Weihang Bao

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis

BACKGROUND The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. RESULTS A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes An Analysis From the CARDS Trial

OBJECTIVE Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25–2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11–1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38–1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.

Fasting Triglycerides Predict Recurrent Ischemic Events in Patients With Acute Coronary Syndrome Treated With Statins

BACKGROUND Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p<0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34 to 1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p=0.03), with a hazard ratio of 1.50 [corrected] (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. CONCLUSIONS Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515).

RETRACTED: Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial: A Nested Case-Control Study

OBJECTIVES The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients. BACKGROUND Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects. METHODS We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs). RESULTS Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose. CONCLUSIONS PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Phospholipase A2 Enzymes, High-Dose Atorvastatin, and Prediction of Ischemic Events After Acute Coronary Syndromes

Background— Secretory phospholipase A2 (sPLA2) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are enzyme biomarkers of increased cardiovascular risk and targets of emerging therapeutic agents. Their relationship to cardiovascular events in the setting of high-dose statin therapy compared with placebo in patients with acute coronary syndrome is not known. Methods and Results— sPLA2 and Lp-PLA2 mass and activity were measured in 2587 patients in the Myocardial Ischemia Reduction With Acute Cholesterol Lowering (MIRACL) trial at baseline and after 16 weeks of treatment with atorvastatin 80 mg/d or placebo. Baseline levels of sPLA2 and Lp-PLA2 mass and activity were not associated with the primary efficacy measure of the trial of death, myocardial infarction, or unstable angina. However, in the overall cohort, baseline sPLA2 mass predicted risk of death after multivariable adjustment (hazard ratio for 2-fold increase, 1.30; 95% confidence interval, 1.09–1.56; P=0.004). This association remained significant when examined separately in the placebo group but not in the atorvastatin group. Compared with placebo, atorvastatin reduced median sPLA2 mass (−32.1% versus −23.1%), sPLA2 activity (−29.5% versus −19.2%), Lp-PLA2 mass (−35.8% versus −6.2%), and Lp-PLA2 activity (−24.3% versus 5.4%; P<0.001 for all). Atorvastatin reduced the hazard of death associated with elevated sPLA2 mass and activity by ≈50%. Conclusions— sPLA2 mass independently predicts death during a 16-week period after acute coronary syndrome. High-dose atorvastatin significantly reduces sPLA2 and Lp-PLA2 mass and activity after acute coronary syndrome and mitigates the risk of death associated with sPLA2 mass. Atorvastatin may exert antiinflammatory effects on phospholipases that contribute to its therapeutic benefit after acute coronary syndrome.

Inflammatory Biomarkers, Death, and Recurrent Nonfatal Coronary Events After an Acute Coronary Syndrome in the MIRACL Study

Background In acute coronary syndromes, C‐reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. Methods and Results We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin‐6 (IL‐6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E‐selectin, P‐selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.006), SAA (P=0.012), and IL‐6 (P<0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes. VCAM and tPA related to the risk of death (P<0.001, P=0.021, respectively) and to nonfatal acute coronary syndromes (P=0.021, P=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however, CRP and SAA continued to relate to death. Conclusions In acute coronary syndromes, the CRP inflammatory axis relates to the risk of death and may reflect myocardial injury. VCAM and tPA may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.

LADA and CARDS: A Prospective Study of Clinical Outcome in Established Adult-Onset Autoimmune Diabetes

OBJECTIVE Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non–insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established “type 2 diabetes” participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years’ diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.

Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers

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).

Relationship of Oxidized Phospholipids on Apolipoprotein B-100 to Cardiovascular Outcomes in Patients Treated With Intensive Versus Moderate Atorvastatin Therapy: The TNT Trial

BACKGROUND Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown. OBJECTIVES This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD. METHODS In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE. RESULTS Patients with events (n = 156) had higher randomization levels of OxPL-apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24). CONCLUSIONS Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

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.

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.