ABSTRACT
OBJECTIVES: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. BACKGROUND: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. METHODS: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. RESULTS: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. CONCLUSIONS: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Fibroblast Growth Factors/blood , Indoles/therapeutic use , Myocardial Ischemia/blood , Myocardial Ischemia/drug therapy , Aged , Biomarkers/blood , Cardiovascular Diseases/etiology , Female , Fibroblast Growth Factor-23 , Humans , Male , Middle Aged , Myocardial Ischemia/complications , Prognosis , RiskABSTRACT
Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7 days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6 months. The median baseline anti-PC concentration was 40.9 U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8 %, Q2: 4.2 %, Q3: 7.8 %, Q4: 5.4 %, p-trend = 0.87), all-cause mortality (Q1: 1.4 %, Q2: 0.7 %, Q3: 2.4 %, Q4: 0.9 %, p-trend = 0. 96), or any of the other individual endpoint components (MI: p-trend = 0.87, Stroke: p-trend = 0.43, SRI: p-trend = 0.66). Using the previously reported anti-PC cutpoint of 17 U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17 U/mL: 8.1 % vs. ≥17 U/mL: 5.8 %; p = 0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p = 0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.
Subject(s)
Acute Coronary Syndrome , Antibodies, Antiphospholipid/blood , Factor Xa Inhibitors/administration & dosage , Immunoglobulin M/blood , Morpholines/administration & dosage , Myocardial Infarction , Phosphorylcholine , Stroke , Thiophenes/administration & dosage , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/drug therapy , Aged , Female , Humans , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/etiology , Myocardial Infarction/prevention & control , Rivaroxaban , Stroke/blood , Stroke/etiology , Stroke/prevention & controlABSTRACT
BACKGROUND: Patients with atrial fibrillation (AF) are at increased risk of thromboembolic events. The long-term prognostic implications of AF in patients with atherothrombosis are unknown. METHODS: We compared 4-year CV outcomes in patients with and without a history of AF recorded at their baseline visit in the REACH Registry, an international, prospective cohort of patients with established atherosclerotic arterial disease (CAD, CVD, PAD) or at least 3 risk factors (RFO). RESULTS: AF status and 4 year follow-up data were available on 44,518 patients. The prevalence of AF at baseline was 10.3% (n=4582). Overall, patients with AF had approximately a 2-fold increase in the composite of CV death, MI, or stroke compared with patients without AF after adjustment for age, gender, prior ischemic event, vascular disease, congestive heart failure, diabetes, smoking, body mass index, region, aspirin and statin use (18.9% vs. 9.4%, p<0.0001). This increased risk was observed both in patients with established atherothrombosis (CAD: 15.5% vs. 8.0%, p=0.0001; CVD: 23.6% vs. 13.6%, p<0.0001; PAD: 24.3% vs. 13.5%, p=0.089) and those with multiple risk factors (RFO: 12.1% vs. 5.9%, p=0.017). Only 52% of patients with a history of AF at baseline were receiving anticoagulation at 4 years. CONCLUSIONS: Patients with a history of both AF and atherothrombosis have particularly high long-term CV risk. Despite this increased risk, almost half of all patients with AF do not receive guideline recommended anticoagulation, highlighting an important public health priority.
Subject(s)
Atherosclerosis/epidemiology , Atrial Fibrillation/epidemiology , Thrombosis/epidemiology , Aged , Aged, 80 and over , Atherosclerosis/mortality , Atrial Fibrillation/mortality , Diabetes Mellitus/epidemiology , Diabetes Mellitus/mortality , Female , Fibrinolytic Agents/therapeutic use , Follow-Up Studies , Heart Failure/epidemiology , Heart Failure/mortality , Humans , Hyperlipidemias/epidemiology , Hyperlipidemias/mortality , Hypertension/epidemiology , Hypertension/mortality , Male , Middle Aged , Prevalence , Prognosis , Prospective Studies , Registries/statistics & numerical data , Risk Factors , Stroke/epidemiology , Stroke/mortality , Thrombosis/mortality , Thrombosis/prevention & control , Time FactorsABSTRACT
OBJECTIVES: The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND: Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS: Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS: Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS: Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.
Subject(s)
Acute Coronary Syndrome/blood , Coronary Artery Disease/blood , Lipoprotein(a)/blood , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/therapy , Biomarkers/blood , Coronary Artery Disease/diagnosis , Coronary Artery Disease/drug therapy , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Prognosis , Randomized Controlled Trials as Topic , Risk Assessment , Secondary PreventionABSTRACT
BACKGROUND: Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. METHODS: We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. FINDINGS: 42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59-0·81 vs 0·93, 0·76-1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84-1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43-1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02-1·60; p=0·045). INTERPRETATION: This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. FUNDING: None.
Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Warfarin/therapeutic use , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Atrial Fibrillation/complications , Embolism/etiology , Embolism/prevention & control , Humans , Randomized Controlled Trials as Topic , Stroke/etiology , Stroke/prevention & control , Treatment Outcome , Warfarin/administration & dosage , Warfarin/adverse effectsABSTRACT
BACKGROUND: The incidence of metabolic syndrome (MetS), diabetes mellitus (DM), and their coexistence is increasing but whether MetS increases cardiovascular risk beyond component risk factors is controversial. DESIGN: We compared the risk of cardiovascular death, myocardial infarction, or stroke among patients with MetS, newly detected DM, established DM, or coexistent MetS and DM in the global REduction of Atherothrombosis for Continued Health (REACH) registry. METHODS: Outpatients with or at risk for atherothrombosis were recruited between 1 December 2003 and 31 December 2004 and followed up to 4 years for cardiovascular events. Risk was compared in patients with or without MetS or DM after adjustment for age, sex, risk factors, vascular disease, fasting blood glucose, therapy, and region. RESULTS: Among 44,548 REACH participants, 17,887 (40%) were without MetS or DM; 6459 had MetS (15%); 12,059 had established DM (27%); 7503 had both (17%); and 640 had newly detected DM (1%). Presence of MetS was not associated with higher cardiovascular events (12.6%, adjusted HR 0.98, 95% CI 0.89-1.08). In addition, once DM was evident, patients with coexistent MetS had similar increased risk (16.1%, adjusted HR 1.33, 95% CI 1.21-1.47) as DM alone (16.7%, adjusted HR 1.36, 95% CI 1.24-1.48). Newly detected DM was associated with increased cardiovascular risk (18.5%, adjusted HR 1.26, 95% CI 1.02-1.57), similar to longstanding DM. MetS was associated with incident DM (adjusted OR 1.94). CONCLUSIONS: In the REACH registry, presence of newly detected DM but not metabolic syndrome was associated with an increased risk of cardiovascular events.
Subject(s)
Atherosclerosis/epidemiology , Diabetes Mellitus/epidemiology , Metabolic Syndrome/epidemiology , Outpatients , Thrombosis/epidemiology , Aged , Aged, 80 and over , Atherosclerosis/diagnosis , Atherosclerosis/mortality , Comorbidity , Diabetes Mellitus/diagnosis , Diabetes Mellitus/mortality , Female , Humans , Incidence , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/mortality , Middle Aged , Myocardial Infarction/diagnosis , Myocardial Infarction/epidemiology , Myocardial Infarction/mortality , Prevalence , Proportional Hazards Models , Registries , Risk Assessment , Risk Factors , Stroke/diagnosis , Stroke/epidemiology , Stroke/mortality , Thrombosis/diagnosis , Thrombosis/mortalityABSTRACT
IMPORTANCE: Among nontraditional cardiovascular risk factors, recent influenzalike infection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES: To determine if influenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDY SELECTION: A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURES: Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization. RESULTS: Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE: In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points.
Subject(s)
Cardiovascular Diseases/prevention & control , Influenza Vaccines/administration & dosage , Influenza, Human/complications , Aged , Cardiovascular Diseases/complications , Cardiovascular Diseases/epidemiology , Female , Humans , Influenza, Human/prevention & control , Male , Randomized Controlled Trials as Topic , Risk , VaccinationABSTRACT
IMPORTANCE: The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial. OBJECTIVE: To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection. INTERVENTIONS: Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7. RESULTS: Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups. CONCLUSIONS AND RELEVANCE: Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01076764.
Subject(s)
Acute Coronary Syndrome/drug therapy , Anticoagulants/therapeutic use , Cyclic N-Oxides/therapeutic use , Factor Xa Inhibitors , Hemorrhage/chemically induced , Heparin/therapeutic use , Peptides/therapeutic use , Pyridines/therapeutic use , Acute Coronary Syndrome/complications , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Cause of Death , Cyclic N-Oxides/adverse effects , Double-Blind Method , Eptifibatide , Female , Humans , Infusions, Intravenous , Injections, Intravenous , Male , Middle Aged , Myocardial Infarction/etiology , Myocardial Infarction/prevention & control , Percutaneous Coronary Intervention , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Pyridines/adverse effects , Risk , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear. METHODS: We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively). CONCLUSIONS: DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.).
Subject(s)
Adamantane/analogs & derivatives , Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Adamantane/adverse effects , Adamantane/therapeutic use , Aged , Aged, 80 and over , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Dipeptides/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Double-Blind Method , Female , Heart Failure/epidemiology , Hospitalization/statistics & numerical data , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Pancreatitis/chemically induced , Pancreatitis/epidemiologyABSTRACT
Chronic exposure to high levels of arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM), but the association between lower levels of arsenic and T2DM is more controversial. Therefore, this study evaluated the association between low to moderate arsenic exposure and T2DM. In 2009-2011, we conducted a study of 957 Bangladeshi adults who participated in a case-control study of skin lesions in 2001-2003. The odds ratio of T2DM was evaluated in relationship to arsenic exposure measured in drinking water and in subjects' toenails (in 2001-2003) prior to the diagnosis of T2DM (in 2009-2011). Compared with those exposed to the lowest quartile of arsenic in water (≤ 1.7 µg/L), the adjusted odds ratio for T2DM was 1.92 (95% confidence interval (CI): 0.82, 4.35) for those in the second quartile, 3.07 (95% CI: 1.38, 6.85) for those in the third quartile, and 4.51 (95% CI: 2.01, 10.09) for those in the fourth quartile. The relative excess risk of T2DM was 4.78 for individuals who smoked and 8.93 for people who had a body mass index (weight (kg)/height (m)(2)) greater than 25. These findings suggest that exposure to modest levels of arsenic in drinking water was associated with increased risk of T2DM in Bangladesh. Being overweight or smoking was also associated with increased risk of T2DM.
Subject(s)
Arsenic/analysis , Diabetes Mellitus, Type 2/epidemiology , Environmental Exposure/statistics & numerical data , Skin Diseases/epidemiology , Water Pollutants, Chemical/analysis , Water Pollution, Chemical/statistics & numerical data , Adult , Bangladesh/epidemiology , Body Weights and Measures , Case-Control Studies , Female , Humans , Male , Middle Aged , Nails/chemistry , Risk Factors , Smoking/epidemiology , Socioeconomic Factors , Water Pollutants, Chemical/metabolismABSTRACT
BACKGROUND: Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). METHODS AND RESULTS: As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (P<0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (P<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. CONCLUSIONS: AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient's atherogenic lipid profile.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Lipoprotein(a)/blood , Proprotein Convertases/immunology , Serine Endopeptidases/immunology , Aged , Antibodies, Monoclonal, Humanized , Biomarkers/blood , Cholesterol, LDL/blood , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Logistic Models , Male , Middle Aged , Myocardial Infarction/drug therapy , Proprotein Convertase 9 , Risk Factors , Thrombolytic TherapyABSTRACT
BACKGROUND: The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood. OBJECTIVES: We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts. METHODS: Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program. Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs. RESULTS: A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%). Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%). CONCLUSIONS: Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
Subject(s)
Asthma/diagnosis , Bronchodilator Agents , Budesonide , Nedocromil , Asthma/physiopathology , Child , Female , Forced Expiratory Volume , Humans , Male , Sensitivity and SpecificityABSTRACT
BACKGROUND: Acute coronary syndrome (ACS) activates neurohormonal pathways, including elevations in circulating aldosterone, with deleterious cardiovascular effects. We aimed to determine if early, more complete renin-angiotensin-aldosterone system inhibition (RAASI) in post-ACS patients without ventricular dysfunction or heart failure would result in a graded reduction in aldosterone concentrations. METHODS: We performed serial measurement of serum aldosterone within the Aliskiren and Valsartan to Reduce NT-proBNP via Renin-Angiotensin-Aldosterone-System Blockade (AVANT GARDE)-Thrombolysis in Myocardial Infarction (TIMI) 43 trial, a randomized double-blind, placebo controlled trial of RAASI by valsartan, aliskiren, or both in post-ACS patients with preserved ventricular function but increased natriuretic peptides. Aldosterone was measured at randomization and week 8. RESULTS: Median aldosterone concentrations were comparable across treatment arms at baseline (9.26 ng/dL; interquartile range 7.12-12.76; n = 1073). In the placebo group, there was a significant increase in aldosterone over 8 weeks (19.7% rise, 2.20 (0.36) ng/dL, P < 0.0001) that was significantly reduced across active RAASI therapies (1.36 (0.39) ng/dL with aliskiren; 1.02 (0.37) ng/dL with valsartan; and 0.85 (0.37) ng/dL with combination therapy, P trend = 0.008). Compared to placebo, RAASI monotherapy resulted in a pooled relative absolute aldosterone change of -1.01 (0.45) ng/dL (P = 0.026 vs placebo), and combination therapy resulted in a relative absolute aldosterone change of -1.35 (0.52) ng/dL (P = 0.01 vs placebo). No significant difference in aldosterone concentrations was achieved between dual vs single RAASI (P = 0.47). CONCLUSIONS: In ACS patients with preserved ventricular function but increased natriuretic peptides, serum aldosterone rises over time and is blunted by more complete RAASI. The clinical implications and role for RAASI in this population warrant further investigation.
Subject(s)
Acute Coronary Syndrome/blood , Aldosterone/blood , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Renin-Angiotensin System/drug effects , Ventricular Function, Left/drug effects , Aldosterone/metabolism , Amides/pharmacology , Down-Regulation/drug effects , Female , Fumarates/pharmacology , Humans , Male , Middle Aged , Retrospective Studies , Tetrazoles/pharmacology , Valine/analogs & derivatives , Valine/pharmacology , ValsartanABSTRACT
BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin. METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730. FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening. INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. FUNDING: Amgen.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Anticholesteremic Agents/administration & dosage , Azetidines/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hypercholesterolemia/drug therapy , Proprotein Convertases/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Analysis of Variance , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Anticholesteremic Agents/adverse effects , Azetidines/adverse effects , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Ezetimibe , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Immunoglobulin G/immunology , Male , Middle Aged , Proprotein Convertase 9 , Proprotein Convertases/immunology , Serine Endopeptidases/immunology , Treatment Outcome , Young AdultABSTRACT
CONTEXT: ß-Blockers remain the standard of care after a myocardial infarction (MI). However, the benefit of ß-blocker use in patients with coronary artery disease (CAD) but no history of MI, those with a remote history of MI, and those with only risk factors for CAD is unclear. OBJECTIVE: To assess the association of ß-blocker use with cardiovascular events in stable patients with a prior history of MI, in those with CAD but no history of MI, and in those with only risk factors for CAD. DESIGN, SETTING, AND PATIENTS: Longitudinal, observational study of patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n = 14,043), known CAD without MI (n = 12,012), or those with CAD risk factors only (n = 18,653). Propensity score matching was used for the primary analyses. The last follow-up data collection was April 2009. MAIN OUTCOME MEASURES: The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. RESULTS: Among the 44,708 patients, 21,860 were included in the propensity score-matched analysis. With a median follow-up of 44 months (interquartile range, 35-45 months), event rates were not significantly different in patients with ß-blocker use compared with those without ß-blocker use for any of the outcomes tested, even in the prior MI cohort (489 [16.93%] vs 532 [18.60%], respectively; hazard ratio [HR], 0.90 [95% CI, 0.79-1.03]; P = .14). In the CAD without MI cohort, the associated event rates were not significantly different in those with ß-blocker use for the primary outcome (391 [12.94%]) vs without ß-blocker use (405 [13.55%]) (HR, 0.92 [95% CI, 0.79-1.08]; P = .31), with higher rates for the secondary outcome (1101 [30.59%] vs 1002 [27.84%]; odds ratio [OR], 1.14 [95% CI, 1.03-1.27]; P = .01) and for the tertiary outcome of hospitalization (870 [24.17%] vs 773 [21.48%]; OR, 1.17 [95% CI, 1.04-1.30]; P = .01). In the cohort with CAD risk factors only, the event rates were higher for the primary outcome with ß-blocker use (467 [14.22%]) vs without ß-blocker use (403 [12.11%]) (HR, 1.18 [95% CI, 1.02-1.36]; P = .02), for the secondary outcome (870 [22.01%] vs 797 [20.17%]; OR, 1.12 [95% CI, 1.00-1.24]; P = .04) but not for the tertiary outcomes of MI (89 [2.82%] vs 68 [2.00%]; HR, 1.36 [95% CI, 0.97-1.90]; P = .08) and stroke (210 [6.55%] vs 168 [5.12%]; HR, 1.22 [95% CI, 0.99-1.52]; P = .06). However, in those with recent MI (≤1 year), ß-blocker use was associated with a lower incidence of the secondary outcome (OR, 0.77 [95% CI, 0.64-0.92]). CONCLUSION: In this observational study of patients with either CAD risk factors only, known prior MI, or known CAD without MI, the use of ß-blockers was not associated with a lower risk of composite cardiovascular events.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Cardiovascular Diseases/mortality , Coronary Artery Disease/drug therapy , Coronary Artery Disease/mortality , Myocardial Infarction/drug therapy , Aged , Cardiovascular Diseases/prevention & control , Female , Hospitalization/statistics & numerical data , Humans , Incidence , Longitudinal Studies , Male , Middle Aged , Myocardial Revascularization/statistics & numerical data , Propensity Score , Risk Factors , Stroke/epidemiologyABSTRACT
BACKGROUND: Cow's milk allergy is the most common food allergy in childhood. Many children with IgE-mediated cow's milk allergy may tolerate baked milk products, but few data exist on predictors of outcomes of baked milk challenges. OBJECTIVE: To determine the relation of milk protein allergen specific IgE (sIgE) levels and skin prick test (SPT) wheal size with baked milk challenge outcomes. METHODS: A retrospective medical record review was conducted of 35 baked milk challenges. SPT results, sIgE levels, demographic characteristics, and food challenge results were analyzed. RESULTS: Thirty-five children underwent open challenges to baked milk and 29 (83%) passed. Of those who failed, 3 (50%) passed the initial clinic challenge but developed symptoms to ongoing exposure at home, days to months later. One child who ultimately failed at home required epinephrine. Compared with those who passed, children who failed were younger (median age, 8.9 and 3.7 years, respectively; P = .02). Children with a milk SPT wheal less than 12 mm were more than 90% likely to pass a baked milk challenge, and no child with a milk SPT wheal less than 7 mm failed a baked milk challenge. We were also able to establish more than 90% predictive values for passing baked milk challenges with a casein SPT wheal of 9 mm, a milk sIgE level of 1.0 kU/L, and a casein sIgE level of 0.9 kU/L. CONCLUSION: Most children allergic to cow's milk tolerated baked milk. Milk protein SPT wheal may be more reliable than sIgE level in predicting outcomes of baked milk challenges. It is important to be aware of the possibility of late reactions to ongoing baked milk exposure.
Subject(s)
Antibody Specificity , Cooking , Immunoglobulin E/physiology , Milk Hypersensitivity/diagnosis , Milk Hypersensitivity/immunology , Hot Temperature , Humans , Immunoglobulin E/biosynthesis , Predictive Value of Tests , Retrospective Studies , Skin Tests , Treatment OutcomeABSTRACT
OBJECTIVES: The forced expiratory volume in 1 second (FEV(1)) felt to be an objective measure of airway obstruction is often normal in asthmatic children. The forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) reflects small airway patency and has been found to be reduced in children with asthma. The aim of this study was to determine whether FEF(25-75) is associated with increased childhood asthma severity and morbidity in the setting of a normal FEV(1), and to determine whether bronchodilator responsiveness (BDR) as defined by FEF(25-75) identifies more childhood asthmatics than does BDR defined by FEV(1). METHODS: The Boston Children's Hospital Pulmonary Function Test database was queried and the most recent spirometry result was retrieved for 744 children diagnosed with asthma between 10 and 18 years of age between October 2000 and October 2010. Electronic medical records in the 1 year prior and the 1 year following the date of spirometry were examined for asthma severity (mild, moderate, or severe) and morbidity outcomes for the three age, race, and gender-matched subgroups: Group A (n = 35) had a normal FEV(1), FEV(1)/forced vital capacity (FVC), and FEF(25-75); Group B (n = 36) had solely a diminished FEV(1)/FVC; and Group C (n = 37) had a normal FEV(1), low FEV(1)/FVC, and low FEF(25-75). Morbidity outcomes analyzed included the presence of hospitalization, emergency department visit, intensive care unit admission, asthma exacerbation, and systemic steroid use. RESULTS: Subjects with a low FEF(25-75) (Group C) had nearly 3 times the odds ratio (OR) (OR = 2.8, p < .01) of systemic corticosteroid use and 6 times the OR of asthma exacerbations (OR = 6.3, p > .01) compared with those who had normal spirometry (Group A). Using FEF(25-75) to define BDR identified 53% more subjects with asthma than did using a definition based on FEV(1). CONCLUSIONS: A low FEF(25-75) in the setting of a normal FEV(1) is associated with increased asthma severity, systemic steroid use, and asthma exacerbations in children. In addition, using the percent change in FEF(25-75) from baseline may be helpful in identifying BDR in asthmatic children with a normal FEV(1).
Subject(s)
Asthma/physiopathology , Maximal Midexpiratory Flow Rate , Adolescent , Asthma/epidemiology , Case-Control Studies , Child , Female , Forced Expiratory Volume , Humans , Male , Morbidity , Severity of Illness Index , SpirometryABSTRACT
Previous studies suggest that children with egg allergy may be able to tolerate baked egg. Reliable predictors of a successful baked egg challenge are not well established. We examined egg white-specific IgE levels, skin-prick test (SPT) results, and age as predictors of baked egg oral food challenge (OFC) outcomes. We conducted a retrospective chart review of children, aged 2-18 years, receiving an egg white-specific IgE level, SPT, and OFC to baked egg from 2008 to 2010. Fifty-two oral baked egg challenges were conducted. Of the 52 challenges, 83% (n = 43) passed and 17% (n = 9) failed, including 2 having anaphylaxis. Median SPT wheal size was 12 mm (range, 0-35 mm) for passed challenges and 17 mm (range, 10-30 mm) for failed challenges (p = 0.091). The negative predictive value for passing the OFC was 100% (9 of 9) if SPT wheal size was <10 mm. Median egg white-specific IgE was 2.02 kU/L (range, <0.35-13.00 kU/L) for passed challenges and 1.52 kU/L (range, 0.51-6.10 kU/L) for failed challenges (p = 0.660). Receiver operating characteristic (ROC) curve analysis for SPT revealed an area under the curve (AUC) of 0.64. ROC curve analysis for egg white-specific IgE revealed an AUC of 0.63. There was no significant difference in age between patients who failed and those who passed (median = 8.8 years versus 7.0 years; p = 0.721). Based on our sample, SPT, egg white-specific IgE and age are not good predictors of passing a baked egg challenge. However, there was a trend for more predictability with SPT wheal size.
Subject(s)
Egg Hypersensitivity/diagnosis , Eggs/adverse effects , Immunoglobulin E/immunology , Skin Tests , Adolescent , Child , Child, Preschool , Egg Hypersensitivity/immunology , Female , Humans , Male , ROC CurveABSTRACT
BACKGROUND: Endotoxins are stimulators of the immune system and, despite their potential to protect against allergy, have been associated with early wheezing and asthma morbidity. OBJECTIVE: To compare inner-city school endotoxin exposure with home endotoxin exposure in children with asthma. METHODS: Students with asthma were recruited from 12 urban elementary schools. Settled and airborne dust samples, linked to enrolled students, were collected from school classrooms, gymnasiums, and cafeterias twice during the academic year. For comparison, settled dust was collected once from the bedrooms of students with asthma. RESULTS: Two hundred twenty-nine school settled dust samples and 118 bedroom settled dust samples were collected and analyzed for endotoxin. The median endotoxin concentration for school samples was 13.4 EU/mg (range, 0.7-360.7 EU/mg) and for home samples was 7.0 EU/mg (range = LLOD-843.0 EU/mg). The median concentration within each individual school varied from 6.6 EU/mg to 24.0 EU/mg. One hundred four students with asthma had matched classroom and bedroom endotoxin exposure measurements performed in the same season and demonstrated significantly higher concentrations of endotoxin in the students' classrooms (mean log value, 1.13 vs 0.99, P = .04). The median of the classrooms was 12.5 EU/mg compared with their bedrooms, with a median of 7.0 EU/mg. Within the school environment, no significant difference was seen between the fall and spring samples (mean log value 1.14 vs 1.09; P = .35). CONCLUSION: Inner-city children with asthma were exposed to higher concentrations of endotoxin in their classrooms as compared with their bedrooms. Further studies are needed to evaluate school endotoxin exposure as a factor in asthma morbidity.