This study sought to assess whether baseline and change in contemporary sensitive troponin I (TnI) levels predicts coronary heart disease (CHD) death and myocardial infarction (MI), and to determine ...the effects of pravastatin on TnI levels.
The role of troponins in predicting long-term outcomes in patients with stable CHD is not clearly defined.
The LIPID (Long-Term Intervention With Pravastatin in Ischaemic Disease) study randomized patients with cholesterol levels of 155 to 271 mg/dl 3 to 36 months after MI or unstable angina to placebo or pravastatin 40 mg per day. TnI levels were measured at baseline and after 1 year in 7,863 patients. Median follow-up was 6 years. Change in TnI was defined as moving up or down 1 tertile or ≥50% change.
Baseline TnI tertiles were <0.006 ng/ml, 0.006 to <0.018 ng/ml, and ≥0.018 ng/ml. TnI levels were related to CHD death and MI after adjustment for 23 risk factors and treatment (≥0.018 ng/ml vs. <0.006 ng/ml hazard ratio HR: 1.64; 95% CI: 1.41 to 1.90; p < 0.001). TnI levels increased in 23.0%, were unchanged in 51.3%, and decreased in 25.7% of patients. Pravastatin decreased TnI levels by 0.003 ng/ml versus placebo (p = 0.002). In landmark analyses, increases in TnI levels were associated with increased numbers of CHD death and MI (HR: 1.31; 95% CI: 1.06 to 1.62) and decreases with decreased risk (HR: 0.90; 95% CI: 0.74 to 1.09; overall p = 0.01). Data were similar with 50% change criteria. Net reclassification improvement by adding TnI to the baseline model for CHD death and MI was 4.8% (p = 0.01).
Baseline TnI levels and change at 1 year are independent predictors of CHD death and MI. TnI levels are strong predictors of risk, and change modifies risk.
Aims/hypothesis
Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We ...examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes.
Methods
We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR.
Results
In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2,
p
< 0.001) than the non-progressors (
n
= 3521). On Cox regression analysis, each ∆∆C
t
decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 95% CI 1.13, 1.30,
p
< 0.001); the association remained significant after adjusting for baseline age, sex, HbA
1c
, lipids, renal function and other risk factors (HR 1.11 95% CI 1.03, 1.19,
p
= 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 95% CI 1.15, 1.30,
p
< 0.001; adjusted OR 1.09 95% CI 1.01, 1.17,
p
= 0.024).
Conclusions/interpretation
rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.
Graphical abstract
Statin therapy has been associated with pancreatitis in observational studies. Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, ...fibrates may lead to the development of gallstones, a risk factor for pancreatitis.
To investigate associations between statin or fibrate therapy and incident pancreatitis in large randomized trials.
Relevant trials were identified in literature searches of MEDLINE, EMBASE, and Web of Science (January 1, 1994, for statin trials and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data were tabulated where available (6 trials). Unpublished data were obtained from investigators (22 trials).
We included randomized controlled cardiovascular end-point trials investigating effects of statin therapy or fibrate therapy. Studies with more than 1000 participants followed up for more than 1 year were included.
Trial-specific data described numbers of participants developing pancreatitis and change in triglyceride levels at 1 year. Trial-specific risk ratios (RRs) were calculated and combined using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I2 statistic.
In 16 placebo- and standard care-controlled statin trials with 113,800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 95% CI, 0.62-0.97; P = .03; I2 = 0%). In 5 dose-comparison statin trials with 39,614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 95% CI, 0.59-1.12; P = .21; I2 = 0%). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65-0.95; P = .01; I2 = 0%). In 7 fibrate trials with 40,162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 95% CI, 1.00-1.95; P = .053; I2 = 0%).
In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.
Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could ...identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.
Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.
In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (
trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA
DS
-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA
DS
-VASc score of 3.
Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA
DS
-VASc scores, the GRS identified patients with risk comparable to those with higher CHA
DS
-VASc scores.
People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular ...weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.
BACKGROUNDBiomarkers are known to predict major adverse cardiovascular events. However, the association of biomarkers with complex coronary revascularization procedures or high-risk coronary anatomy ...at the time of revascularization is not understood. OBJECTIVESWe examined the associations between baseline biomarkers and major coronary events (MCE) and complex revascularization procedures. METHODSFOURIER was a randomized trial of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab vs placebo in 27,564 patients with stable atherosclerosis. We analyzed adjusted associations among the biomarkers, MCE (coronary death, myocardial infarction, or revascularization), and complex revascularization (coronary artery bypass graft or complex percutaneous coronary intervention) using a multimarker score with 1 point assigned for each elevated biomarker (high-sensitivity C-reactive protein ≥2 mg/L; N-terminal pro-B-type natriuretic peptide ≥450 pg/mL; high-sensitivity troponin I ≥6 ng/L; growth-differentiation factor-15 ≥1,800 pg/mL). RESULTSWhen patients were grouped by the number of elevated biomarkers (0 biomarkers, n = 6,444; 1-2 biomarkers, n = 12,439; ≥3 biomarkers, n = 2,761), there was a significant graded association between biomarker score and the risk of MCE (intermediate score: HRadj: 1.57 95% CI: 1.38-1.78; high score: HRadj: 2.90 95% CI: 2.47-3.40), and for complex revascularization (intermediate: HRadj: 1.33 95% CI: 1.06-1.67; high score: HRadj: 2.07 95% CI: 1.52-2.83) and its components (Ptrend <0.05 for each). The number of elevated biomarkers also correlated with the presence of left main disease, multivessel disease, or chronic total occlusion at the time of revascularization (P < 0.05 for each). CONCLUSIONSA biomarker-based strategy identifies stable patients at risk for coronary events, including coronary artery bypass graft surgery and complex percutaneous coronary intervention, and predicts high-risk coronary anatomy at the time of revascularization. These findings provide insight into the relationships between cardiovascular biomarkers, coronary anatomical complexity, and incident clinical events. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk FOURIER; NCT01764633).
Higher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in ...statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants.
After 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization.
Higher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction.
Higher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients.
•Elevated FGF21 levels at randomization were associated with incident MCVE.•At 1-year, FGF21 levels were lower in 80 mg versus 10 mg atorvastatin group•Elevated FGF21 levels at 1-year were associated with subsequent MCVE.•Changes in FGF21 levels over 1-year were not related to subsequent MCVE risk.•FGF21 provides incremental value in risk prediction in statin-treated patients.
Aims
Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown ...which diabetes‐related characteristics are independently associated with fracture risk. In this post‐hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility.
Materials and Methods
The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50–75 years) to receive oral co‐micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex‐specific diabetes‐related parameters independently associated with incident fractures.
Results
Over 49,470 person‐years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8–5∙2) and 7∙7 per 1000 person‐years (95% CI 6∙5–9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05–2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03–2∙55, p = 0∙03), and HDL‐cholesterol (HR 2∙20, 95% CI 1∙11–4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16–3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02–2∙33, p = 0∙04).
Conclusions
Insulin use and sex‐specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.
Genetic aortopathy (GA) underlies thoracic aortic aneurysms (TAA) in younger adults. Comparative survival and predictors of outcomes in nonsyndromic TAA (NS-TAA) are incompletely defined compared to ...Marfan syndrome (MFS) and bicuspid aortic valve (BAV).
The study sought to compare survival and clinical outcomes for individuals with NS-TAA, MFS, and BAV.
From 1988 to 2014, all patients presenting with GA 16 to 60 years of age were enrolled in a prospective study of clinical outcomes. Risk factors for death and aortic dissection were identified by Cox proportional hazards modeling and a mortality risk score developed.
Diagnosis of GA was made for 760 patients (age 36.9 ± 13.6 years, 26.8% female; NS-TAA, n = 311; MFS, n = 221; BAV, n = 228). MFS patients were younger than NS-TAA and BAV. Presentation with aortic dissection was more common for NS-TAA than MFS or BAV. The 687 patients surviving >30 days after presentation were followed for a median of 7 years. Calculated 10-year mortality was 7.8% for NS-TAA, 8.7% for MFS, and 3.5% for BAV (NS-TAA and MFS vs. BAV p <0.05). Factors associated with all-cause mortality were MFS (p = 0.04), age at presentation, and family history of dissection.
Clinical outcomes for MFS and NS-TAA are similar but worse than BAV. Independent predictors of mortality, including family history of aortic dissection and age, can be included in an Aortopathy Mortality Risk Score to predict survival. Management of NS-TAA, including surgical intervention, should be similar to that of MFS.
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