Combined Cardiovascular Disease End Point Research Articles

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

How reliable is the statistical evidence for limiting saturated fat intake? A fresh look at the influential Hooper meta-analysis.

Evidence from meta-analyses has been influential in deciding whether or not limiting saturated fat intake reduces the incidence of cardiovascular disease. Recently, random effects analyses have been criticised for exaggerating the influence of publication bias and an alternative proposed which obviates this issue: 'inverse-variance heterogeneity'. We re-analysed the influential Hooper meta-analysis that supports limiting saturated fat intake to decide whether or not the results of the study were sensitive to the method used. Inverse-variance heterogeneity analysis of this summary study was carried out, and the results contrasted with standard methods. Publication bias was also considered. Inverse variance heterogeneity analysis of the Hooper combined cardiovascular disease end point results returned a pooled relative risk of 0.93 (95% confidence interval: 0.74-1.16). This finding contrasts with the traditional random effects analysis with the corresponding statistic of 0.83 (95% confidence interval: 0.72-0.96). Egger tests, funnel and Doi plots along with recently published suppressed trial results suggest that publication bias is present. This study questions the use of the Hooper study as evidence to support limiting saturated fat intake. Our re-analysis, together with concordant results from other meta-analyses of trials indicate that routine advice to reduce saturated fat intake in people with (or at risk for) cardiovascular disease be reconsidered.

APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults.

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status (Pinteraction=0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus.

Hs-cTroponins for the prediction of recurrent cardiovascular events in patients with established CHD – A comparative analysis from the KAROLA study

High-sensitivity Troponins (hs-cTnT and hs-cTnI) are established biomarkers to identify patients with an acute myocardial infarction. However, data comparing the capacity of these two subtypes in predicting recurrent cardiovascular disease (CVD) events in a population with stable coronary heart disease (CHD) after adjustment for several other modern biomarkers are lacking. We measured both troponins at baseline in 1068 CHD patients, followed them for 13years, assessed a combined CVD endpoint, and adjusted for multiple traditional and novel risk factors. Both troponins correlated significantly with age, low and high BMI, male gender, statin therapy, and emerging biomarkers (e.g. cystatin C, NT-proBNP, GDF-15, hsCRP or galectin 3). During follow-up of 13years, 267 fatal and non-fatal CVD events occurred. Top quartiles of both troponin concentrations were significantly associated with CVD events compared to the bottom quartile after adjustment for age, gender and established CVD risk factors (hs-cTnT: hazard ratio (HR) 2.54 (95% CI, 1.60-4.03), p for trend: <0.0001; hs-cTnI: HR 2.20 (95% CI, 1.44-3.36), p for trend: <0.0002 and 0.0003). However, after adjustment for other emerging biomarkers, the associations were no longer statistically significant (hs-cTnT: HR 1.63 (95% CI, 0.97-2.73), p for trend: 0.17; hs-cTnI: HR 1.61 (95% CI, 1.00-2.60), p for trend: 0.067). Both troponins are reliable biomarkers of recurrent cardiovascular events, especially if other novel, important markers such as NT-proBNP, GDF-15 and galectin 3 are not available. Nevertheless, a further workup is still needed to explain the complex interaction of biomarkers indicating vascular and myocardial function.

Prognostic Utility of Galectin-3 for Recurrent Cardiovascular Events During Long-term Follow-up in Patients with Stable Coronary Heart Disease: Results of the KAROLA Study.

Galectin-3 has emerged as a potential useful novel biomarker for heart failure and cardiovascular disease (CVD). However, it remains unclear whether galectin-3 is associated with recurrent cardiovascular events during long-term follow-up of patients with stable coronary heart disease (CHD) after adjustment for multiple established and novel risk factors. We measured galectin-3 at baseline in a cohort consisting of 1035 CHD patients and followed them for 13 years to assess a combined CVD end point. Moreover, we adjusted for multiple traditional and novel risk factors. Galectin-3 concentration was positively associated with the number of affected coronary arteries, history of heart failure, and multiple traditional risk factors. Also, galectin-3 correlated significantly with emerging risk factors [e.g., cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity (hs)-troponin]. During follow-up (median 12.0 years), 260 fatal and nonfatal CVD events occurred. The top quartile of galectin-3 concentration was significantly associated with CVD events compared to the bottom quartile after adjustment for age and sex [hazard ratio (HR) 1.88 (95% CI, 1.30-2.73), P = 0.001 for trend] as well as for established CVD risk factors (HR 1.67, 95% CI, 1.14-2.46, P = 0.011 for trend). However, after adjustment for other biomarkers available [including eGFR (estimated glomerular filtration rate), sST2 protein, GDF-15 (growth differentiation factor 15), NT-proBNP, and hs-troponin], the association was no longer statistically significant [HR 1.11 (95% CI 0.72-1.70), P = 0.82 for trend]. Galectin-3 does not independently predict recurrent cardiovascular events in patients with established CHD after adjustment for markers of hemodynamic stress, myocardial injury, inflammation, and renal dysfunction.

High aortic augmentation index predicts mortality and cardiovascular events in men from a general population, but not in women

A recent meta-analysis concluded that augmentation index (AIx), a measure of pulse wave reflections influencing the central blood pressure, is related to mortality and cardiovascular disease (CVD) events and is likely to be clinically useful. However, prospective data based on non high-risk populations and women are lacking. In a random sample comprising 1300 men and 1773 women from Copenhagen, Denmark, AIx was measured non-invasively by use of the SphygmoCor device. The population was followed prospectively for a mean of 6.5 years for all-cause mortality and a combined CVD end point (time to first myocardial infarction, ischaemic cerebrovascular disease, percutaneous coronary intervention, coronary by-pass graft, or death from any cause). In men, hazard ratio (HR) in highest AIx tertile vs. lowest was 1.68 (95% CI 1.02-2.76) for all-cause mortality and 1.60 (95% CI 1.07-2.39) for the combined CVD end point after multivariable adjustment for CVD risk factors. In women, however, AIx was not related to either outcome with adjusted HR of 0.70 (95% CI 0.46-1.05) for all-cause mortality and 1.12 (95% CI 0.78-1.58) for the combined CVD end point. Our findings support that AIx relates to CVD in men but question the value in women. This gender differences may relate to different development in AIx with increasing age in men and women. Further studies are needed before AIx can be considered in CVD risk stratification or clinical practice.

Abstract 17392: High-Sensitivity Troponin T Predicts Recurrent Cardiovascular Disease Events in Stable Coronary Heart Disease Patients: 8-Year Follow-Up of the KAROLA Study

Purpose: The clinical relevance of only slightly elevated circulating troponin levels in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of a new high-sensitivity troponin T assay (hsTnT) for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of hsTnT (Roche Elecsys 2010) were measured at baseline in a cohort of 1,050 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of hsTnT on a combined CVD endpoint after adjustment for covariates. Results: The median hsTnT level was 10.9 ng/L (IQR 5.1-18.9). Elevated hsTnT levels were associated with higher age, history of hypertension, history of diabetes, a higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction. In addition as determined by 12-lead routine ECG, rhythm disorders, and anterior wall infarction were associated with higher hsTnT levels. Furthermore, hsTnT was highly correlated with NT-proBNP and cystatin C (R=0.61 and R=0.32, respectively, both p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.0%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model, hsTnT was associated with a hazard ratio (HR) for secondary CVD events of 2.83 (95% CI, 1.68-4.79) when extreme quartiles were compared. Further adjustment for cystatin C, NT-proBNP, and CRP attenuated the association only slightly (2.27; 95% CI, 1.31-3.95), p for trend &lt;0.002). ROC analysis of a clinical model which included hsTnT to a baseline model showed a modest improvement in the AUC (0.69 vs 0.67). Conclusions: Slightly elevated hsTnT levels in stable CHD patients are associated with a number of CVD disorders and predict long-term CVD events in these patients.

Abstract 16978: Midregional Pro-Atrial Natriuretic Peptide and Risk of Recurrent Cardiovascular Disease Events in Patients with Stable Coronary Heart Disease Followed Over 8 Years

Aim: Natriuretic peptides provide valuble information about cardiac dysfunction. The clinical relevance of elevated circulating midregional pro-atrial natriuretic peptide (MR-proANP) in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of MR-proANP for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of MR-proANP (BRAHMS) were measured at baseline in a cohort of 1,048 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of MR-proANP on a combined CVD endpoint after adjustment for covariates. Results: The median MR-proANP level was 135.2 pmol/L (interquartile range 95.2-185.8). Elevated MR-proANP levels were associated with higher age, obesity, history of hypertension, diabetes, and heart failure, higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction in a statistically significant way. Furthermore, after adjustment for age and gender MR-proANP was correlated with CRP (correlation coefficient (R=0.21), NT-proBNP (R=0.72), creatinine clearance (R= -0.32), cystatin C (R=0.43), hsTnT (R= 0.51) respectively (all p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.1%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model MR-proANP was associated with a hazard ratio (HR) of secondary CVD events of 3.00 (95% confidence interval (CI), 1.70-5.28) when extreme quartiles were compared. Further adjustment for NT-proBNP attenuated the association only slightly (HR 2.67; 95% CI, 1.48-4.79). Conclusions: Elevated MR-proANP levels in stable CHD patients are associated with several CVD disorders and predict long-term CVD events in these patients.