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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.

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

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.

ObjectiveTo 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.DesignThe 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.SettingFive Copenhagen University cardiology departments and a coordinating centre.Participants1998 participants with stable coronary artery disease.OutcomesDeath and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death.ResultsWhen 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%.ConclusionWhen ‘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 Trial registration numberNCT00121550.

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.

Objectives. To elucidate the prognostic power of serum osteoprotegerin (OPG) in patients with stable coronary artery disease (CAD). Methods. Serum OPG levels were measured in the CLARICOR trial cohort of 4063 patients with stable CAD on blood samples drawn at randomization. The follow-up was 2.6 years for detailed cardiovascular events and 6 years for all-cause mortality. Results. OPG levels were significantly increased in non-survivors (21%) compared to survivors (median [quartiles] 2092 ng/L [1636; 2800] compared to 1695 ng/L [1322; 2193, p < 0.0001]). The 2.6-year follow-up showed that OPG adds to the prediction of both cardiovascular and all-cause mortality in combination with clinical risk factors (HR [one log10 unit increase] 6.1 [95% CI 2.4–15.6, p = 0.0001]) and HR 6.5 [95% CI 3.4–12.5, p < 0.0001], respectively). Similar, in the 6-year follow-up, OPG was found to be a strong predictor for all-cause mortality. Importantly, OPG remained an independent predictor of mortality even after adjustment for both clinical and conventional cardiovascular risk markers (HR 2.5 [95% CI 1.6–3.9, p < 0.0001]). Conclusions. Serum OPG has a long-lasting independent predictive power as to all-cause mortality and cardiovascular death in patients with stable CAD. Trial registration:ClinicalTrials.gov identifier: NCT00121550.

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 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.

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: FEV(1)/FVC < 0.7 (GOLD), and FEV(1)/FVC < lower limit of normality (LLN). RSP was defined as FEV(1)/FVC > 0.7 and FVC LLN and FVC

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 ( 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.

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.

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 TNFR 1 and TNFR 2 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 TNFR 1; hazard ratio, 1.16; 95% confidence interval, 1.08–1.24; P TNFR 2). 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 TNFR 1 and TNFR 2 to established cardiovascular risk factors improved prediction only modestly ( Conclusions Increased concentrations of circulating TNFR 1 and TNFR 2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR 1 and TNFR 2 to improve risk prediction in these patients appears limited. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 00121550.

ObjectiveTo 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.MethodsThis 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.ResultsFew ‘standard predictors’ were associated (pC 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 numberNCT00121550.

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 10 years follow up. Methods The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2 weeks of clarithromycin 500 mg a day versus placebo. 10 year 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 10 years (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 10 years 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 4 years, 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.

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.Patients aged18years (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 (p0.001 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, p0.001).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.

Pregnancy associated plasma protein-A (PAPP-A) is a potential new marker for vulnerable plaques in the coronary arteries only examined in stable coronary disease (CAD) in patients undergoing coronary angiography. Here we address the prognostic value of serum PAPP-A in unselected stable CAD patients.Blood samples were drawn at study entry. Serum PAPP-A values ≥4mIU/L were considered elevated. Mortality and non-fatal myocardial infarction was prospectively registered. The primary outcome was the composite outcome of myocardial infarction and all-cause mortality, secondary outcomes were all-cause mortality and myocardial infarction.Patients (n=4243) were followed for a median of 2.8 years. In a Cox analysis, elevated PAPP-A was significantly related to the composite outcome of myocardial infarction and death (HR 1.99, 95% CI 1.62-2.45, p0.0005), all-cause mortality (HR 2.42, 1.92-3.06, p0.0005), and myocardial infarction (HR 1.40, 1.01-1.94, p=0.046). After Holm's correction, the latter significance disappeared. After adjustment for risk factors and medication at entry, elevated PAPP-A remained significantly related to the composite outcome (HR 1.51, 1.22-1.86, p0.0005) and all-cause mortality (HR 1.68, 1.32-2.13, p0.0005).In patients with stable CAD elevated serum PAPP-A seems promising as aid in identifying patients at high risk for death.

The long-term prognostic importance of hyperkinesia is unknown following an acute myocardial infarction (AMI). The American Society of Echocardiography recommends that hyperkinesia should not be included in calculation of wall motion index (WMI). The objective of the present study was to determine if hyperkinesia should be included in WMI when it is estimated for prognostic purposes following an AMI. Six thousand, six hundred seventy-six consecutive patients were screened 1 to 6 days after AMI in 27 Danish hospitals. WMI was measured in 6,232 patients applying the 9-segment model and the following scoring system: 3 for hyperkinesia, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia, and −1 for dyskinesia. All patients were followed with respect to mortality for at least 3 years. WMI was calculated in 2 different ways: 1 including hyperkinetic segments (hyperkinetic-WMI) and the other excluding nonhyperkinetic segments (nonhyperkinetic-WMI) by converting the hyperkinetic segments to normokinetic segments. Hyperkinesia occurred in 736 patients (11.8 %). WMI was an important prognostic factor (relative risk 2.49; p = 0.0001) for long-term mortality together with heart failure, history of hypertension, angina, or diabetes, previous AMI, age, thrombolytic therapy, arrhythmias, and bundle branch block. In a multivariate analysis including nonhyperkinetic-WMI, hyperkinesia was associated with a relative risk of 0.84, which was statistically significant (confidence intervals 0.74 to 0.96; p = 0.01). When hyperkinesia was included, both in WMI (hyperkinetic-WMI) and as an independent variable, no additional prognostic information (relative risk 0.93; p = 0.26) was obtained. An echocardiographic evaluation shortly after an AMI gave important prognostic information, especially if the information concerning hyperkinesia was included. If WMI is used for prognostic purposes, hyperkinesia should be included in calculation of the index.

Smoking is an important risk factor for atherosclerotic heart disease, but several studies have shown smoking to be associated with a favourable prognosis in patients who have suffered an acute myocardial infarction (AMI). We studied a large group of consecutive patients admitted alive to hospital with an infarction in order to further study the prognostic importance of smoking status at the time of myocardial infarction. The study cohort comprised 6676 patients with an enzyme-confirmed myocardial infarction admitted to 27 Danish hospitals over a 26-month period between 1990 and 1992. Smoking status was determined at the time of hospitalisation and complete follow-up was obtained in October 1996. Smokers were on average 10 years younger, had fewer concomitant cardiac risk factors, and were more likely to be male and to receive thrombolytic therapy more frequently than non-smokers. In univariate analysis, smoking was associated with reduced 30-day and long-term mortality (risk ratio at 30 days 0.55, P

AIMS: Low prevalence of detectable cardiac troponin in healthy people and low-risk patients previously curtailed its use. With a new high-sensitive cardiac troponin assay (hs-cTnT), concentrations below conventional detection may have prognostic value, notably in combination with N-terminal pro-B-type natriuretic peptide (NT-pro-BNP). METHODS AND RESULTS: Biomarker concentrations were determined from serum obtained at enrolment in the CLARICOR trial involving 4197 patients with stable coronary artery disease (CAD) followed for 2.6 years. Serum hs-cTnT was detectable (above 3 ng/l) in 78% and above the conventional 99th percentile (13.5 ng/l) in 23%. Across all levels of hs-cTnT there was a graded increase in the risk of cardiovascular death after adjustment for known prognostic indicators: hazard ratio (HR) per unit increase in the natural logarithm of the hs-cTnT level, 1.49; 95% confidence interval (CI), 1.23-1.81; similarly for all-cause mortality (HR 1.48, 95% CI 1.29-1.70) and myocardial infarction (HR 1.37, 95% CI 1.13-1.67). Increasing values of hs-cTnT were associated with increased mortality across all values of NT-pro-BNP, but this was particularly prominent when NT-pro-BNP >400 ng/l. CONCLUSIONS: In patients with stable CAD, any detectable hs-cTnT level is significantly associated with all-cause mortality, cardiovascular death, and myocardial infarction after adjustment for traditional risk factors and NT-pro-BNP. Excess mortality is particularly pronounced in patients with NT-pro-BNP >400 ng/l.

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.

Early myocardial scintigraphic imaging has become technically feasible in patients admitted to hospital with suspected acute myocardial infarction. After prompt injection of 99mTc-sestamibi, subsequent scintigraphic imaging of perfused myocardium can be performed. During a 5-month period, 237 patients were admitted to the coronary care unit of a district hospital on suspicion of acute ischaemic syndrome, and injection of 99mTc-sestamibi for the performance of myocardial scintigraphy was carried out in 134 patients, on average 2 h after onset of symptoms. The investigation was repeated in 126 patients, on average 18 h after the injection. Three planar views were taken in the coronary care unit with a mobile gamma camera. The prevalence of acute myocardial infarction was 53%. The predictive value at the first scintigraphic imaging for a positive or negative test for myocardial infarction 54% and 56%, respectively. Even exclusion of patients with a previous infarction did not increase the diagnostic validity. The predictive value of a negative test, 77%, at the second scintigraphy was still insufficient to make immediate therapeutic decisions. Myocardial scintigraphy performed early, on suspicion of acute myocardial infarction, cannot therefore be used routinely as a diagnostic test prior to intervention in unselected patients because some 90% of this patient group have myocardial perfusion defects.

We investigated whether the inflammatory biomarker YKL-40 could improve the long-term prediction of death made by common risk factors plus high-sensitivity C-reactive protein (hs-CRP) and N-terminal-pro-B natriuretic peptide (NT-proBNP) in patients with stable coronary artery disease (CAD).Non-hospitalized CAD patients are usually followed in general practice. There is a need for identify biomarkers which could help to foresee the prognoses of these patients. Elevated serum YKL-40 is a short-term predictor for myocardial infarction, cardiovascular mortality and all-cause mortality in patients with stable CAD.Serum YKL-40, hs-CRP, and NT-proBNP were measured in 4265 (97.6%) of the 4372 patients with stable CAD included in the CLARICOR trial, and death was registered in a 6-years follow-up period.The median serum YKL-40 was 110 μg/L [IQR=93], hs-CRP 2.8 mg/L [IQR=4.74], and NT-proBNP 203 ng/L [IQR=407]. During 6 years follow-up period 923 (21.1%) patients died. After adjustment for type of intervention, risk factors (age, sex, hypertension, diabetes, smoking status, and previous myocardial infarction) and medical treatment (diuretics, digoxin, and statin) serum YKL-40 (transformed as ln(max(82, YKL-40/μg/L)) was significantly associated with all-cause mortality [hazard ratio (HR)=1.55, 95% CI=1.39-1.73, p0.001]. After additional adjustment for ln(hs-CRP) and ln(NT-proBNP) this was still true [HR=1.38, 95% CI=1.21-1.53, p0.001].Serum YKL-40 is a predictor of long-term mortality in patients with stable CAD independent of common risk factors and ln(hs-CRP) and ln(NT-proBNP). Serum YKL-40 can be used for prognostication in these patients.

Objective In clinical trials, agreement on outcomes is of utmost importance for valid estimation of intervention effects. As there is limited knowledge about adjudicator agreement in cardiology, we examined the level of agreement among three cardiology specialists adjudicating all possible events in a randomized controlled clinical trial of patients with stable coronary heart disease. Study Design and Setting All information (hospital records, death certificates, etc.) was forwarded to two randomly selected blinded adjudicators. If they disagreed, the third arbiter had to choose the more likely of the two alternatives. Files of 5,475 nonfatal and 362 fatal events were evaluated. Results For nonfatal outcomes, pairwise kappa values ranged from 0.75 to 0.80. The three adjudicators had 4.3%, 9.5%, and 6.1% of their nonfatal outcome classifications overruled by their arbiter. If stable angina pectoris, unstable angina pectoris, and acute myocardial infarction were treated as one, agreement increased minimally. For fatal outcomes, the pairwise kappa values ranged from 0.65 to 0.90. The three adjudicators had 12%, 9%, and 10% of their death classifications overruled. Conclusion Specialists in cardiology can attain a reasonably high agreement on outcomes in patients with stable coronary heart disease.

Objectives: To elucidate potential mechanisms for the clarithromycin-induced excess mortality observed in the CLARICOR trial during 2.6 year follow-up of patients with stable coronary artery disease. Methods: Cox analyses using out-of-hospital death as a proxy for sudden death compared to in-hospital (nonsudden) death. Result: In 100 of 189 (53%) cardiovascular (CV) deaths in which it was possible to examine the question, there was a strong association between place of death and the classification of CV death as sudden or not-sudden. The excess mortality in the clarithromycin group was confined to sudden CV death in patients not on statins at trial entry (HR: 2.61, 95% CI: 1.69–4.05, p < 0.0005). Other categories of deaths showed no marked drug-placebo difference. Conclusions: Short-term clarithromycin administration was significantly associated with increased risk of sudden CV death in stable coronary heart disease patients not using statins.

Background. Patients with stable coronary artery disease (CAD) have a poor prognosis. The aim of the study was to evaluate the extent to which serum high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement alone or together could be prognostic biomarkers in patients with stable CAD. Materials and methods. During the 2.6-year follow-up period 270 patients among the 4264 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 cardiovascular deaths (CVD)). Results. Serum NT-proBNP was significantly associated with MI (hazard ratio (HR), 1. 65 (refers to a 2.72 fold increase in serum level, p = 0.0005), CVD (HR, 2.42, p

Background Myocardial perfusion imaging (MPI) can detect myocardial perfusion abnormalities but many examinations are without pathological findings. This study examines whether circulating biomarkers can be used as screening modality prior to MPI. Methodology/Principal Findings 243 patients with an intermediate risk of CAD or with known CAD with renewed suspicion of ischemia were referred to MPI. Blood samples were analyzed for N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), YKL-40, IL-6, matrix metalloproteinase 9 (MMP-9) and high sensitive C-reactive protein (hsCRP). Patients with myocardial perfusion defects had elevated levels of NT-proBNP (p95% regardless of existing CAD. Conclusions 20-25% of patients suspected of CAD could have been spared a MPI by using a NT-proBNP cut-off concentration at 25 ng/l with a negative predictive value >95%. NT-proBNP has the potential use of being a screening marker of CAD before referral of the patient to MPI.

AIMS: The purpose of the present study was to determine the prognostic importance for all-cause mortality of lung function variables obtained by spirometry in an unselected group of patients admitted with heart failure (HF).METHODS AND RESULTS: This was a prospective prognostic study performed as part of the EchoCardiography and Heart Outcome Study (ECHOS). This analysis included 532 patients admitted with a clinical diagnosis of HF. All patients underwent spirometry and echocardiography and the diagnosis of HF was made according to established criteria. Mean forced expiratory volume in 1 s (FEV(1)) was 65% of the predicted value [95% confidence interval (CI) 63-67%], mean forced vital capacity (FVC) was 71% of predicted (95% CI 69-72%), and FEV(1)/FVC was 0.72 (95% CI 0.71-0.73). FEV(1), FVC, and FEV(1)/FVC were all significant prognostic factors for all-cause mortality in univariate analyses. In a multivariate analysis, FEV(1) had independent prognostic value (hazard ratio 0.86 per 10% change, P < 0.001) after adjusting for demographic variables, known risk factors, ejection fraction, and self-reported chronic obstructive pulmonary disease.CONCLUSION: Pulmonary function provides significant prognostic information for all-cause mortality in patients admitted with HF. Spirometry therefore seems to be worth considering for all patients admitted with HF in order to identify patients at high risk.

Udgivelsesdato: 2010-Apr The association observed between coronary heart disease (CHD) and Chlamydia (Chlamydophila) pneumoniae antibodies prompted, during the 1990s, several primary and secondary prevention trials with various antibiotics. In our CLARICOR trial, a randomized placebo-controlled trial in 4372 patients with stable CHD, a brief clarithromycin regimen was followed, unexpectedly, by increased long-term mortality. We now compare C. pneumoniae antibody levels at entry with population levels, with the patients' individual histories, and with their subsequent outcomes. IgG antibody levels were somewhat raised, but elevated IgA and IgG titers were unrelated to entry data (including prior acute myocardial infarction), except for an association with smoking and with not using statins. Hazards of mortality and of other outcomes tended to slightly increase with IgA and decrease with IgG titers, but the unfavorable clarithromycin effect was unrelated to antibody levels and remains unexplained. Smoking-related lung disease probably underlies the link between heart disease and increased IgG titers.

Udgivelsesdato: 2010-Feb In the CLARICOR trial, significantly increased cardiovascular (CV) and all-cause mortality in stable patients with coronary heart disease were observed after a short course of clarithromycin. We report on the impact of statin treatment at entry on the CV and all-cause mortality. The multicenter CLARICOR trial randomized patients to oral clarithromycin (500 mg daily; n = 2172) versus matching placebo (daily; n = 2201) for 2 weeks. Patients were followed through public databases. In the 41% patients on statin treatment at entry, no significant effect of clarithromycin was observed on CV (hazard ratio [HR], 0.68, 95% confidence interval [CI], 0.38-1.22; P = 0.20) or all-cause mortality (HR, 1.08; 95% CI, 0.71-1.65; P = 0.72) at 2.6-year follow up. In the patients not on statin treatment at entry, clarithromycin was associated with a significant increase in CV (HR, 1.90; 95% CI, 1.34-2.67; P = 0.0003; statin-clarithromycin interaction P = 0.0029) and all-cause mortality (HR, 1.33; 95% CI, 1.05-1.67; P = 0.016; statin-clarithromycin interaction P = 0.41). Multivariate analysis and 6-year follow up confirmed these results. Concomitant statin treatment in stable patients with coronary heart disease abrogated the observed increased CV mortality associated with 2 weeks of clarithromycin.

Smoking is a risk factor for acute myocardial infarction; paradoxically, many studies have shown a lower post-infarct mortality among smokers. There are some important differences between smokers and non-smokers, which might explain the observed difference in mortality: smokers have less multivessel disease and atherosclerosis but are more thrombogenic; thrombolytic therapy seems to be more effective among smokers; smoking might result in an increased out-of-hospital mortality rate, by being more arrhythmogenic; and smokers are on average a decade younger than non-smokers at the time of infarction, and have less concomitant disease. Adjusting for these differences in regression analyses shows that smoking is not an independent risk factor for mortality after acute myocardial infarction. The difference in age and risk factors are responsible for the lower mortality among smokers.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self-reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function.DESIGN: Prospective substudy.SETTING: Systematic screening at 11 centres.SUBJECTS: Consecutive patients (n = 532) admitted with HF requiring medical treatment with diuretics and an episode with symptoms corresponding to New York Heart Association class III-IV within a month prior to admission.INTERVENTIONS: Forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were measured by spirometry and ventricular function by echocardiography. The diagnosis of COPD and HF were made according to established criteria.RESULTS: The prevalence of COPD was 35%. Only 43% of the patients with COPD had self-reported COPD and one-third of patients with self-reported COPD did not have COPD based on spirometry. The prevalence of COPD in patients with preserved left ventricular ejection fraction (i.e. LVEF >or=45%) was significantly higher than in patients with impaired LVEF (41% vs. 31%, P = 0.03). FEV(1) and FVC were negatively correlated with right ventricular end-diastolic diameter and tricuspid annular plane systolic excursion and FVC positively correlated with systolic gradient across the tricuspid valve.CONCLUSION: Chronic obstructive pulmonary disease is frequent in patients admitted with HF and self-reported COPD only identifies a minority. The prevalence of COPD was high in both patients with systolic and nonsystolic HF.

Objectives: We have reported increased 2.6-year mortality in clarithromycin- versus placebo-exposed stable coronary heart disease patients, but meta-analysis of randomized trials in coronary heart disease patients showed no significant effect of antibiotics on mortality. Here we report the 6-year mortality of clarithromycin- versus placebo-exposed patients and updated meta-analyses. Methods: Centrally randomized, placebo controlled multicenter trial. All parties were blinded. Analyses were by intention to treat. Meta-analyses followed the Cochrane Collaboration methodology. Results: We randomized 4,372 patients with stable coronary heart disease to clarithromycin 500 mg (n = 2,172) or placebo (n = 2,200) once daily for 2 weeks. Mortality was followed through public register. Nine hundred and twenty-three patients (21.1%) died. Six-year mortality was significantly higher in the clarithromycin group (hazard ratio 1.21, 95% confidence interval 1.06–1.38). Adjustment for entry characteristics (sex, age, prior myocardial infarction, center, and smoking) did not change the results (1.18, 1.04–1.35). Addition of our data to that of other randomized trials on antibiotics for patients with coronary heart disease versus placebo/no intervention (17 trials, 25,271 patients, 1,877 deaths) showed a significantly increased relative risk of death from antibiotics of 1.10 (1.01–1.20) without heterogeneity. Conclusions: Our results stress the necessity to consider carefully the strength of the indication before administering antibiotics to patients with coronary heart disease.

Pulmonary hypertension is a well-known complication in heart failure, but its prognostic importance is less well established. This study assessed the risk associated with pulmonary hypertension in patients with heart failure with preserved or reduced left ventricular (LV) ejection fractions. Patients with known or presumed heart failure (n = 388) underwent the echocardiographic assessment of pulmonary systolic pressure and LV ejection fraction. Patients were followed for up to 5.5 years. Increased pulmonary pressure was associated with increased short- and long-term mortality (p

Uric acid can serve as a marker of pathophysiological mechanisms in patients with cardiovascular disease, which may explain why serum uric acid contains prognostic information. Uric acid is the end product of purine degradation. It is catalyzed by the enzyme xanthin oxidase, which is responsible for the production of uric acid and damaging free radicals. This is a central link in the association between serum uric acid and myocardial ischemia, myocardial dysfunction and non-cardial function, which is determined primarily by impaired peripheral blood flow. Inhibition of xanthin oxidase with allopurinol may be used in future treatment of heart patients.

Aims Results of previous studies on the influence of gender on prognosis in heart failure have been conflicting and most studies have been conducted in selected populations. The aim of this study was determine whether mortality risk in women and men hospitalized with congestive heart failure is different. Methods and results Survival analysis of 5491 consecutive patients admitted with congestive heart failure to 34 Danish hospitals between 1993–1996. Follow-up time was 5–8 years. Forty percent of the patients were female. Females were older, had less evidence of ischaemic heart disease and their left ventricular systolic function was preserved to a greater extent than in males. Men were more often treated with ACE inhibitors. During the follow-up period 1569 women (72%) and 2386 (72%) of the men died. When the age difference between men and women was adjusted for, male gender was associated with an increased risk of death (RR 1.25 (1.17–1.34)) and the increased risk was confirmed in a multivariate model containing several covariates. Conclusion In patients hospitalized with congestive heart failure male gender is an independent predictor of mortality. Female heart failure patients may be under-treated with ACE inhibitors.

Aims: To evaluate the importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction. Methods and results: Prospective registration of 6669 consecutive patients admitted with infarction and screened for a randomised controlled trial. A history of COPD was present in 765 (11.5%) patients. Thirty-day and 5-year survival in patients with chronic obstructive pulmonary disease was 86.3 and 42.9%. In patients without pulmonary disease the figures were 87.7 and 57.5%, respectively, giving a relative risk of 1.49 (1.35–1.65). In multivariate analysis the relative risk was 1.15 (1.04–1.28). The prevalence of congestive heart failure was 65.9% in patients with chronic obstructive pulmonary disease and 52.0% in patients without. This difference was most distinct in patients with normal or only slightly decreased left ventricular systolic function. In patients without congestive heart failure, chronic obstructive pulmonary disease was of prognostic importance [RR=1.44 (1.17–1.78)], but not in patients with congestive heart failure [RR=1.09 (0.96–1.23)]. Conclusion: Chronic obstructive pulmonary disease is a predictor of long-term mortality in patients with acute myocardial infarction without congestive heart failure, but is also a confounding factor for the diagnosis of congestive heart failure.

Aims The purpose of this study was to assess renal dysfunction as an independent predictor of mortality after acute myocardial infarction. Methods The study population was 6252 patients with a myocardial infarction admitted alive from 1990 to 1992. The mortality status was obtained after at least 6 years. Results Cox proportional-hazards model demonstrated that the unadjusted risk ratio associated with a calculated creatinine clearance ≤40ml.min−1 compared to a clearance above 85ml.min−1 was 7·1 (95% confidence interval 6·2–8·0). Adjustment for multiple available covariates reduced this risk to 2·0 (1·6–2·4). The unadjusted risk ratio associated with clearance from 41 to 55ml.min−1 and from 71 to 85ml.min−1 was 3·7 (3·3–4·2) and 1·5 (1·3–1·7) respectively, but after adjustment for all available variables these risks were reduced to 1·4 (1·2–1·6) and 1·1 (0·9–1·3) respectively. Conclusion Renal dysfunction is an important risk factor after acute myocardial infarction. When the risk is adjusted for available competing risk factors only severely reduced renal function is associated with an important and independent risk of mortality after acute myocardial infarction. The risk of a moderate reduction in renal function is almost fully explained by an association with other conditions.

Background: The prognostic importance of dyskinesia after acute myocardial infarction is unknown, and recommendations have been made that dyskinesia be included in calculations of wall motion index (WMI). Objective: To determine whether it is necessary to distinguish between dyskinesia and akinesia when WMI is estimated for prognostic purposes following acute myocardial infarction. Design: Multicentre prospective study. Patients: 6676 consecutive patients, screened one to six days after acute myocardial infarction in 27 Danish hospitals. Interventions: WMI was measured in 6232 patients, applying the nine segment model, scoring 3 for hyperkinesia, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia, and −1 for dyskinesia. Calculation of WMI either included information on dyskinesia or excluded this information by giving dyskinesia the same score as akinesia. Main outcome measures: Long term outcome (up to seven years) with respect to mortality. Results: Dyskinesia occurred in 673 patients (10.8%). In multivariate analysis, WMI was an important prognostic factor, with a relative risk of 2.4 (95% confidence interval (CI), 2.2 to 2.7), while dyskinesia had no independent long term prognostic importance (relative risk 1.00; 95% CI, 0.89 to 1.12). For 30 day mortality dyskinesia had a relative risk of 1.23 (95% CI, 1.00 to 1.53) (p = 0.045). Conclusions: Echocardiographic evaluation of left ventricular systolic function shortly after an acute myocardial infarct gives important prognostic information, but the presence of dyskinesia only has prognostic importance for the first 30 days.

In the third week after acute myocardial infarction, mean 18 days, exercise tests have been performed in 209 patients prior to discharge from the Coronary Care Unit. The exercise was done on a bicycle ergometer with electrically controlled braking, starting at the load 300 kpm/min (equal to 50 W), increasing with 300 kpm/min every 6th min, aiming at a maximal symptom-limited performance. ECG, in 3 extremity leads and 3 precordial leads, and heart rate (HR) were continuously recorded, and blood pressure (BP) was measured every minute. The most common cause for discontinuing exercise was fatigue (in 58%). Anginal pain or dyspnoea was the cause in 23.8%. Only in 9.1% was the exercise interrupted by the investigator because of rhythm disturbances or pronounced ST-T changes. Maximal work varied from 1 min exercise at 300 kpm/min to 6 min at 900 kpm/min (150 W); 18% of all patients were able to work for 6 min at 600 kpm/min (100 W). HR increased on an average from 80 beats/min at rest to 129 beats/min at maximal work load. Systolic blood pressure (SBP) increased on an average from 126 to 170 mmHg. The maximal values reached during exercise were HR 170/min, and SBP 270 mmHg. The product HR × SBP increased a little more than two-fold on an average. ST-T changes indicating myocardial ischaemia during exercise were observed in 70%. During exercise ventricular ectopic beats occurred in 42 %. All rhythm disturbances provoked by exercise disappeared spontaneously shortly after work. Persistent ECG changes, reinfarction or other serious complications were not observed in connection with the exercise test. It is concluded that an exercise test under controlled circumstances is safe in patients of all ages in the third week after myocardial infarction. It is an objective measure of physical work capacity and describes the reaction to physical activity. It gives a basis for advising return to normal life and is of great psychological importance to the patient.

The occurrence of rupture of the external cardiac wall (CR) in a consecutive series of 2 244 admissions with confirmed acute myocardial infarction (AMI) has been analysed. The series comprises the unselected admissions to a single department, evaluated according to uniform criteria, with postmortem examination in 95% of fatal cases. The incidence of CR was 3.2% af all cases of AMI, and 12.6% of all deaths. CR was significantly more frequent in women than in men, and in both sexes significantly more frequent after the age of 60, though the age distribution did not differ significantly from that of the patients dying from other causes. Moreover, CR was significantly more frequent in anterior wall infarctions, and in patients with no previous AMI. The majority of CR (84%) occurred within the first week, and a considerable part (32%) within the first 24 hours after the onset of infarction. According to findings at autopsy, CR was accompanied particularly often (in 71%) by complete occlusion of a major coronary artery. Autopsy findings gave no evidence that attempts at resuscitation, including external cardiac massage (65 patients), as well as intracardial injections (55 patients) and transthoracic introduction of a pace catheter (3 patients), could have any connection with the development of CR. The usual strict immobilization of the patients was applied during the first part of the series, but in the latter half (1 337 admissions) the patients were allowed to be out of bed from the first day with no imposed immobilization at all. The incidence of CR did not change significantly throughout the period, and the indication for maintaining the traditional immobilization of patients with AMI is questioned.

A total of 644 patients, admitted to the Coronary Care Unit of a district hospital on account of acute myocardial infarction, have been discharged during a 3-year period. Of these patients, 71% had been employed at the time of the infarction and more than 80% of this group returned to work. Among the long-term survivors (LTS) aged less than 65 years who had been employed at the time of infarction, 87% of the male and 74% of the female patients had resumed work some time afterwards. Among 347 LTS age was found to be the main factor to determine whether or not patients would be able to resume work, whereas the number of experienced infarctions as well as signs and/or symptoms of heart failure during the acute phase were of no consequence. The occurrence of additional symptoms of ischaemic heart diseases (recurrences of infarction, presence of angina pectoris, demand for drugs) was of prognostic importance for whether or not patients would have to abandon work. The ability of patients to resume their previous work. The ability of patients to resume their previous work depended on the character of the latter, i.e. its type and the physical strain involved. About 80% of the LTS resumed work within three months. Patients in whom heart failure had occurred during the acute phase tended to return to work later than those without this complication. No more than half of the LTS who had abandoned work declared that cardiac symptoms had been the reason.