90 results on '"Waters, David D."'
Search Results
2. Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials.
- Author
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Vogt L, Bangalore S, Fayyad R, Melamed S, Hovingh GK, DeMicco DA, and Waters DD
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- Acute Coronary Syndrome epidemiology, Aged, Cardiovascular Diseases epidemiology, Cardiovascular Diseases mortality, Cardiovascular Diseases prevention & control, Comorbidity, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Kidney Function Tests, Male, Middle Aged, Myocardial Infarction epidemiology, Proportional Hazards Models, Renal Insufficiency, Chronic epidemiology, Stroke epidemiology, Treatment Outcome, Atorvastatin administration & dosage, Cardiovascular Diseases drug therapy, Creatinine metabolism, Glomerular Filtration Rate, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Renal Insufficiency, Chronic metabolism
- Abstract
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<0.0001) negative association between kidney function and cardiovascular outcomes was found. Conclusions In patients at risk of or with cardiovascular disease, atorvastatin improved kidney function over time in a dose-dependent manner. In the 3 treatment groups, kidney function improvement was strongly associated with lower cardiovascular risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT00327418; NCT00147602; NCT00327691.- Published
- 2019
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3. Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.
- Author
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Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, Hovingh GK, Kastelein JJ, Melamed S, Barter P, Waters DD, and Ray KK
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- Adult, Aged, Atorvastatin adverse effects, Biomarkers blood, Cause of Death, Cholesterol, LDL blood, Coronary Disease blood, Coronary Disease etiology, Coronary Disease mortality, Disease Progression, Dyslipidemias blood, Dyslipidemias diagnosis, Dyslipidemias mortality, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Male, Middle Aged, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Atorvastatin administration & dosage, Cholesterol blood, Coronary Disease drug therapy, Dyslipidemias drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Lipoproteins blood, Triglycerides blood
- Abstract
Background: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets)., Methods: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression., Results: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008)., Conclusions: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.
- Published
- 2018
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4. Relationship of High-Density Lipoprotein Cholesterol With Renal Function in Patients Treated With Atorvastatin.
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Ong KL, Waters DD, Fayyad R, Vogt L, Melamed S, DeMicco DA, Rye KA, and Barter PJ
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- Aged, Atorvastatin adverse effects, Biomarkers blood, Coronary Disease blood, Coronary Disease diagnosis, Double-Blind Method, Dyslipidemias blood, Dyslipidemias diagnosis, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Kidney physiopathology, Male, Middle Aged, Time Factors, Treatment Outcome, Atorvastatin therapeutic use, Cholesterol, HDL blood, Coronary Disease drug therapy, Dyslipidemias drug therapy, Glomerular Filtration Rate drug effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Kidney drug effects
- Abstract
Background: It is not known whether the concentration of high-density lipoprotein (HDL) cholesterol is related to renal function in statin-treated patients. We therefore investigated whether HDL cholesterol levels predicted renal function in atorvastatin-treated patients in the TNT (Treating to New Targets) trial., Methods and Results: A total of 9542 participants were included in this analysis. Renal function was assessed by estimated glomerular filtration rate (eGFR). HDL cholesterol levels at month 3 were used as this is the time point at which on-treatment HDL cholesterol levels became stable. Among 6319 participants with a normal eGFR (≥60 mL/min per 1.73 m
2 ) at baseline, higher HDL cholesterol levels at month 3 were significantly associated with lower risk of decline in eGFR (ie, having eGFR <60 mL/min per 1.73 m2 ) during follow-up (HR of 1.04, 0.88, 0.85, and 0.77 for HDL cholesterol quintiles 2, 3, 4, and 5, respectively, relative to quintile 1, P for trend=0.006). Among 3223 participants with an eGFR (<60 mL/min per 1.73 m2 ) at baseline, higher HDL cholesterol levels at month 3 had less impact on eGFR during follow-up, with statistical significance observed only when analyzing HDL cholesterol levels as a continuous variable ( P =0.043), but not as a categorical quintile variable ( P for trend=0.27)., Conclusions: In patients treated with atorvastatin, higher HDL cholesterol levels were associated with lower risk of eGFR decline in patients with normal eGFR at baseline. However, further study is needed to establish whether there is any causal relationship between HDLs and renal function., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00327691., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)- Published
- 2018
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5. Are Cholesterol Treatment Targets a Deterrent to Optimal Lipid-Lowering Therapy?
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Waters DD
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- Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Cholesterol, Cholesterol, LDL, Humans, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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- 2017
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6. Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials).
- Author
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Kohli P, Knowles JW, Sarraju A, Waters DD, and Reaven G
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- Biomarkers metabolism, Blood Glucose metabolism, Body Mass Index, Female, Glucose Tolerance Test, Humans, Incidence, Insulin Resistance, Ischemic Attack, Transient drug therapy, Lipids blood, Male, Middle Aged, Retrospective Studies, Stroke drug therapy, Atorvastatin therapeutic use, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Prediabetic State drug therapy, Prediabetic State metabolism
- Abstract
The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m
2 ), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m2 <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2016
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7. Emerging Cardiovascular Disease Biomarkers and Incident Diabetes Mellitus Risk in Statin-Treated Patients With Coronary Artery Disease (from the Treating to New Targets [TNT] Study).
- Author
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Arsenault BJ, Kohli P, Lambert G, DeMicco DA, Laskey R, Messig MM, Kastelein JJ, and Waters DD
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- 1-Alkyl-2-acetylglycerophosphocholine Esterase blood, Adiponectin blood, Aged, Biomarkers blood, C-Reactive Protein metabolism, CD40 Ligand blood, Cardiovascular Diseases blood, Chemokine CCL2 blood, Coronary Artery Disease blood, Cystatin C blood, Diabetes Mellitus, Type 2 blood, Female, Humans, Incidence, Insulin blood, Intercellular Adhesion Molecule-1 blood, Lipoprotein(a) blood, Male, Matrix Metalloproteinase 9 blood, Middle Aged, Multivariate Analysis, Natriuretic Peptide, Brain blood, Neopterin blood, Osteopontin blood, Peptide Fragments blood, Peroxidase blood, Randomized Controlled Trials as Topic, Receptor for Advanced Glycation End Products blood, Risk Factors, Secondary Prevention, Vascular Cell Adhesion Molecule-1 blood, Vitamin D blood, Atorvastatin therapeutic use, Coronary Artery Disease drug therapy, Diabetes Mellitus, Type 2 epidemiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Whether biomarkers associated with cardiovascular disease risk also predict incident diabetes mellitus (DM) is unknown. Our objective was to determine if a panel of 18 biomarkers previously associated with risk of cardiovascular disease also predicts incident DM in statin-treated patients with coronary artery disease (CAD). The Treating to New Targets (TNT) study is a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of coronary heart disease events. Fasting plasma levels of standard lipids and of 18 emerging CAD risk biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in a random sample of 1,424 TNT patients. After exclusion of patients with DM at baseline (n = 253), 101 patients developed DM during the median follow-up of 4.9 years. Patients with incident DM had lower levels of total and high-molecular weight adiponectin, lipoprotein-associated phospholipase A2 (Lp-PLA2), soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. In contrast, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with those without. Plasma levels of C-reactive protein, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro-B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with and without incident DM. After multivariate adjustment, total and high-molecular weight adiponectin as well as Lp-PLA2 were negatively associated with incident DM. Results of this study suggest that plasma lipids and some emerging CAD risk biomarkers, such as adiponectin and Lp-PLA2, may be useful for predicting incident DM in statin-treated patients with stable CAD., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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8. Statin-centric versus low-density lipoprotein-centric approach for atherosclerotic cardiovascular disease prevention: a Singapore perspective.
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Yan P, Tan EK, Choo JC, Liew CF, Lau T, and Waters DD
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- Aging, Cardiology standards, Humans, Life Style, Practice Guidelines as Topic, Risk Assessment, Risk Factors, Singapore, Atherosclerosis drug therapy, Cardiovascular Diseases drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Lipoproteins, LDL blood
- Abstract
The link between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD) is well-established. In Singapore, there is an increasing prevalence of risk factors for ASCVD. Like many Asian countries, Singapore's population is rapidly ageing and increasingly sedentary, which predisposes individuals to chronic health problems. Current international and local guidelines recommend statin therapy for the primary and secondary prevention of ASCVD. However, despite the effectiveness of statin therapy, some studies have highlighted that Asian patients with cardiovascular disease are not achieving target lipid goals. Furthermore, it is widely believed that the responses of Asians (both patients and physicians) to statin therapy are different from those of their Western counterparts. Experts convened in 2014 to determine the impact of current guidelines on clinical practice in Singapore. This review summarises the key findings and recommendations of these guidelines, and presents key principles to aid clinicians to manage the cardiovascular risk of their patients more effectively., (Copyright: © Singapore Medical Association.)
- Published
- 2016
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9. 2013 Cholesterol Guidelines Revisited: Percent LDL Cholesterol Reduction or Attained LDL Cholesterol Level or Both for Prognosis?
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Bangalore S, Fayyad R, Kastelein JJ, Laskey R, Amarenco P, DeMicco DA, and Waters DD
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- Aged, Atherosclerosis diagnosis, Atherosclerosis prevention & control, Female, Humans, Male, Middle Aged, Practice Guidelines as Topic, Prognosis, Atherosclerosis blood, Atorvastatin administration & dosage, Cholesterol, LDL blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Simvastatin administration & dosage
- Abstract
Background: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol recommends moderate- to high-intensity statins for patients with atherosclerotic cardiovascular disease but departs from the traditional treat-to-target approach. Whether percent low-density lipoprotein cholesterol (LDL-C) reduction or attained LDL-C levels add incremental prognostic value to statin dose is not known., Methods: Patients in the Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patient-level data) randomized to a statin arm (atorvastatin 80 mg/10 mg or simvastatin 20 mg) were chosen. Patients were divided into groups based on attained LDL-C levels (≤70 vs >70 mg/dL) and percent LDL-C reduction (≥50% vs <50%). Primary outcome was major cardiovascular event defined as death due to coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. Incremental prognostic value was assessed by using a forward conditional Cox proportional hazards model. Two models were tested: Model 1: Step 1 statin dose; Step 2 add attained LDL-C levels (continuous variable); Step 3 add percent LDL-C reduction (continuous variable). Model 2: Steps 2 and 3 were reversed., Results: Among 13,937 patients included in this study, percent LDL-C reduction added incremental prognostic value over both statin dose and attained LDL-C levels (global chi-square increased from 3.64 to 26.1 to 47.5; P <.0001). However, attained LDL-C level did not provide incremental prognostic value over statin dose and percent LDL-C reduction (global chi-square increased from 3.64 to 47.5 to 47.5; P <.0001 and .94, respectively). Among patients with attained LDL-C ≤70 mg/dL, those with percent LDL-C reduction of <50% had a significantly higher risk of primary outcome (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.16-1.97; P = .002) and stroke (HR, 2.07; 95% CI, 1.46-2.93; P <.0001) and a numerically higher risk of death (HR, 1.37; 95% CI, 0.98-1.90; P = .06) when compared with the group with percent LDL-C reduction of ≥50%., Conclusions: In patients with atherosclerotic cardiovascular disease, percent LDL-C reduction provides incremental prognostic value over statin dose and attained LDL-C levels. However, the attained LDL-C level does not provide additional prognostic value over statin dose and percent LDL-C reduction., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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10. The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.
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Preiss D, Campbell RT, Murray HM, Ford I, Packard CJ, Sattar N, Rahimi K, Colhoun HM, Waters DD, LaRosa JC, Amarenco P, Pedersen TR, Tikkanen MJ, Koren MJ, Poulter NR, Sever PS, Ridker PM, MacFadyen JG, Solomon SD, Davis BR, Simpson LM, Nakamura H, Mizuno K, Marfisi RM, Marchioli R, Tognoni G, Athyros VG, Ray KK, Gotto AM, Clearfield MB, Downs JR, and McMurray JJ
- Subjects
- Female, Humans, Male, Middle Aged, Myocardial Infarction prevention & control, Randomized Controlled Trials as Topic, Risk Factors, Secondary Prevention, Treatment Outcome, Heart Failure prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Aims: The 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 Results: We 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 <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98)., Conclusion: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)
- Published
- 2015
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11. LDL-cholesterol lowering and renal outcomes.
- Author
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Waters DD
- Subjects
- Cardiovascular Diseases blood, Cardiovascular Diseases etiology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Hypercholesterolemia blood, Hypercholesterolemia complications, Kidney drug effects, Kidney physiopathology, Practice Guidelines as Topic, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic drug therapy, Risk Factors, Treatment Outcome, Cardiovascular Diseases prevention & control, Cholesterol, LDL blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia drug therapy, Renal Insufficiency, Chronic complications
- Abstract
Purpose of Review: Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events. Statins reduce cardiovascular risk in a broad spectrum of patients. This article summarizes the evidence that statins reduce risk in CKD patients, and that statins have a small but favorable effect on renal function. Current guidelines for lipid management in patients with CKD are also reviewed., Recent Findings: Two well conducted randomized trials showed no significant benefit for statins among patients receiving dialysis. One large trial demonstrated that simvastatin/ezetimibe reduced cardiovascular events in a broad spectrum of CKD patients. A recent meta-analysis concluded that CKD patients benefit from statins, and that the relative benefit decreases as the severity of CKD worsens. In large trials, statin-treated patients have slightly less worsening of renal function overtime, and there are data to suggest that statins actually do not only preserve, but also increase renal function. Recent guidelines recommend a statin for CKD patients aged 50 years or older, for younger patients with known vascular disease, diabetes, or a 10-year risk greater than 10%, and for adult renal transplant recipients., Summary: Statins should be prescribed to older patients with CKD, and to younger patients with CKD who are at high CVD risk.
- Published
- 2015
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12. Risk of new-onset diabetes and cardiovascular risk reduction from high-dose statin therapy in pre-diabetics and non-pre-diabetics: an analysis from TNT and IDEAL.
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Kohli P, Waters DD, Nemr R, Arsenault BJ, Messig M, DeMicco DA, Laskey R, and Kastelein JJP
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- Cardiovascular Diseases prevention & control, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Prediabetic State complications, Randomized Controlled Trials as Topic, Diabetes Mellitus chemically induced, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects
- Published
- 2015
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13. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
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Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R, Stender S, Johnson PC, Scott RA, Leusink M, Verweij N, Sharp SJ, Guo Y, Giambartolomei C, Chung C, Peasey A, Amuzu A, Li K, Palmen J, Howard P, Cooper JA, Drenos F, Li YR, Lowe G, Gallacher J, Stewart MC, Tzoulaki I, Buxbaum SG, van der A DL, Forouhi NG, Onland-Moret NC, van der Schouw YT, Schnabel RB, Hubacek JA, Kubinova R, Baceviciene M, Tamosiunas A, Pajak A, Topor-Madry R, Stepaniak U, Malyutina S, Baldassarre D, Sennblad B, Tremoli E, de Faire U, Veglia F, Ford I, Jukema JW, Westendorp RG, de Borst GJ, de Jong PA, Algra A, Spiering W, Maitland-van der Zee AH, Klungel OH, de Boer A, Doevendans PA, Eaton CB, Robinson JG, Duggan D, Kjekshus J, Downs JR, Gotto AM, Keech AC, Marchioli R, Tognoni G, Sever PS, Poulter NR, Waters DD, Pedersen TR, Amarenco P, Nakamura H, McMurray JJ, Lewsey JD, Chasman DI, Ridker PM, Maggioni AP, Tavazzi L, Ray KK, Seshasai SR, Manson JE, Price JF, Whincup PH, Morris RW, Lawlor DA, Smith GD, Ben-Shlomo Y, Schreiner PJ, Fornage M, Siscovick DS, Cushman M, Kumari M, Wareham NJ, Verschuren WM, Redline S, Patel SR, Whittaker JC, Hamsten A, Delaney JA, Dale C, Gaunt TR, Wong A, Kuh D, Hardy R, Kathiresan S, Castillo BA, van der Harst P, Brunner EJ, Tybjaerg-Hansen A, Marmot MG, Krauss RM, Tsai M, Coresh J, Hoogeveen RC, Psaty BM, Lange LA, Hakonarson H, Dudbridge F, Humphries SE, Talmud PJ, Kivimäki M, Timpson NJ, Langenberg C, Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Reiner AP, Keating BJ, Hingorani AD, and Sattar N
- Subjects
- Aged, Body Mass Index, Cholesterol, HDL metabolism, Cholesterol, LDL metabolism, Female, Genetic Testing, Humans, Male, Middle Aged, Randomized Controlled Trials as Topic, Risk Factors, Body Weight genetics, Diabetes Mellitus, Type 2 genetics, Hydroxymethylglutaryl CoA Reductases genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target., Methods: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis., Findings: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials)., Interpretation: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition., Funding: The funding sources are cited at the end of the paper., (Copyright © 2015 Swerdlow et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2015
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14. Reply: statin-induced low low-density lipoprotein cholesterol level: is lower better?
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Boekholdt SM, Hovingh GK, Waters DD, Grundy SM, and Kastelein JJP
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- Humans, Atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Lipoproteins blood, Randomized Controlled Trials as Topic
- Published
- 2015
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15. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.
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Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, and Kastelein JJ
- Subjects
- Biomarkers blood, Coronary Disease diagnosis, Female, Humans, Male, Middle Aged, Prognosis, Time Factors, Coronary Disease blood, Coronary Disease drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Lipids blood, Molecular Targeted Therapy
- Abstract
Unlabelled: Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P ≤ 0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs., Trial Registration: ClinicalTrials.gov NCT00327691.
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- 2014
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16. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
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Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, LaRosa JC, Waters DD, DeMicco DA, Simes RJ, Keech AC, Colquhoun D, Hitman GA, Betteridge DJ, Clearfield MB, Downs JR, Colhoun HM, Gotto AM Jr, Ridker PM, Grundy SM, and Kastelein JJ
- Subjects
- Biomarkers blood, Cardiovascular Diseases blood, Cardiovascular Diseases drug therapy, Cardiovascular Diseases prevention & control, Global Health, Humans, Incidence, Lipoproteins drug effects, Risk Factors, Atherosclerosis blood, Atherosclerosis drug therapy, Atherosclerosis epidemiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Lipoproteins blood, Randomized Controlled Trials as Topic
- Abstract
Background: Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented., Objectives: The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk., Methods: This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up., Results: Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB., Conclusions: The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
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- 2014
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17. Statin and the risk of renal-related serious adverse events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials.
- Author
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Bangalore S, Fayyad R, Hovingh GK, Laskey R, Vogt L, DeMicco DA, and Waters DD
- Subjects
- Aged, Atorvastatin, Cardiovascular Diseases drug therapy, Cardiovascular Diseases prevention & control, Controlled Clinical Trials as Topic, Dose-Response Relationship, Drug, Drug Administration Schedule, Evaluation Studies as Topic, Female, Heptanoic Acids administration & dosage, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Incidence, Male, Middle Aged, Myocardial Infarction drug therapy, Myocardial Infarction prevention & control, Prognosis, Pyrroles administration & dosage, Randomized Controlled Trials as Topic, Reference Values, Risk Assessment, Survival Analysis, Acute Kidney Injury chemically induced, Acute Kidney Injury epidemiology, Heptanoic Acids adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Pyrroles adverse effects
- Abstract
A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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18. Meta-analyses of statin trials: clear benefit for primary prevention in the elderly.
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Waters DD
- Subjects
- Female, Humans, Male, Cardiovascular Diseases mortality, Cardiovascular Diseases prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Published
- 2013
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19. Reply: To PMID 23219296.
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Waters DD, Boekholdt SM, and Pedersen TR
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- Female, Humans, Male, Cardiovascular Diseases prevention & control, Coronary Disease drug therapy, Diabetes Mellitus, Type 2 diagnosis, Heptanoic Acids administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Pyrroles administration & dosage, Simvastatin administration & dosage
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- 2013
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20. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.
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Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A, and Pedersen TR
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- Adult, Aged, Atorvastatin, Cohort Studies, Coronary Disease mortality, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Heart Arrest prevention & control, Heptanoic Acids adverse effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Incidence, Male, Middle Aged, Myocardial Infarction prevention & control, Pyrroles adverse effects, Risk Factors, Simvastatin adverse effects, Stroke prevention & control, Cardiovascular Diseases prevention & control, Coronary Disease drug therapy, Diabetes Mellitus, Type 2 diagnosis, Heptanoic Acids administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Pyrroles administration & dosage, Simvastatin administration & dosage
- Abstract
Objectives: The 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., Background: Statins 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., Methods: We 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., Results: Among 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., Conclusions: Compared 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., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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21. Vitamin D levels do not predict cardiovascular events in statin-treated patients with stable coronary disease.
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Bittner V, Wenger NK, Waters DD, DeMicco DA, Messig M, and LaRosa JC
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- Aged, Atorvastatin, Cardiovascular Diseases epidemiology, Cardiovascular Diseases mortality, Case-Control Studies, Cohort Studies, Coronary Disease blood, Double-Blind Method, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Proportional Hazards Models, Risk Factors, Treatment Outcome, Vitamin D Deficiency epidemiology, Coronary Disease drug therapy, Heptanoic Acids administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Pyrroles administration & dosage, Vitamin D blood
- Abstract
Background: This post hoc nested case-control analysis of the TNT study was designed to investigate whether baseline vitamin D level is a significant predictor of cardiovascular risk among statin-treated patients and whether changes in vitamin D after treatment with atorvastatin are associated with improved cardiovascular outcomes., Methods: A total of 10,001 patients with stable coronary heart disease were randomized to atorvastatin 80 or 10 mg for a median of 4.9 years. This analysis included 1,509 patients (497 with a subsequent cardiovascular event and 1,012 without an event) with vitamin D levels determined at baseline and 1 year. Event rates were analyzed by Cox proportional hazard model by baseline vitamin D levels, with vitamin D as a continuous variable, and with change in vitamin D level as the predictor., Results: Vitamin D deficiency (<15 ng/mL) or insufficiency (15- <30 ng/mL) was present in 108 (7.2%) of 1,509 and 625 (41.4%) of 1,509 of patients, whereas 46 (3.0%) of 1,509 had elevated vitamin D. There was no relationship between baseline vitamin D levels or change in vitamin D levels and cardiovascular events or mortality. Modeling of events with vitamin D as a continuous variable similarly showed no relationship of vitamin D to events. These findings held true after adjustment for seasonal variations in vitamin D and other confounders., Conclusion: In statin-treated patients with stable coronary heart disease, vitamin D levels did not predict cardiovascular risk. Changes in plasma concentrations of vitamin D after 1 year of treatment made no contribution to the efficacy of atorvastatin therapy., (Copyright © 2012 Mosby, Inc. All rights reserved.)
- Published
- 2012
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22. Relation of improvement in estimated glomerular filtration rate with atorvastatin to reductions in hospitalizations for heart failure (from the Treating to New Targets [TNT] study).
- Author
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Ho JE, Waters DD, Kean A, Wilson DJ, Demicco DA, Breazna A, Wun CC, Deedwania PC, and Khush KK
- Subjects
- Adult, Aged, Atorvastatin, Double-Blind Method, Female, Follow-Up Studies, Heptanoic Acids administration & dosage, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Male, Middle Aged, Proportional Hazards Models, Pyrroles administration & dosage, Retrospective Studies, Glomerular Filtration Rate physiology, Heart Failure drug therapy, Heptanoic Acids therapeutic use, Hospitalization statistics & numerical data, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Pyrroles therapeutic use
- Abstract
Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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23. Comparison of lipid profiles and attainment of lipid goals in patients <65 years versus patients ≥65 years (from the Lipid Treatment Assessment Project [L-TAP] 2).
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Rodriguez F, Santos RD, Messig M, Tarasenko L, Ferrières J, Jukema JW, Chiang CW, Waters DD, and Foody JM
- Subjects
- Age Factors, Aged, Asia, Dyslipidemias complications, Dyslipidemias drug therapy, Europe, Female, Humans, Latin America, Male, Middle Aged, North America, Risk Factors, Treatment Outcome, Cholesterol, HDL blood, Dyslipidemias blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Lipoproteins, LDL blood
- Abstract
There is a well-established link between dyslipidemia and cardiovascular events, although this risk is modified by age. Little is known about how treatment of dyslipidemia and low-density lipoprotein (LDL) cholesterol goal attainment differ between older and younger patients. We obtained clinical data from 9,926 dyslipidemic patients across 9 countries in North and Latin America, Europe, and Asia from 2006 through 2007. Multivariate regressions were performed to determine predictors of lipid level goal attainment. The study sample consisted of 5,733 adults <65 and 4,193 adults ≥65 years old. Compared with younger patients, older patients were more likely to have diabetes (32.5% vs 30.0%, p = 0.0014) and hypertension (73.4% vs 57.0%, p <0.0001), to be classified as high risk (68.6% vs 53.2%, p <0.0001), and to be taking a statin (79.1% vs 72.0%, p <0.0001). However, they were less likely to smoke (8.2% vs 17.6%, p <0.0001) or to have metabolic syndrome (29.0% vs 34.4%, p <0.0001). Older patients had lower LDL cholesterol levels (95.1 vs 103.9 mg/dl, p <0.0001) and higher levels of high-density lipoprotein cholesterol (54.2 vs 51.5 mg/dl, p <0.0001). LDL cholesterol goal attainment was 74.7% in older and 71.1% in younger patients (p = 0.036). Older patients were more likely to achieve LDL targets whether low risk (89.8% vs 84.6%, p = 0.002), moderate risk (79.0% vs 71.9%, p = 0.0006), or high risk (70.5% vs 64.4%, p <0.0001). In conclusion, older patients had different risk profiles and better lipid levels compared with their younger counterparts. They were more likely to attain their LDL cholesterol goal, perhaps because of greater statin use, different risk profiles, or survival bias., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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24. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study.
- Author
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Mora S, Wenger NK, Demicco DA, Breazna A, Boekholdt SM, Arsenault BJ, Deedwania P, Kastelein JJ, and Waters DD
- Subjects
- Adult, Age Factors, Aged, Atorvastatin, Body Mass Index, Cardiopulmonary Resuscitation, Cholesterol, LDL blood, Death, Sudden, Cardiac prevention & control, Female, Heart Arrest prevention & control, Heart Arrest therapy, Humans, Hypertension drug therapy, Male, Middle Aged, Myocardial Infarction prevention & control, Risk, Sex Factors, Stroke prevention & control, Anticholesteremic Agents therapeutic use, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Pyrroles therapeutic use
- Abstract
Background: Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this "residual risk" have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors., Methods and Results: A total of 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age (adjusted hazard ratio [aHR], 1.13 per 1 SD [8.8 years]; 95% confidence interval [CI], 1.04-1.23), increased body mass index (aHR, 1.09; 95% CI, 1.02-1.17 per 4.5 kg/m(2)), male sex (aHR, 1.33; 95% CI, 1.07-1.65), hypertension (aHR, 1.38; 95% CI, 1.17-1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11-1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11-1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03-1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70-0.94), aspirin use (aHR, 0.67; 95% CI, 0.56-0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84-0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679)., Conclusions: Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00327691.
- Published
- 2012
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25. The 719Arg variant of KIF6 and cardiovascular outcomes in statin-treated, stable coronary patients of the treating to new targets and incremental decrease in end points through aggressive lipid-lowering prospective studies.
- Author
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Arsenault BJ, Boekholdt SM, Hovingh GK, Hyde CL, DeMicco DA, Chatterjee A, Barter P, Deedwania P, Waters DD, LaRosa JC, Pedersen TR, and Kastelein JJ
- Subjects
- Aged, Alleles, Atorvastatin, Cholesterol, LDL blood, Female, Follow-Up Studies, Genotype, Heterozygote, Homozygote, Humans, Kinesins metabolism, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors, Simvastatin therapeutic use, Treatment Outcome, Cardiovascular Diseases drug therapy, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Kinesins genetics, Pyrroles therapeutic use
- Abstract
Background: Carriers of the KIF6 719Arg variant may be at increased risk for CVD and may benefit more from statin therapy, in terms of CVD risk reduction, than noncarriers. Our objective was to investigate whether carriers of the KIF6 719Arg genetic variant (rs20455) are at increased cardiovascular risk and obtain more benefit from high-dose statin therapy than do noncarriers., Methods and Results: We used an adjusted Cox proportional hazard model to assess the hazard ratio (HR) for the reduction of major cardiovascular events by 80 mg/d atorvastatin over 10 mg/d atorvastatin in 4599 patients of the Treating to New Targets (TNT) study and by 80 mg/d atorvastatin over 20-40 mg/d simvastatin in 6541 patients of the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study. A total of 381 and 648 patients had a cardiovascular event during follow-up in TNT and IDEAL, respectively. Heterozygotes and homozygotes for the minor allele were not at increased risk compared with noncarriers. In TNT, for noncarriers of the 719Arg allele, the HR for high- versus low-dose atorvastatin was 0.81 (95% confidence interval, 0.59-1.11). In carriers of 1 or 2 minor alleles, the HR was 0.85 (0.66-1.11) and carriers of 2 copies of the minor allele obtained a significant risk reduction (HR: 0.44, 95% confidence interval, 0.23-0.84). In IDEAL, the respective HRs were 0.85 (0.67-1.10), 0.88 (0.62-1.07) and 0.91 (0.58-1.43). The interaction term for carrier status by treatment was also nonsignificant (P=0.810 in TNT and P=0.909 in IDEAL)., Conclusions: In these 2 large, randomized clinical trials, carriers of the KIF6 719Arg allele were not at increased cardiovascular risk and did not obtain consistent cardiovascular benefit from high-dose statin therapy compared with noncarriers.
- Published
- 2012
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26. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
- Author
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Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, and Ray KK
- Subjects
- Cardiovascular Diseases epidemiology, Dose-Response Relationship, Drug, Humans, Odds Ratio, Randomized Controlled Trials as Topic, Risk, Cardiovascular Diseases prevention & control, Diabetes Mellitus epidemiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects
- Abstract
Context: A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus., Objective: To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy., Data Sources: We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators., Study Selection: We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year., Data Extraction: Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic., Results: In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events., Conclusion: In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.
- Published
- 2011
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27. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.
- Author
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Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, and Barter P
- Subjects
- Adult, Aged, Atorvastatin, Female, Forecasting, Humans, Incidence, Male, Middle Aged, Risk Factors, Diabetes Mellitus, Type 2 chemically induced, Diabetes Mellitus, Type 2 epidemiology, Heptanoic Acids adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Pyrroles adverse effects
- Abstract
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., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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28. On-treatment lipoprotein components and risk of cerebrovascular events in the Treating to New Targets study.
- Author
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van den Bogaard B, van den Born BJ, Fayyad R, Waters DD, DeMicco DA, LaRosa JC, Kastelein JJ, and Holme I
- Subjects
- Aged, Cholesterol, HDL metabolism, Cholesterol, LDL metabolism, Coronary Disease drug therapy, Coronary Disease epidemiology, Female, Follow-Up Studies, Humans, Ischemic Attack, Transient drug therapy, Ischemic Attack, Transient epidemiology, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Stroke drug therapy, Stroke epidemiology, Time Factors, Anticholesteremic Agents therapeutic use, Coronary Disease prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Ischemic Attack, Transient prevention & control, Lipoproteins metabolism, Stroke prevention & control
- Abstract
Background: The Treating to New Targets (TNT) study has recently provided evidence that reduction in LDL-C levels below 2·6 mmol L⁻¹ lowers the risk of cerebrovascular events by an additional 20% to 25%, thereby confirming the value of statin therapy in preventing transient ischaemic attacks and stroke. Despite the protective effects of statin therapy, the epidemiological association between lipid components and cerebrovascular events is less clear. We therefore assessed the strength of association between in-trial lipoprotein components and cerebrovascular disease in patients receiving intensive lipid-lowering therapy., Methods: In 9247 patients (mean age 61·0 years, 81·2% males), the association between lipoprotein components and the risk of cerebrovascular events after the first year into the TNT trial was assessed after stratification of lipoprotein components into approximate quartiles. Cox proportional hazards models were used to explore the association between lipoprotein components and time to first cerebrovascular event after adjustment for potential confounding variables., Results: All lipoprotein components, except LDL-C, showed a significant gradient for incidence of cerebrovascular events with increasing quartiles of the lipoprotein component. If the lipoprotein components were treated as continuous variables, the adjusted hazard ratios (95% CI) for cerebrovascular events for 1 SD difference in 1-year lipoprotein components were 1·13 (1·02-1·25) for LDL-C, 0·86 (0·76-0·97) for HDL-C, 1·17 (1·04-1·28) for apoB, 0·83 (0·74-0·94) for apoA-1, 1·22 (1·10-1·34) for TC/HDL-C and 1·24 (1·12-1·37) for apoB/apoA-1., Conclusions: In coronary heart disease patients receiving intensive lipid-lowering treatment, the on-treatment apoB/apoA-1 ratio provides the strongest association with incidence of cerebrovascular events followed by TC/HDL-C., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)
- Published
- 2011
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29. Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers.
- Author
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Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, and Kastelein JJ
- Subjects
- Atorvastatin, C-Reactive Protein metabolism, Cholesterol, HDL blood, Cholesterol, LDL blood, Coronary Disease blood, Coronary Disease diagnosis, Death, Sudden, Cardiac epidemiology, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Heptanoic Acids administration & dosage, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Incidence, Male, Middle Aged, Myocardial Infarction blood, Myocardial Infarction epidemiology, Prognosis, Pyrroles administration & dosage, Retrospective Studies, Stroke blood, Stroke epidemiology, Time Factors, Biomarkers blood, Coronary Disease drug therapy, Death, Sudden, Cardiac prevention & control, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Myocardial Infarction prevention & control, Pyrroles therapeutic use, Stroke prevention & control
- Abstract
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.)
- Published
- 2011
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30. Statins before stents: does an ounce of prevention improve outcomes?
- Author
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Frey P and Waters DD
- Subjects
- Atorvastatin, Biomarkers blood, Carotid Artery Diseases blood, Carotid Artery Diseases prevention & control, Creatine Kinase, MB Form blood, Evidence-Based Medicine, Heptanoic Acids administration & dosage, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Preoperative Care, Pyrroles administration & dosage, Risk Assessment, Risk Factors, Stroke prevention & control, Treatment Outcome, Troponin I blood, Troponin T blood, Carotid Artery Diseases drug therapy, Carotid Artery Diseases surgery, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Pyrroles therapeutic use, Stents
- Published
- 2010
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31. Exploring new indications for statins beyond atherosclerosis: Successes and setbacks.
- Author
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Waters DD
- Subjects
- Humans, Alzheimer Disease prevention & control, Aortic Valve Stenosis drug therapy, Atherosclerosis drug therapy, Heart Failure drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta-analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C-reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer's disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer's disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications., (Copyright 2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2010
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32. Early statin therapy in acute coronary syndromes: the successful cycle of evidence, guidelines, and implementation.
- Author
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Waters DD and Ku I
- Subjects
- Cholesterol, LDL drug effects, Confidence Intervals, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Risk, Risk Reduction Behavior, Time Factors, Acute Coronary Syndrome drug therapy, Evidence-Based Medicine, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Practice Guidelines as Topic
- Abstract
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.
- Published
- 2009
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33. Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease.
- Author
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Faergeman O, Holme I, Fayyad R, Bhatia S, Grundy SM, Kastelein JJ, LaRosa JC, Larsen ML, Lindahl C, Olsson AG, Tikkanen MJ, Waters DD, and Pedersen TR
- Subjects
- Adult, Aged, Cholesterol blood, Cohort Studies, Coronary Artery Disease etiology, Female, Humans, Male, Middle Aged, Myocardial Infarction drug therapy, Predictive Value of Tests, Proportional Hazards Models, Recurrence, Retrospective Studies, Risk Factors, Coronary Artery Disease blood, Coronary Artery Disease drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Myocardial Infarction blood, Myocardial Infarction etiology, Triglycerides blood
- Abstract
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.
- Published
- 2009
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34. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals.
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Waters DD, Brotons C, Chiang CW, Ferrières J, Foody J, Jukema JW, Santos RD, Verdejo J, Messig M, McPherson R, Seung KB, and Tarasenko L
- Subjects
- Aged, Cholesterol, HDL blood, Diabetes Mellitus epidemiology, Female, Global Health, Guideline Adherence, Health Care Surveys, Humans, Hypercholesterolemia blood, Male, Middle Aged, Risk Factors, Smoking epidemiology, Cholesterol, LDL blood, Coronary Disease epidemiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia drug therapy, Hypercholesterolemia epidemiology, Hypolipidemic Agents therapeutic use
- Abstract
Background: Information about physicians' adherence to cholesterol management guidelines remains scant. The present survey updates our knowledge of lipid management worldwide., Methods and Results: Lipid levels were determined at enrollment in dyslipidemic adult patients on stable lipid-lowering therapy in 9 countries. The primary end point was the success rate, defined as the proportion of patients achieving appropriate low-density lipoprotein cholesterol (LDL-C) goals for their given risk. The mean age of the 9955 evaluable patients was 62+/-12 years; 54% were male. Coronary disease and diabetes mellitus had been diagnosed in 30% and 31%, respectively, and 14% were current smokers. Current treatment consisted of a statin in 75%. The proportion of patients achieving LDL-C goals according to relevant national guidelines ranged from 47% to 84% across countries. In low-, moderate-, and high-risk groups, mean LDL-C was 119, 109, and 91 mg/dL and mean high-density lipoprotein cholesterol was 62, 49, and 50 mg/dL, respectively. The success rate for LDL-C goal achievement was 86% in low-, 74% in moderate-, and 67% in high-risk patients (73% overall). However, among coronary heart disease patients with > or =2 risk factors, only 30% attained the optional LDL-C goal of <70 mg/dL. In the entire cohort, high-density lipoprotein cholesterol was <40 mg/dL in 19%, 40 to 60 mg/dL in 55%, and >60 mg/dL in 26% of patients., Conclusions: Although there is room for improvement, particularly in very-high-risk patients, these results indicate that lipid-lowering therapy is being applied much more successfully than it was a decade ago.
- Published
- 2009
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35. Clinical insights from the Treating to New Targets trial.
- Author
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Waters DD
- Subjects
- Atorvastatin, Cardiovascular Diseases epidemiology, Cholesterol, LDL blood, Comorbidity, Coronary Artery Bypass, Diabetes Mellitus epidemiology, Glomerular Filtration Rate, Humans, Hypertension epidemiology, Metabolic Syndrome epidemiology, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic physiopathology, Risk Assessment, Risk Factors, Coronary Disease drug therapy, Heptanoic Acids administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Pyrroles administration & dosage
- Abstract
The Treating to New Targets (TNT) trial enrolled 10,001 patients with coronary disease to treatment with atorvastatin, 80 or 10 mg/d, and observed them for a median of 4.9 years. Mean low-density lipoprotein cholesterol (LDL-C) levels were 77 mg/dL in the 80-mg group and 101 mg/dL in the 10-mg group. The primary end point, a composite of cardiovascular death, myocardial infraction, resuscitated cardiac arrest, and stroke, occurred in 10.9% of patients in the 10-mg and 8.7% of patients in the 80-mg group (P = .0002). In large subgroups of patients in TNT, specifically those with diabetes, the metabolic syndrome, chronic kidney disease, or previous coronary bypass (CABG) surgery, the risk of an event was significantly higher than in patients without these features. The absolute risk reduction in the 80-mg group was greater in each of these subgroups than in other TNT patients. The rates of stroke and hospitalization for heart failure were significantly lower in the more aggressively treated patients. A total of 18,696 patients have taken 80 mg of atorvastatin in clinical trials, usually for 4 to 5 years, with an excellent safety record. Pharmacoeconomic studies indicate that treatment with the 80-mg dose instead of the 10-mg dose almost costs neutral in US TNT-like patients (additional cost $181 for 5 years). In summary, wider use of the 80-mg dose of atorvastatin in patients with stable coronary disease is safe, cost-effective, and provides an incremental reduction in coronary events.
- Published
- 2009
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36. Preventing and treating stroke and transient ischemic attack.
- Author
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DeFaria Yeh D and Waters DD
- Subjects
- Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Ischemic Attack, Transient prevention & control, Platelet Aggregation Inhibitors administration & dosage, Practice Guidelines as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Platelet Aggregation Inhibitors therapeutic use, Stroke prevention & control
- Published
- 2008
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37. Inflammation, statin therapy, and risk of stroke after an acute coronary syndrome in the MIRACL study.
- Author
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Kinlay S, Schwartz GG, Olsson AG, Rifai N, Szarek M, Waters DD, Libby P, and Ganz P
- Subjects
- Acute Coronary Syndrome drug therapy, Acute Coronary Syndrome physiopathology, Aged, Atorvastatin, C-Reactive Protein physiology, Cholesterol, LDL drug effects, Female, Humans, Inflammation physiopathology, Interleukin-6 blood, Interleukin-6 metabolism, Male, Middle Aged, ROC Curve, Risk Factors, Serum Amyloid A Protein metabolism, Stroke epidemiology, Stroke immunology, Acute Coronary Syndrome complications, C-Reactive Protein drug effects, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Inflammation drug therapy, Pyrroles therapeutic use, Serum Amyloid A Protein drug effects, Stroke prevention & control
- Abstract
Objective: Patients with acute coronary syndromes have an increased risk of stroke. We measured markers of inflammation in the MIRACL study, a randomized trial of atorvastatin versus placebo in acute coronary syndromes, to assess the relationship of inflammation to stroke., Methods and Results: Baseline C-reactive protein (CRP), serum amyloid A (SAA), and interleukin-6 (IL-6) were collected in 2926 (95%) subjects. Baseline markers were related to stroke risk over the 16 weeks of the study. Subjects who subsequently experienced a stroke had higher CRP (27.5 versus 10.2 mg/L, P=0.0032), SAA (30.5 versus 16.0 mg/L, P=0.031), IL-6 (11 231 versus 6841 pg/L, P=0.004), and troponin (6.03 versus 3.19 ng/mL P=0.0032). The risk of stroke was related to greater CRP, SAA, and IL-6 in the placebo group only. Similarly, there was a graded increase in risk of stroke across quartiles of inflammatory markers in the placebo patients only., Conclusions: In acute coronary syndromes, the early risk of stroke relates to both heightened inflammation and size of myocardial necrosis. Treatment with atorvastatin abrogated the risk associated with elevated markers of inflammation in this study, a finding that provides a novel rationale for the use of statins in acute coronary syndromes.
- Published
- 2008
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38. Statin therapy in acute coronary syndrome.
- Author
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Friedewald VE, McPherson R, Roberts R, Roberts WC, and Waters DD
- Subjects
- Acute Disease, Humans, Syndrome, Coronary Disease drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Published
- 2007
- Full Text
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39. Effects of statin therapy on the development and progression of heart failure: mechanisms and clinical trials.
- Author
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Khush KK and Waters DD
- Subjects
- Animals, Autonomic Nervous System drug effects, Autonomic Nervous System physiopathology, Cardiac Output, Low pathology, Clinical Trials as Topic, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Humans, Inflammation pathology, Neurotransmitter Agents antagonists & inhibitors, Ventricular Remodeling drug effects, Cardiac Output, Low physiopathology, Cardiac Output, Low prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Background: Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction., Methods and Results: This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF., Conclusion: Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.
- Published
- 2006
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40. What the statin trials have taught us.
- Author
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Waters DD
- Subjects
- Animals, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Rabbits, Randomized Controlled Trials as Topic, Treatment Outcome, Cholesterol, LDL drug effects, Coronary Disease drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
It has taken a century since Anitschkow began feeding cholesterol to rabbits to study the role of cholesterol in atherosclerosis to be fully appreciated and for the potential of cholesterol reduction to prevent cardiovascular events to be fully realized. The body of clinical trial data testing the effects of statins on coronary heart disease is extensive and convincing. A 1% reduction in low-density lipoprotein cholesterol reduces coronary events by approximately 1%. With large doses of potent statins, low-density lipoprotein cholesterol levels and coronary events can thus be reduced by approximately 50%. The anti-inflammatory effects of large doses of atorvastatin likely contribute to the early event reduction seen early after acute coronary syndromes. Translating this information into clinical practice presents a challenge: many patients who would benefit from statins remain untreated or undertreated or discontinue treatment soon after it is initiated.
- Published
- 2006
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41. Safety of high-dose atorvastatin therapy.
- Author
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Waters DD
- Subjects
- Atorvastatin, Drug Administration Schedule, Heptanoic Acids administration & dosage, Heptanoic Acids adverse effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Pyrroles administration & dosage, Pyrroles adverse effects, Simvastatin administration & dosage, Simvastatin adverse effects, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Myocardial Infarction prevention & control, Pyrroles therapeutic use, Simvastatin therapeutic use
- Abstract
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.
- Published
- 2005
- Full Text
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42. Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
- Author
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LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, and Wenger NK
- Subjects
- Adult, Aged, Alanine Transaminase blood, Anticholesteremic Agents administration & dosage, Anticholesteremic Agents adverse effects, Atorvastatin, Cardiovascular Diseases epidemiology, Cardiovascular Diseases mortality, Cardiovascular Diseases prevention & control, Cholesterol blood, Coronary Disease blood, Dose-Response Relationship, Drug, Female, Heptanoic Acids administration & dosage, Heptanoic Acids adverse effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Incidence, Male, Middle Aged, Prospective Studies, Pyrroles administration & dosage, Pyrroles adverse effects, Risk, Triglycerides blood, Anticholesteremic Agents therapeutic use, Cholesterol, LDL blood, Coronary Disease drug therapy, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Pyrroles therapeutic use
- Abstract
Background: Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD)., Methods: A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke., Results: The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality., Conclusions: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels., (Copyright 2005 Massachusetts Medical Society.)
- Published
- 2005
- Full Text
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43. The effects of hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors on platelet thrombus formation.
- Author
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Thompson PD, Moyna NM, White CM, Weber KM, Giri S, and Waters DD
- Subjects
- Aged, Analysis of Variance, Blood Platelets physiology, Chi-Square Distribution, Coronary Artery Disease prevention & control, Coronary Thrombosis prevention & control, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Male, Middle Aged, Probability, Reference Values, Treatment Outcome, Blood Platelets drug effects, Coronary Artery Disease drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Pravastatin administration & dosage, Simvastatin administration & dosage
- Abstract
Background: Hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors (HMG CoA RIs) markedly improve the lipid profile of patients with hypercholesterolemia, but the magnitude and time course of the effect of these drugs on other risk factors for atherosclerosis are not well defined., Methods: We employed a random assignment, double-blind design to compare the effect of 8 weeks of HMG CoA RI therapy with either pravastatin (40 mg QD; n=12) or simvastatin (20 mg QD; n=12) with placebo (n=13) on serum lipids, platelet thrombus formation (PTF), and markers of inflammation and thrombosis in patients with coronary artery disease. PTF was measured using a validated ex vivo perfusion chamber system., Results: Total and LDL cholesterol decreased 20.3 +/- 12.7% and 31.4 +/- 16.5% in the HMG CoA RI group and were unchanged with placebo (P<0.01). Triglycerides also decreased 15.3 +/- 22.5% with HMG CoA RI therapy, but increased 8.4 +/- 30.0% with placebo (P=0.01). PTF increased 54.1 +/- 89.0% with placebo and decreased 8.0 +/- 46.82% with HMG CoA RI treatment (P<0.01)., Conclusions: HMG CoA RI therapy with pravastatin or simvastatin reduces PTF after only 8 weeks of therapy. Such lipid effects may contribute to the prompt reduction in cardiovascular events noted in some clinical trials.
- Published
- 2002
- Full Text
- View/download PDF
44. Effect of Change in Body Weight on Incident Diabetes Mellitus in Patients With Stable Coronary Artery Disease Treated With Atorvastatin (from the Treating to New Targets Study)
- Author
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Ong, Kwok-Leung, Waters, David D, Messig, Michael, DeMicco, David A, Rye, Kerry-Anne, and Barter, Philip J
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Research ,Obesity ,Diabetes ,Nutrition ,Prevention ,Cardiovascular ,Heart Disease ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Metabolic and endocrine ,Atorvastatin ,Body Weight ,Coronary Artery Disease ,Diabetes Mellitus ,Dose-Response Relationship ,Drug ,Female ,Follow-Up Studies ,Global Health ,Heptanoic Acids ,Humans ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Incidence ,Life Style ,Male ,Middle Aged ,Pyrroles ,Risk Factors ,Time Factors ,Weight Loss ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology - Abstract
Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p
- Published
- 2014
45. Improving Statin Noncompliance: If You Build It, Will They Come?
- Author
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Sparrow, Robert T, Ferreira-Legere, Laura, Udell, Jacob A, and Waters, David D
- Subjects
Cholesterol ,Cardiovascular System & Hematology ,Cardiovascular Diseases ,Hypercholesterolemia ,Humans ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiorespiratory Medicine and Haematology ,Alberta ,LDL - Published
- 2019
46. Are Cholesterol Treatment Targets a Deterrent to Optimal Lipid-Lowering Therapy?
- Author
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Waters, David D
- Subjects
Cholesterol ,Treatment Outcome ,Monoclonal ,Humans ,Antibodies, Monoclonal ,Cholesterol, LDL ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Antibodies ,LDL - Published
- 2017
47. Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials)
- Author
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Kohli, Payal, Knowles, Joshua W, Sarraju, Ashish, Waters, David D, and Reaven, Gerald
- Subjects
Blood Glucose ,Male ,Cardiorespiratory Medicine and Haematology ,Body Mass Index ,Prediabetic State ,Diabetes Mellitus ,Atorvastatin ,Humans ,Atorvastatin Calcium ,Retrospective Studies ,Ischemic Attack ,Transient ,Incidence ,nutritional and metabolic diseases ,Glucose Tolerance Test ,Middle Aged ,Lipids ,Stroke ,Diabetes Mellitus, Type 2 ,Cardiovascular System & Hematology ,Ischemic Attack, Transient ,Female ,Insulin Resistance ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Type 2 ,Biomarkers - Abstract
The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m2), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m2 1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.
- Published
- 2016
48. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
- Author
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Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen EL, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul CD, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene CW, Tzoulaki, Ioanna, Buxbaum, Sarah G, van der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Roman, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, de Borst, Gert Jan, de Jong, Pim A, Algra, Ale, Spiering, Wilko, Maitland-van der Zee, Anke H, Klungel, Olaf H, de Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John JV, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, WM Monique, Redline, Susan, and Patel, Sanjay R
- Subjects
Male ,HDL ,Clinical Trials and Supportive Activities ,DIAGRAM Consortium ,Medical and Health Sciences ,Body Mass Index ,LDL ,Clinical Research ,Risk Factors ,General & Internal Medicine ,Genetics ,Diabetes Mellitus ,Humans ,Genetic Testing ,Polymorphism ,Metabolic and endocrine ,Nutrition ,Aged ,Randomized Controlled Trials as Topic ,MAGIC Consortium ,Diabetes ,Body Weight ,Evaluation of treatments and therapeutic interventions ,Single Nucleotide ,InterAct Consortium ,Middle Aged ,Cholesterol ,6.1 Pharmaceuticals ,Hydroxymethylglutaryl CoA Reductases ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Type 2 - Abstract
BackgroundStatins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.MethodsWe used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.FindingsData were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).InterpretationThe increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.FundingThe funding sources are cited at the end of the paper.
- Published
- 2015
49. The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials
- Author
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Preiss, David, Campbell, Ross T., Murray, Heather M., Ford, Ian, Packard, Chris J., Sattar, Naveed, Rahimi, Kazem, Colhoun, Helen M., Waters, David D., LaRosa, John C., Amarenco, Pierre, Pedersen, Terje R., Tikkanen, Matti J., Koren, Michael J., Poulter, Neil R., Sever, Pete S., Ridker, Paul M., MacFadyen, Michael J., Solomon, Scott D., Davis, Barry R., Simpson, Lara M., Nakamura, Haruo, Mizuno, Kyoichi, Marfisi, Rosa M., Marchioli, Roberto, Tognoni, Gianni, Athyros, Vasilios G., Ray, Kausik K., Gotto, Antonio M., Clearfield, Michael B., Downs, John R., McMurray, John J., Clinicum, Department of Medicine, University of Helsinki, Medicum, Kardiologian yksikkö, Imperial College Healthcare NHS Trust- BRC Funding, and National Institute for Health Research
- Subjects
Male ,Cardiac & Cardiovascular Systems ,Clinical Sciences ,Myocardial Infarction ,Cardiorespiratory Medicine and Haematology ,PLACEBO-CONTROLLED TRIAL ,1102 Cardiovascular Medicine And Haematology ,HYPERTENSIVE PATIENTS ,Clinical Research ,Risk Factors ,AVERAGE CHOLESTEROL LEVELS ,Secondary Prevention ,Humans ,HIGH-DOSE ATORVASTATIN ,Randomized Controlled Trials as Topic ,Heart Failure ,Science & Technology ,VASCULAR EVENTS ,ACUTE CORONARY SYNDROMES ,Prevention ,Heart Failure/Cardiomyopathy ,Statin ,Middle Aged ,Meta-analysis ,Treatment Outcome ,MYOCARDIAL-INFARCTION ,Cardiovascular System & Hematology ,CARDIOVASCULAR-DISEASE ,3121 General medicine, internal medicine and other clinical medicine ,Cardiovascular System & Cardiology ,Female ,LDL CHOLESTEROL ,Randomized trial ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,PRIMARY PREVENTION ,Life Sciences & Biomedicine - Abstract
Aims The 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.\ud Methods and results We 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
- Published
- 2014
50. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers
- Author
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Arsenault, Benoit J, Barter, Philip, DeMicco, David A, Bao, Weihang, Preston, Gregory M, LaRosa, John C, Grundy, Scott M, Deedwania, Prakash, Greten, Heiner, Wenger, Nanette K, Shepherd, James, Waters, David D, Kastelein, John JP, Treating to New Targets (TNT) Investigators, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Berger, Jeffrey S
- Subjects
Male ,Time Factors ,Physiology ,Epidemiology ,Atorvastatin ,lcsh:Medicine ,Coronary Disease ,Coronary Artery Disease ,Cardiovascular Physiology ,Pathology and Laboratory Medicine ,Cardiovascular ,Biochemistry ,Vascular Medicine ,Gastroenterology ,chemistry.chemical_compound ,Medicine and Health Sciences ,Molecular Targeted Therapy ,Myocardial infarction ,lcsh:Science ,Immune Response ,education.field_of_study ,Multidisciplinary ,Neopterin ,Middle Aged ,Prognosis ,Lipids ,Heart Disease ,Research Design ,6.1 Pharmaceuticals ,Blood Circulation ,Female ,lipids (amino acids, peptides, and proteins) ,Anatomy ,Research Article ,medicine.drug ,medicine.medical_specialty ,Drug Research and Development ,Statin ,Clinical Research Design ,General Science & Technology ,medicine.drug_class ,Immunology ,Clinical Trials and Supportive Activities ,Population ,Cardiology ,Research and Analysis Methods ,Treating to New Targets (TNT) Investigators ,Diagnostic Medicine ,Clinical Research ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,education ,Cardiovascular Disease Epidemiology ,Heart Disease - Coronary Heart Disease ,Inflammation ,Pharmacology ,Adiponectin ,Cholesterol ,business.industry ,Pharmacoepidemiology ,Prevention ,lcsh:R ,Immunity ,Biology and Life Sciences ,Evaluation of treatments and therapeutic interventions ,Atherosclerosis ,medicine.disease ,Biomarker Epidemiology ,Endocrinology ,chemistry ,Cardiovascular Anatomy ,Clinical Immunology ,lcsh:Q ,Clinical Medicine ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Biomarkers - Abstract
Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive - 2014 Arsenault et al. This Funding: This study was funded by Pfizer Inc. Benoit J. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en santé du Québec and the Fondation de l9Institut universitaire de cardiologie et de pneumologie de Québec. Two authors are Pfizer employees and may hold stock in the company. As sponsor, Pfizer in cooperation with the steering committee had a role in all aspects of the study. The secondary biomarker analysis was funded by Pfizer. However, the decision to publish and preparation of the manuscript was driven solely by the authors. of recurrent MCVEs (P#0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.
- Published
- 2014
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