < 0.001. Combining suPAR and triage yielded an AUC of 0.87 (0.82-0-93). The Youden's cut-off of suPAR was 5.9 ng/mL and reclassified triage using this value resulted in a more accurate risk stratification regarding hospital admission and mortality. CONCLUSION: Addition of suPAR to triage potentially improves prediction of short-term mortality. Measurement of suPAR in relation to the triage process may allow a more accurate identification of ED patients at risk. TRIAL REGISTRATION: Clinicaltrials.gov , NCT02643459. Registered 31 December 2015. https://clinicaltrials.gov/ct2/show/NCT02643459?cond=NCT02643459&rank=1 .

Prognostic value of routinely available data in patients with stable coronary heart disease. A 10-year follow-up of patients sampled at random times during their disease course.

Objective: To characterise the long-term prognosis of patients with stable coronary artery heart disease by means of 'standard predictors' defined as demographic, clinical and biochemical quantities routinely available in general practices and ascertained at an interview not prompted by renewed cardiac complaints. Methods: This is an observational study based on data from 2199 Copenhagen placebo patients from the 'clarithromycin for patients with stable coronary heart disease' trial of patients with stable coronary heart disease. In the trial, we compared the effects of 14 days of clarithromycin treatment versus placebo. The predictors were based on the interview forms and blood samples collected at entry, along with demographic information from hospital files.We studied 'standard predictors' of a composite outcome (myocardial infarction, unstable angina, cerebrovascular disease or all-cause death) and of all-cause death. Using Cox regression, we compared predictions of status at 3, 6 and 9 years without and with the use of 'standard predictors' and used receiver operating characteristic statistic. Results: Few 'standard predictors' were associated (p<0.01) with the composite outcome or with all-cause death. When no 'standard predictors' were included, 63.2% of the model-based predictions of the composite outcome and 79.9% of death predictions were correct. Including all 'standard predictors' in the model increased the figures to 68.4% and 83.4%, respectively. C indices were low, except when all-cause death was assessed as a single outcome where C was 0.79. Conclusion: 'Standard predictors' routinely available in general practices contribute only modestly to risk assessment in consecutively sampled patients with stable coronary heart disease as ascertained at a contact not prompted by renewed cardiac complaints. Novel biomarkers may improve the assessment. Trial registration number: NCT00121550.

Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study.

BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. RESULTS: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. CONCLUSIONS: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.

Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality: a cluster-randomized clinical trial (TRIAGE III).

BACKGROUND: Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients. METHODS: The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality. RESULTS: The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results. CONCLUSIONS: The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice. TRIAL REGISTRATION: clinicaltrials.gov, NCT02643459 . Registered 31 December 2015.

10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.

BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease. METHODS AND RESULTS: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%). CONCLUSIONS: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

The prognostic significance of lung function in stable heart failure outpatients.

BACKGROUND: This study investigated the impact on all-cause mortality of airflow limitation indicative of chronic obstructive pulmonary disease or restrictive spirometry pattern (RSP) in a stable systolic heart failure population. HYPOTHESIS: Decreased lung function indicates poor survival in heart failure. METHODS: Inclusion criteria: NYHA class II-IV and left ventricular ejection fraction (LVEF) < 45%. Prognosis was assessed with multivariate Cox proportional hazards models. Two criteria of obstructive airflow limitation were applied: FEV1 /FVC < 0.7 (GOLD), and FEV1 /FVC < lower limit of normality (LLN). RSP was defined as FEV1 /FVC > 0.7 and FVC<80% or FEV1 /FVC > LLN and FVC

Prevalence of airflow obstruction in patients with stable systolic heart failure.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in heart failure (HF). However, routine use of spirometry in outpatient HF clinics is not implemented. The aim of the present study was to determine the prevalence of both airflow obstruction and non obstructive lung function impairment in patients with HF and to examine the effect of optimal medical treatment for HF on lung function parameters. METHODS: Consecutive patients with HF (ejection fraction (EF) < 45%) and New York Heart Association (NYHA) functional class II-IV at 10 different outpatient heart failure clinics were examined with spirometry at their first visit and after optimal medical treatment for HF was achieved. airflow obstruction was classified and graded according to the GOLD 2011 revision. RESULTS: Baseline spirometry was performed in 593 included patients and 71 (12%) had a clinical diagnosis of COPD. Mean age was 69 ± 11 years and mean EF was 30 ± 9%. Thirty-two % of the patients were active smokers and 53% were previous smokers. Mean FEV1 and FVC was 77.9 ± 1.7% and 85.4 ± 1.5% of predicted respectively. Obstructive pattern was observed in 233 (39%) of the patients. Of these, 53 patients (9%) had mild disease (GOLD I) and 180 (30%) patients had moderate to very severe disease (GOLD II-IV). No difference in spirometric variables was observed following up titration of medication. CONCLUSION: In stable patients with HF airflow obstruction is frequent and severely underdiagnosed. Spirometry should be considered in all patients with HF in order to improve diagnosis and treatment for concomitant pulmonary disease.

Iron Deficiency in COPD Associates with Increased Pulmonary Artery Pressure Estimated by Echocardiography.

OBJECTIVES: Iron deficiency (ID) might augment chronic pulmonary hypertension in chronic obstructive pulmonary disease (COPD). This observational study investigates the association between ID and systolic pulmonary artery pressure estimated by echocardiography in non-anaemic COPD outpatients. METHODS: Non-anaemic COPD patients (GOLD II-IV) with no history of cardiovascular disease were recruited from outpatient clinics. Iron deficiency was defined as ferritin<100µg/L. Pulmonary artery pressure was estimated from the tricuspid regurgitation maximum velocity (TR Vmax). Tricuspid regurgitation Vmax indicative of pulmonary hypertension was considered present for values ≥ 2.9 m/s. RESULTS: In a total of 75 included patients, 31 (41%) had ID. These patients had a significantly higher TR Vmax (3.02 vs. 2.77 m/s, p=0.01) and lower diffusion capacity of carbon monoxide (40% vs. 50% of predicted, p<0.01), though similar in age, sex, pack years, FEV1 and high-sensitive CRP (p>0.05). Ferritin inversely correlated with TR Vmax in ID patients (-0.37 (p=0.04)). The prevalence of TR Vmax ≥ 2.9 m/s was twice as high in patients with ID (58% vs. 29%) and odds ratio of pulmonary hypertension in ID (compared to no ID) was 3.3 (95% CI 1.3-8.6, p=0.015). CONCLUSION: Iron deficiency in non-anaemic COPD patients was associated with a modest increase in systolic pulmonary artery pressure and limitation of diffusion capacity.

Predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC): statistical analysis plan for data originating from the CLARICOR (clarithromycin for patients with stable coronary heart disease) trial.

BACKGROUND: The purpose of the predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC) study is exploratory and hypothesis generating. We want to identify biochemical quantities which-conditionally on the values of available standard demographic, anamnestic, and biochemical data-may improve the prediction of cardiovascular outcomes and/or death in patients suffering from stable ischaemic heart disease. The candidate biochemical quantities include N-terminal pro-B-type natriuretic peptide, YKL-40, osteoprotegerin, high-sensitive assay cardiac troponin T (hs-cTnT), pregnancy-associated plasma protein-A (PAPP-A), cathepsin B, cathepsin S, soluble TNF receptor 1 and 2, neutrophil gelatinase-associated lipocalin, endostatin, and calprotectin. As an extra objective, we also want to assess if skewness in these predictors may explain why the clarithromycin for patients with stable coronary heart disease (CLARICOR) trial found increased all-cause and cardiovascular (CV) mortality on a brief clarithromycin regimen compared with placebo. METHODS: Baseline data were obtained from the hospital files at five cardiology clinics covering the Copenhagen area. The CLARICOR trial included data from 4372 stable coronary artery disease patients recruited among such patients alive and diagnosed with acute myocardial infarction or unstable angina pectoris during 1993 to 1999 in Copenhagen and randomised during October 1999 to April 2000 to the CLARICOR trial of 14 days clarithromycin versus placebo.Initial follow-up lasted for 2.6 years, during which outcomes were collected through hospital and death registries and assessed by an adjudication committee. Corresponding register data later showed to produce similar results. The adjudicated outcomes were therefore replaced and augmented by register data on outcomes to cover 10 years of follow-up. Biochemical marker data were obtained from analysis of serum from the CLARICOR bio-bank collected at randomisation and stored at -80° C.Using Cox proportional hazard method, we will identify among the candidate biochemical quantities those which are significant predictors when used alone and in combination with the standard predictors as defined in the present study. DISCUSSION: Patients who became stable during the period 1993 to 1999 and died before October 1999 are missing. The data from the placebo patients are nevertheless useful to identify new prognostic biomarkers in patients with stable coronary artery disease, and data from both trial groups are useful to assess important potential skewness between randomised groups. However, due to the potential selection bias, we do not feel that it is advisable to try to rank identified biochemical predictors relative to each other nor to use the results for predictive purposes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00121550 Date of registration 13 July 2005Date of enrolment of first participant 12 October 1999.

Introduction of a prognostic biomarker to strengthen risk stratification of acutely admitted patients: rationale and design of the TRIAGE III cluster randomized interventional trial.

BACKGROUND: Several biomarkers have shown to carry prognostic value beyond current triage algorithms and may aid in initial risk stratification of patients in the emergency department (ED). It has yet to be established if information provided by biomarkers can be used to prevent serious complications or deaths. Our aim is to determine whether measurement of the blood level of the biomarker soluble urokinase plasminogen activator receptor (suPAR) can enhance early risk stratification leading to reduced mortality, lower rate of complications, and improved patient flow in acutely admitted adult patients at the ED. The main hypothesis is that the availability of suPAR can reduce all-cause mortality, assessed at least 10 months after admission, by drawing attention towards patients with an unrecognized high risk, leading to improved diagnostics and treatment. METHODS: The study is designed as a cross-over cluster randomized interventional trial. SuPAR is measured within 2 h after admission and immediately reported to the treating physicians in the ED. All ED physicians are educated in the prognostic capabilities of suPAR prior to the inclusion period. The inclusion period began January 11(th) 2016 and ends June 6(th) 2016. The study aims to include 10.000 patients in both the interventional and control arm. The results will be presented in 2017. DISCUSSION: The present article aims to describe the design and rationale of the TRIAGE III study that will investigate whether the availability of prognostic information can improve outcome in acutely admitted patients. This might have an impact on health care organization and decision-making. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (ID NCT02643459 , November 13, 2015) and at the Danish Data Protection agency (ID HGH-2015-042 I-Suite no. 04087).

Prevalence and significance of troponin elevations in patients without acute coronary disease.

BACKGROUND: Cardiac troponin T and I are important diagnostic and prognostic markers in patients with acute coronary syndrome (ACS). Troponin elevations in various non-ACS scenarios have been documented, but few studies have been conducted on the general hospitalized population, none compared the diagnostic performance of troponin I and T. METHODS AND RESULTS: Patients aged >18years (n=1097), consecutively admitted to a district hospital, were included in the study. Blood samples were collected at admission and analysed with three different troponin assays. Serum was available in 92.2%, giving a study population of 1012 patients (mean age 61.6years, 510 (50.4%) female). ACS was diagnosed among 125 (12.4%) of the patients. Remaining patients were admitted with a broad spectrum of medical and surgical conditions. Of the total population, sc-cTnI was above the 99th percentile in 93 (9.2%), hs-cTnI was above the 99th percentile in 80 (7.9%) and hs-cTnT was above the 99th percentile in 400 (39.5%) of the patients (p<0.001 for all differences). Hs-cTnT was stronger correlated with estimated glomerular filtration rate (r [2]=0.13 vs r [2]=0.06) and haemoglobin (r [2]=0.1 vs r2=0.02) than with hs-cTnI, none were correlated with C-reactive protein (r [2]=0.04 vs r [2]=0.02). The correlation between ln(hs-cTnT) and ln(hs-cTnI) was better in ACS patients than in non-ACS patients (r [2]=0.79 vs r [2]=0.47, p<0.001). CONCLUSION: Hs-cTnT was elevated above the 99th percentile in more than one third of the non-ACS patients, while hs-cTnI and sc-cTnI were elevated in approximately one tenth. The correlation between hs-cTnT and hs-cTnI concentrations was significantly stronger in ACS patients than in non-ACS patients.

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial.

BACKGROUND: The CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10years follow up. METHODS: The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression. RESULTS: Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10years was violated for cardiovascular death (P=0.01) and cardiovascular death outside hospital (P<0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88). CONCLUSION: Clarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition.

Agreement between public register and adjudication committee outcome in a cardiovascular randomized clinical trial.

UNLABELLED: The objective of this study is to describe the agreement between randomized trial outcome assessment by committee and outcomes entirely identified through public registers. METHODS: In the CLARICOR trial, 4,372 patients with stable coronary heart disease received a short course of clarithromycin versus placebo and were followed up for 2.6 years. The pertinent hospital records and death certificates had originally been evaluated by the adjudication committee using common definitions of outcomes mapped into a 6-category list. We now mechanically converted the International Classification of Diseases-coded diagnoses of the public registries into the same categories. After cross-tabulation of the committee diagnoses with National Patient Register diagnoses and Register of Causes of Death, we calculate agreement and compare the estimated intervention effects of the 2 data sets. RESULTS: With public register data, the protocol-specified categories were slightly more frequent. Overall agreement was 74% for hospital discharges and 60% for cause of death, but the intervention effect, expressed as a hazard ratio, stayed within 4% of the value originally obtained with the adjudication committee (P ≥ .35). CONCLUSIONS: Our results show a modest agreement between formal adjudication and outcomes deducible from public registers. However, the estimated intervention effect did not differ noticeably between the 2 data sources. If studies on a wide range of public registers confirm these findings, register outcomes may be considered as a replacement for adjudication committees.