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Objective: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT)., Research Design and Methods: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction., Results: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008)., Conclusions: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention., (© 2024 by the American Diabetes Association.)

Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis., Methods and Results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98)., Conclusion: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype., Clinical Trial Registration: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939., Competing Interests: Conflict of interest: J.C.T. has received research grant and honoraria from Amarin; research grant from AstraZeneca; research grant, honoraria, and minor equity interest from DalCor; research grant from Esperion; research grant from Ionis; research grant and honoraria from Sanofi; research grant and honoraria from Servier; a patent on pharmacogenomics-guided CETP inhibition was obtained, and J.C.T. and M.P.D. are mentioned as authors. M.P.D. has a minor equity interest in DalCor and has received honoraria from DalCor. M.A.P. receives research support from Novartis; he serves as a consultant for AstraZeneca, Corvidia, DalCor, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Takeda; and has equity in DalCor. D.D.W. has received remuneration for participation in clinical trial committees from CSL Ltd, Daiichi Sankyo, DalCor, the Medicines Company, Novo Nordisk, Regeneron, Resverlogix, and Sanofi, and honoraria for lectures from DalCor and Pfizer. W.K. reports personal fees (consulting) from DalCor and consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, Kowa, a Corvidia, Esperion, Genentech, Omeicos, Novo Nordisk, Daiichi Sankyo, and Amgen; personal fees (honorarium for lectures) from AstraZeneca, Novartis, Amgen, Sanofi, Bristol-Myers-Squibb, and Berlin-Chemie; grants and non-financial support (provision of reagents for biomarker measurements free of charge) from Roche Diagnostics, Beckmann, Singulex, and Abbott, outside the submitted work. A.P.M. has received personal fees for participation in study committee from DalCor, and personal fees for participation in study committees from AstraZeneca, Bayer, Novartis, and Fresenius. J.J.V.M. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Oxford University and Bayer; grants paid to his institution from Theracos; grants paid to his institution and fees as steering committee from Abbvie; grants paid to his institution from Pfizer, Merck AstraZeneca, GlaxoSmithKline, and Novartis. J.W.J. and his department have received research grants from and/or was speaker (with or without lecture fees) in CME-accredited meetings sponsored by Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, The Medicine Company, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute and the European Community Framework KP7 Programme. H.D.W. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Sanofi-Aventis, Regeneron Pharmaceutics, National Institutes of Health (USA), CSL Behring, American Regent, Sanofi-Aventis Australia Pty Ltd, and Esperion Therapeutics Inc, outside the submitted work. F.L.T., T.H., and D.M.B. are employed by and have minor equity interest in DalCor. Other authors report no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy., Methods and Results: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy., Conclusion: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI)., Methods: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections > National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions., Results: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P <0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P <0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P <0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P <0.001)., Conclusions: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Aims: The COLchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated the benefits of targeting inflammation after myocardial infarction (MI). We aimed to determine whether time-to-treatment initiation (TTI) influences the beneficial impact of colchicine., Methods and Results: In COLCOT, patients were randomly assigned to receive colchicine or placebo within 30 days post-MI. Time-to-treatment initiation was defined as the length of time between the index MI and the initiation of study medication. The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. The relationship between endpoints and various TTI (<3, 4-7 and >8 days) was examined using multivariable Cox regression models. Amongst the 4661 patients included in this analysis, there were 1193, 720, and 2748 patients, respectively, in the three TTI strata. After a median follow-up of 22.7 months, there was a significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < Day 3 compared with placebo [hazard ratios (HR) = 0.52, 95% confidence intervals (CI) 0.32-0.84], in contrast to patients in whom colchicine was initiated between Days 4 and 7 (HR = 0.96, 95% CI 0.53-1.75) or > Day 8 (HR = 0.82, 95% CI 0.61-1.11). The beneficial effects of early initiation of colchicine were also demonstrated for urgent hospitalization for angina requiring revascularization (HR = 0.35), all coronary revascularization (HR = 0.63), and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all P < 0.05)., Conclusion: Patients benefit from early, in-hospital initiation of colchicine after MI., Trial Registration: COLCOT ClinicalTrials.gov number, NCT02551094., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis., Methods: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed., Results: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03)., Conclusions: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Some studies have shown that body weight variability is a risk factor for cardiovascular events, but this has not been studied in subjects with diabetes mellitus., Methods and Results: We measured intraindividual variations in body weight from baseline and follow-up visits in 6408 subjects with type 2 diabetes mellitus from 3 clinical trials. The primary end point, any coronary event, was a composite of coronary heart disease death, myocardial infarction, resuscitated cardiac arrest, coronary revascularization, and unstable or new-onset angina. After adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body weight variability, measured as average successive variability and used as a time-dependent covariate, was associated with an increase in the risk of any coronary event (hazard ratio, 1.08; 95% CI, 1.01-1.14; P=0.017), major coronary event (hazard ratio, 1.12; 95% CI, 1.04-1.20; P=0.002), any cardiovascular event (hazard ratio, 1.08; 95% CI, 1.03-1.14; P=0.0015), and death (hazard ratio, 1.16; 95% CI, 1.10-1.22; P<0.0001). Among patients in the quintile with the highest variation in body weight compared with the lowest, the risk of any coronary event was 59% higher; the risk of a major coronary event, 82% higher; any cardiovascular event, 75% higher; death, 82% higher; myocardial infarction, 99% higher; and stroke, 92% higher in adjusted models. The results were consistent in a number of sensitivity analyses., Conclusions: Among subjects with type 2 diabetes mellitus, fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events, independent of traditional cardiovascular risk factors., Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00327691 and NCT00327418.

In patients with previous myocardial infarction (MI), aggressive hypertension control and low-density lipoprotein cholesterol (LDL-C) reduction are important secondary prevention measures. However, residual risk remains despite aggressive treatment. Whether variability in blood pressure (BP) and LDL-C can explain this residual risk is not known. Patients enrolled in the Incremental Decrease in End Points Through Aggressive Lipid-Lowering trial with at least 1 post-baseline measurement of LDL-C and blood pressure (BP) were included. Visit-to-visit LDL-C and BP variabilities were evaluated using various measures of variability. Primary outcome was any coronary event with the secondary outcomes of any cardiovascular event (CV), MI, stroke, death, and CV death. Among the 8,658 patients included, each 1-SD (10.8 mg/dl) increase in LDL-C variability increased the risk of any coronary event (adjusted HR [HR adj ] 1.07; 95% CI 1.04 to 1.11; p <0.0001), any CV event, MI, and death (HR adj 1.19; 95% CI 1.14 to 1.25; p <0.0001). Similarly, each 1-SD (7.2 mm Hg) increase in systolic BP variability increased the risk of any coronary event (HR adj 1.15; 95% CI 1.10 to 1.20; p <0.0001), any CV event, MI, stroke, death (HR adj 1.28; 95% CI 1.18 to 1.38; p <0.0001), and CV death. Compared with the group with low variability for both LDL-C and systolic BP, the group with high variability for both had a significant increase in any coronary event (HR adj 1.48; 95% CI 1.30 to 1.70), any CV event (HR adj 1.43; 95% CI 1.27 to 1.61), and MI (HR adj 1.87; 95% CI 1.46 to 2.41). In conclusions, in patients with a history of MI, variabilities in LDL-C and BP are powerful and independent predictors of CV events including death., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the relationship between lipid and nonlipid biomarker levels achieved during statin therapy and the incidence of major cardiovascular events (MCVEs) in patients with stable coronary heart disease (CHD)., Background: Several plasma nonlipid biomarkers have been shown to predict MCVEs in population studies., Methods: This is a nested case-control study in the TNT (Treating to New Targets) study population, a randomized trial that compared the efficacy of high- (80 mg) versus low-dose (10 mg) atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 nonlipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg and again 1 year after being randomized to 10 or 80 mg atorvastatin in 507 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1,020 control subjects. An MCVE was defined as CHD death; nonfatal, non-procedure-related myocardial infarction; resuscitated cardiac arrest; or fatal or nonfatal stroke., Results: Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were all predictive of recurrent MCVEs (p ≤ 0.009). Concentrations of many of the 18 nonlipid biomarkers were lowered by atorvastatin therapy (independent of dose). However, almost none of the nonlipid biomarker levels, whether measured after the 8-week run-in period or after 1 year of treatment with 10 or 80 mg atorvastatin, were predictive of recurrent MCVEs., Conclusions: In patients with stable CHD, atorvastatin improved plasma levels of an expanded panel of nonlipid biomarkers. However, independently of atorvastatin dose, the achieved levels of the vast majority of nonlipid biomarkers did not predict MCVEs. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The heart rate at rest (HR) is a predictor of cardiovascular (CV) mortality. However, its effect on nonfatal CV events is unknown. The aim of the present post hoc analysis of the Treating New Targets (TNT) trial was to assess the effect of the HR at rest on major CV events in patients with stable coronary heart disease. A total of 9,580 subjects were included in the present analysis and were followed up for a median of 4.9 years. The rate of major CV events was 11.9% in those with a baseline HR of > or =70 beats/min versus 8.8% in those with a baseline HR of <70 beats/min. An increased HR at rest was associated with CV events, even after adjustment for differences in baseline characteristics (unadjusted hazard ratio 1.16 for every 10-beats/min increase, 95% confidence interval [CI] 1.10 to 1.23, p <0.0001; adjusted hazard ratio 1.08 per 10-beats/min increase, 95% CI 1.02 to 1.16, p = 0.018). A HR > or =70 beats/min was a significant independent predictor of all-cause mortality (hazard ratio 1.40, 95% CI 1.14 to 1.71, p = 0.001) and heart failure hospitalization (hazard ratio 2.30, 95% CI 1.80 to 2.95, p > or =0.0001). However, this association was not observed for stroke or myocardial infarction (p = 0.11 and p = 0.68, respectively). In conclusion, in patients with stable coronary heart disease, every 10-beats/min increase in the HR at rest was associated with an 8% increase in major CV events. In particular, a HR at rest of > or =70 beats/min was associated with a 40% increased risk of all-cause mortality and more than doubled the risk of heart failure hospitalization, but not the risk of stroke or myocardial infarction., (Copyright 2010 Elsevier Inc. All rights reserved.)

We determined the ability of in-trial measurements of triglycerides (TGs) to predict new cardiovascular events (CVEs) using data from the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials. The trials compared atorvastatin 80 mg/day with moderate-dose statin therapy (simvastatin 20 to 40 mg/day in IDEAL and atorvastatin 10 mg/day in TNT) in patients with clinically evident coronary heart disease or a history of myocardial infarction. The outcome measurement in the present research was CVE occurring after the first year of the trial. After adjusting for age, gender, and study, risk of CVEs increased with increasing TGs (p <0.001 for trend across quintiles of TGs). Patients in the highest quintile had a 63% higher rate of CVEs than patients in the lowest quintile (hazard ratio 1.63, 95% confidence interval 1.46 to 1.81) and the relation of TGs to risk was apparent even within the normal range of TGs. The ability of TG measurements to predict risk decreased when high-density lipoprotein cholesterol and apolipoprotein B:apolipoprotein A-1 were included in the statistical analysis, and it was abolished with inclusion of further variables (diabetes, body mass index, glucose, hypertension, and smoking; (p = 0.044 and 0.621, respectively, for trend across quintiles of TGs). Similar results were obtained in patients in whom low-density lipoprotein cholesterol had been lowered to guideline-recommended levels. In conclusion, even slightly increased TG levels are associated with higher risk of recurrence of CVEs in statin-treated patients and should be considered a useful marker of risk.

This article reviews the safety of statins, with emphasis on high-dose atorvastatin (80 mg), the agent with the most efficacy data for clinical outcomes. Although elevated levels of hepatic enzymes were of concern when statins were first introduced, a review of data from large clinical trials shows that elevations in hepatic enzymes are rare and do not lead to clinically significant liver disease. Despite the withdrawal of cerivastatin because of fatal rhabdomyolysis, the risk of this complication with other statins is extremely low. Mild and often transient myalgia is more commonly reported. The safety of high-dose atorvastatin has been evaluated in >11,000 patients, and rates of clinically significant myopathy and elevated hepatic enzymes were extremely low. Simvastatin at doses up to 40 mg is also associated with low rates of elevated hepatic enzymes and myopathy. However, the 80-mg dose of simvastatin carries a risk of myopathy (muscle symptoms and creatine kinase levels >10,000 U/L) of approximately 1 in 250. The clinical benefits of preventing vascular events, myocardial infarction, stroke, and need for revascularization outweigh the low rates of adverse events associated with high-dose statin therapy in high- and intermediate-risk patients.

We performed a cohort study of 392 postmenopausal women who had coronary disease to assess whether baseline serum endothelin-1 level predicts angiographic disease progression, nonfatal myocardial infarction, or death. Angiographic progression was defined as the annualized change in minimal lumen diameter of all qualifying lesions for each patient. Twenty-nine patients died or had a myocardial infarction during follow-up. Each picogram per milliliter increase in endothelin-1 was associated with a 1.8-fold increased risk of death or myocardial infarction. After adjustment for potential confounders, endothelin-1 remained a predictor of clinical events but was not correlated with angiographic progression.

To evaluate the contribution of hematologic factors and long-term inflammation to the development of myocardial infarction at a young age, we measured hematologic variables, including soluble fibrin and high-sensitivity C-reactive protein, in 90 patients who had myocardial infarction and 138 controls

Background: Patients with HIV infection exhibit increased rates of coronary events; however, the clinical features of acute coronary syndromes (ACS) in HIV-infected patients have not been well defined., Methods and Results: Between 1993 and 2003, 68 HIV-infected patients were hospitalized with ACS. We compared the clinical features and outcome of these patients with those of 68 randomly selected control patients with ACS without HIV. HIV patients were on average more than a decade younger than controls and more likely to be male and current smokers and to have low HDL cholesterol. They were less likely than controls to have diabetes or hyperlipidemia, and their TIMI (Thrombolysis In Myocardial Infarction) risk scores on admission were significantly lower. At coronary angiography, the number of vessels with >50% stenosis was 1.3+/-1.0 in HIV patients and 1.9+/-1.2 in controls (P=0.007). Restenosis developed in 15 of 29 HIV patients who underwent percutaneous coronary intervention compared with 3 of 21 controls (52% versus 14%, P=0.006)., Conclusions: HIV patients with ACS are younger and more likely to be males and current smokers and to have low HDL cholesterol levels compared with other ACS patients. Their TIMI risk scores are lower, and they are more likely to have single-vessel disease; however, their restenosis rates after percutaneous coronary intervention are unexpectedly high.

Smokers differ from nonsmokers in the way they present with acute coronary syndromes and in how they respond to treatment. Although smoking increases the risk of a coronary event and accelerates the progression of established atherosclerosis, paradoxically, smokers have better short-term survival after an acute myocardial infarction, mainly because they are younger and have more favorable coronary anatomy. Thrombolysis appears to be a better treatment in smokers than in nonsmokers, probably because thrombosis plays a more important role in the pathogenesis of acute coronary events in smokers. Patients who continue to smoke after angioplasty or bypass surgery have a worse outcome than nonsmokers or quitters. The 2.5- to 3-fold increase in risk for myocardial infarction or stroke in smokers compared with nonsmokers decreases exponentially after smoking cessation. By 4 years the risk is only slightly higher than the risk of a subject who never smoked.

Background: This report describes the effect of intensive cholesterol lowering with atorvastatin on the incidence of nonfatal stroke, a secondary end point, in a randomized, placebo-controlled trial of patients with unstable angina or non-Q-wave myocardial infarction. The primary end point, a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization, was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group over the 16 weeks of the trial (P=0.048)., Methods and Results: Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. The outcomes of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time to first occurrence during the 16-week trial. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% confidence intervals, 0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% confidence intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred in the placebo group., Conclusion: Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with acute coronary syndromes reduced the overall stroke rate by half and did not cause hemorrhagic stroke. These findings need to be confirmed in future trials.

BackgroundThe randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.MethodsThere were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients.ResultsNone of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant.ConclusionsWe found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

Background Kidney function decreases during the lifetime, and this decline is a powerful predictor of both kidney and cardiovascular outcomes. Statins lower cardiovascular risk, which may relate to beneficial effects on kidney function. We studied whether atorvastatin influences kidney function decline and assessed the association between individual kidney function slopes and cardiovascular outcome. Methods and Results Data were collected from 6 large atorvastatin cardiovascular outcome trials conducted in patients not selected for having kidney disease. Slopes of serum creatinine reciprocals representing measures of kidney function change ([mg/dL]-1/y), were analyzed in 30 621 patients. Based on treatment arms, patients were categorized into 3 groups: placebo (n=10 057), atorvastatin 10 mg daily (n=12 763), and 80 mg daily (n=7801). To assess slopes, mixed-model analyses were performed for each treatment separately, including time in years and adjustment for study. These slopes displayed linear improvement over time in all 3 groups. Slope estimates for patients randomized to placebo or atorvastatin 10 mg and 80 mg were 0.009 (0.0008), 0.011 (0.0006), and 0.014 (0.0006) (mg/dL)-1/y, respectively. A head-to-head comparison of atorvastatin 10 and 80 mg based on data from 1 study ( TNT [Treating to New Targets]; n=10 001) showed a statistically significant difference in slope between the 2 doses ( P=0.0009). From a Cox proportional hazards model using slope as a predictor, a significant ( P

AimsThe effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.Methods and resultsWe searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring

ObjectivesThe purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk.BackgroundStatins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension.MethodsWe compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest.ResultsAmong 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.ConclusionsCompared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.

Background Higher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events. Objective The purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease. Methods We assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9 years. Results In the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11–1.21, P < .0001), for triglycerides (HR 1.09, 95% CI 1.04–1.15, P = .0005), and for LDL-cholesterol (HR 1.14, 95% CI 1.09–1.19, P < .0001). Similar results were found for the 3 other measures of variability, standard deviation, coefficient of variability, and variability independent of the mean. Similar results were seen for CV events, stroke, and nonfatal myocardial infarction. Higher variability in triglyceride and LDL-cholesterol, but not HDL-cholesterol, was predictive of incident diabetes. The correlation among the variability of the 3 lipid measurements was weak. Conclusion Visit-to-visit variability in fasting measurements of HDL-cholesterol, triglycerides, and LDL-cholesterol are predictive of coronary events, CV events, and for triglyceride and low-density lipoprotein cholesterol variability, incident diabetes. The mechanisms accounting for these associations remain to be determined. [ABSTRACT FROM AUTHOR]

Objectives: We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. Background: Statin therapy might modestly increase the risk of new-onset T2DM. Methods: We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. Results: In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). Conclusions: High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials. [ABSTRACT FROM AUTHOR]

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention. [ABSTRACT FROM AUTHOR]

That statins should be prescribed for patients before hospital discharge after an episode of acute coronary syndrome (ACS) is a Level of Evidence: 1A recommendation of the American College of Cardiology/American Heart Association Joint Task Force. This level of recommendation is based upon 2 clinical trials: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trials. In the MIRACL trial, 3,086 patients with unstable angina or non–Q-wave myocardial infarction were randomized within 4 days of the event to atorvastatin 80 mg/day or to placebo and followed for 16 weeks. The primary composite end point occurred in 14.8% of atorvastatin patients and 17.4% of placebo patients, a 16% relative risk reduction (p = 0.048). In the PROVE-IT trial, 4,162 patients hospitalized with an ACS within the preceding 10 days were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and were followed for a mean of 24 months. The primary event rate was 22.4% in the atorvastatin group and 26.3% in the pravastatin group, a 16% relative risk reduction (p = 0.005). A strong trend toward a reduction in total mortality was seen in the atorvastatin group (2.2% vs. 3.2%, p = 0.07). Using a composite end point of death, myocardial infarction, and rehospitalization for ACS, the difference between the treatment groups is already statistically significant at 30 days and remains so throughout the follow-up period. Comprehensive treatment programs in ACS patients that include initiation of statins before hospital discharge have been shown to improve outcomes such as recurrent myocardial infarction and total mortality at 1 year. Guidelines prove their utility when their implementation improves outcomes across a broad population at risk, such as in this instance. [Copyright &y& Elsevier]

Objectives: The aim of this post hoc analysis from the TNT (Treating to New Targets) trial is to determine whether patients with previous coronary artery bypass grafting (CABG) surgery achieved clinical benefit from intensive low-density lipoprotein (LDL)-cholesterol lowering. Background: The development and progression of atherosclerosis is accelerated in coronary venous bypass grafts. Methods: A total of 10,001 patients with documented coronary disease, including 4,654 with previous CABG, were randomized to atorvastatin 80 or 10 mg/day and were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event (cardiac death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke). Results: A first major cardiovascular event occurred in 11.4% of the patients with prior CABG and 8.5% of those without prior CABG (p < 0.001). In CABG patients, mean LDL-cholesterol levels at study end were 79 mg/dl in the 80-mg arm and 101 mg/dl in the 10-mg arm, and the primary event rate was 9.7% in the 80-mg arm and 13.0% in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.62 to 0.87, p = 0.0004). Repeat revascularization during follow-up, either CABG or percutaneous coronary intervention, was performed in 11.3% of the CABG patients in the 80-mg arm and 15.9% in the 10-mg arm (hazard ratio 0.70, 95% confidence interval 0.60 to 0.82, p < 0.0001). Conclusions: Intensive LDL-cholesterol lowering to a mean of 79 mg/dl with atorvastatin 80 mg/day in patients with previous CABG reduces major cardiovascular events by 27% and the need for repeat coronary revascularization by 30%, compared with less intensive cholesterol-lowering to a mean of 101 mg/dl with atorvastatin 10 mg/day. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691) [Copyright &y& Elsevier]

Objective: We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl. Background: Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke. The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated. Methods: We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years. Results: Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 18 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment. Conclusions: Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691). [Copyright &y& Elsevier]

The Treating to New Targets (TNT) trial is a parallel-group study that has randomized 10,003 patients from 14 countries to double-blind treatment with either atorvastatin 10 or 80 mg. During the double-blind period, low-density lipoprotein (LDL) cholesterol levels are expected to reach approximate mean values of 100 mg/dl (2.6 mmol/L) for the low-dose atorvastatin group and 75 mg/dl (1.9 mmol/L) for the high-dose group. Randomized patients are expected to be followed for an average of 5 years. The primary end point is the time to occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit. [Copyright &y& Elsevier]

Women presenting with acute myocardial infarction (AMI) have a higher mortality with conventional medical and thrombolytic therapy when compared with men. The outcome after primary percutaneous transluminal mechanical revascularization has not yet been fully investigated. This study was performed to compare the characteristics and the short- and medium-term outcomes of women and men with AMI treated with primary percutaneous revascularization. A total of 182 consecutive patients (62 women and 120 men) were included. Baseline clinical characteristics were similar except that women were older than men, presented more often in cardiogenic shock, and had smaller reference vessel diameters. Stents and abciximab were used equally, but abciximab was stopped more often in women before completion of the 12-hour infusion because of higher bleeding rates. Acute procedural success rates were similar (92% and 97%) but mortality was much higher in women, both at 30-day follow-up (100% vs 0.9%; p <0.05) and during a mean follow-up of 6.9 +/- 4.1 months (15% vs 4.4%; p <0.05). Women also experienced more unfavorable cardiovascular events (recurrent unstable angina or AMI, target vessel revascularization) than men. However, after control for baseline clinical differences in a multivariate analysis, gender was not an independent predictor of survival, whereas age, cardiogenic shock, and completion of a 12-hour abciximab infusion were. [ABSTRACT FROM AUTHOR]

Context: Vigorous physical exertion transiently increases the risk of acute myocardial infarction (MI), but little is known about the clinical characteristics of exertion-related MI.Objective: To compare the clinical and angiographic characteristics of patients who had an exertion-related acute MI vs those who experienced an MI not related to exertion.Design and Setting: Prospective observational cohort study of patients with an acute MI referred to a tertiary care hospital for primary angioplasty.Patients: Of 1048 patients with acute MI, 640 (64 who experienced an exertion-related MI and 576 who did not) were selected for treatment with primary angioplasty and admitted between August 1995 and November 1998.Main Outcome Measures: Clinical characteristics of the patients, including their habitual physical activity (determined by the Framingham Physical Activity Index and the Lipid Research Clinic Physical Activity Questionnaire), angiographic findings during coronary angiography, and the relative risk (RR) of MI during exertion.Results: Patients who experienced exertion-related MI were more frequently men (86% vs 68%), hyperlipidemic (62% vs 40%), and smokers (59% vs 37%), were more likely to present with ventricular fibrillation (20% vs 11%), Killip classification III or IV heart failure (44% vs 22%), single-vessel disease (50% vs 28%), and a large thrombus in the infarct artery (64% vs 35%) and were more likely to be classified as having very low or low activity (84% vs 66%). The RR of experiencing an MI during exertion was 10.1 times greater than the risk at other times (95% confidence interval [CI], 1.6-65.6), with the highest risk among patients classified as very low active (RR, 30.5; 95% CI, 4.4-209.9) and low active (RR, 20.9; 95% CI, 3.1-142.1).Conclusion: These results show that exertion-related MIs occur in habitually inactive people with multiple cardiac risk factors. These individuals may benefit from modest exercise training and aggressive risk-factor modification before they perform vigorous physical activity. [ABSTRACT FROM AUTHOR]

Introduction: Higher plasma fibroblast growth factor 21 (FGF21) levels predict incident CVD events in type 2 diabetes patients. However, whether FGF21 levels predict CVD events in statin-treated patients is unknown, but important as statins are widely used for CVD prevention and may affect FGF21 levels. We therefore investigated whether plasma FGF21 levels predict major cardiovascular event (MCVE) in participants from the Treating to New Targets (TNT) trial. Methods: In TNT trial, after an 8-week run-in period on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease were randomized to 10 mg or 80 mg/day of atorvastatin and followed for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization by ELISA assay. Among them, 1835 patients had plasma FGF21 measurements at 1-year post-randomization. MCVE was defined as a composite of coronary heart disease death, myocardial infarction, stroke and resuscitated cardiac arrest. Results: FGF21 levels at randomization were higher in patients with incident MCVE, compared to those without (median: 253.5 vs 204.6 pg/ml respectively, P <0.001). Higher FGF21 levels were associated with higher risk of incident MCVE (adjusted HR per SD increase in ln-transformed levels = 1.18, P = 0.020). The same associations were obtained when assessing FGF21 levels in tertiles (adjusted HR = 1.45 and 1.56 for tertiles 2 and 3 respectively, P = 0.037). Results were unchanged in a sensitivity analysis after excluding patients with FGF21 levels in the top and bottom 5%. At 1-year post-randomization, FGF21 levels were lower in patients randomised to receive 80 mg atorvastatin vs 10 mg atorvastatin (186.9 vs 207.5 pg/ml respectively, P = 0.006). Higher FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVE (adjusted HR per SD increase in ln-transformed levels = 1.24, P = 0.009). However, changes in FGF21 levels over one year were not related to subsequent MCVE risk. Conclusions: Higher plasma FGF21 levels were associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin reduces plasma FGF21 levels. Our findings suggest FGF21 as a CVD biomarker in high-risk patients, even during statin treatment. [ABSTRACT FROM AUTHOR]