Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation.

BACKGROUND: In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established. METHODS: We performed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation for which they had not previously received rhythm-control therapy were randomly assigned (1:1) to receive treatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephone monitoring conducted weekly and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success (defined as freedom from initial failure of the procedure or atrial arrhythmia recurrence after a 90-day blanking period to allow recovery from the procedure or drug dose adjustment, evaluated in a Kaplan-Meier analysis). The primary safety end point was assessed in the ablation group only and was a composite of several procedure-related and cryoballoon system-related serious adverse events. RESULTS: Of the 203 participants who underwent randomization and received treatment, 104 underwent ablation, and 99 initially received drug therapy. In the ablation group, initial success of the procedure was achieved in 97% of patients. The Kaplan-Meier estimate of the percentage of patients with treatment success at 12 months was 74.6% (95% confidence interval [CI], 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P<0.001 by log-rank test). Two primary safety end-point events occurred in the ablation group (Kaplan-Meier estimate of the percentage of patients with an event within 12 months, 1.9%; 95% CI, 0.5 to 7.5). CONCLUSIONS: Cryoballoon ablation as initial therapy was superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation. Serious procedure-related adverse events were uncommon. (Supported by Medtronic; STOP AF First ClinicalTrials.gov number, NCT03118518.).

Validating and implementing cardiac telemetry for continuous QTc monitoring: A novel approach to increase healthcare personnel safety during the COVID-19 pandemic.

BACKGROUND: Minimizing direct patient contact among healthcare personnel is crucial for mitigating infectious risk during the coronavirus disease 2019 (COVID-19) pandemic. The use of remote cardiac telemetry as an alternative to 12­lead electrocardiography (ECG) for continuous QTc monitoring may facilitate this strategy, but its application has not yet been validated or implemented. METHODS: In the validation component of this two-part prospective cohort study, a total of 65 hospitalized patients with simultaneous ECG and telemetry were identified. QTc obtained via remote telemetry as measured by 3 independent, blinded operators were compared with ECG as assessed by 2 board-certified electrophysiologists as the gold-standard. Pearson correlation coefficients were calculated to measure the strength of linear correlation between the two methods. In a separate cohort comprised of 68 COVID-19 patients treated with combined hydroxychloroquine and azithromycin, telemetry-based QTc values were compared at serial time points after medication administration using Friedman rank-sum test of repeated measures. RESULTS: Telemetry-based QTc measurements highly correlated with QTc values derived from ECG, with correlation coefficients of 0.74, 0.79, 0.85 (individual operators), and 0.84 (mean of all operators). Among the COVID-19 cohort, treatment led to a median QTc increase of 15 milliseconds between baseline and following the 9th dose (p = 0.002), with 8 (12%) patients exhibiting an increase in QTc ≥ 60 milliseconds and 4 (6%) developing QTc ≥ 500 milliseconds. CONCLUSIONS: Cardiac telemetry is a validated clinical tool for QTc monitoring that may serve an expanding role during the COVID-19 pandemic strengthened by its remote and continuous monitoring capability and ubiquitous presence throughout hospitals.

Hydrogen Diffusion Guided Design of Pt-Based Alloys for Inhibition of Butadiene Over-Hydrogenation.

Alloying Pt with other metals is an effective strategy to tune its performance towards selective hydrogenation reactions. Herein, we have demonstrated a process to screen Pt-based alloys for inhibition of butadiene over-hydrogenation with a model comprising isolated single atoms (ISA) embedded into Pt(111). DFT calculations reveal that the diffusion energy barrier of H co-adsorbed with 1-butene is a key parameter for the screening. The output from the ISA model was validated by testing several typical Pt-based alloys towards butadiene hydrogenation. Furthermore, an unexpected higher selectivity to cis-2-butene compared to the trans isomer and 1-butene over the PtZn alloy was explored employing the ISA model.

Non-HDL Cholesterol and Triglycerides: Implications for Coronary Atheroma Progression and Clinical Events.

OBJECTIVES: Non-high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. APPROACH AND RESULTS: Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) 0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (ß=0.62; P<0.001) compared with changes in LDLC (ß=0.51; P<0.001). Kaplan-Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. CONCLUSIONS: Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk.

Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin.

OBJECTIVES: Patients with acute coronary syndromes (ACS) display diffuse coronary atheroma instability and heightened risk of early and late recurrent coronary events. We compared the long-term antiatherosclerotic efficacy of high-intensity statins in patients with ACS when compared with stable disease. APPROACH AND RESULTS: Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The overall effect of high-intensity statins on the change in coronary percent atheroma volume and major adverse cardiovascular events (death/nonfatal myocardial infarction/coronary revascularization) were evaluated in this post hoc analysis. When compared with non-ACS patients (n=678), patients with ACS (n=361) were younger, actively smoking, and have had a previous myocardial infarction (all P<0.001). At baseline, patients with ACS exhibited lower high-density lipoprotein cholesterol (43.5±11 versus 45.8±11 mg/dL; P=0.002), a higher apolipoprotein B: apolipoprotein A-1 ratio (0.90±0.24 versus 0.83±0.24; P<0.001) and greater percent atheroma volume (37.3±8.5% versus 35.9±8.1%; P=0.01) when compared with non-ACS patients. Despite similar achieved levels of lipid and inflammatory markers after high-intensity statin therapy, patients with ACS demonstrated greater percent atheroma volume regression than non-ACS patients (-1.46±0.14 versus -0.89±0.13; P=0.003). After propensity-weighted multivariable adjustment, baseline percent atheroma volume (P<0.001) and an ACS clinical presentation (P=0.02) independently associated with plaque regression. The 24-month major adverse cardiovascular events-free survival was similar between patients with ACS and non-ACS (90.6 versus 92.9%; P=0.25). CONCLUSIONS: Long-term high-intensity statin therapy caused greater plaque regression and comparable major adverse cardiovascular events rates in ACS when compared with non-ACS patients. Despite a higher clinical risk profile, patients with ACS harbor a more modifiable disease substrate and seem to benefit the most from potent statin therapy.

C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy.

BACKGROUND: Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina). The association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy is unknown. METHODS AND RESULTS: The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in the change from baseline of percent atheroma volume on intravascular ultrasound, CRP-modulating effects, or MACE rates, thus allowing for a (prespecified) post hoc analysis to test associations between the changes in CRP levels with coronary disease progression and MACE. Patients with nonincreasing CRP levels (n=621) had higher baseline (2.3 [1.1-4.7] versus 1.1 [0.5-1.8] mg/L; P<0.001) and lower follow-up CRP levels (0.8 [0.5-1.7] versus 1.6 [0.7-4.1] mg/L; P<0.001) versus those with increasing CRP levels (n=364). Multivariable analysis revealed a nonincreasing CRP level to independently associate with greater percent atheroma volume regression (P=0.01). Although the (log) change in CRP did not associate with MACE (hazard ratio, 1.18; 95% confidence interval, 0.93-1.50; P=0.17), the (log) on-treatment CRP associated significantly with MACE (hazard ratio, 1.28; 95% confidence interval, 1.04-1.56; P=0.02). On-treatment low-density lipoprotein cholesterol levels did not correlate with MACE (hazard ratio, 1.09; 95% confidence interval, 0.88-1.35; P=0.45). CONCLUSIONS: Following 24 months of potent statin therapy, on-treatment CRP levels associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT000620542.

Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy.

AIMS: The impact of baseline coronary plaque burden on the clinical outcome in patients receiving aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy to levels <70 mg/dL is unknown. We assessed the prognostic significance of baseline coronary plaque burden following high-intensity statin therapy. METHODS AND RESULTS: SATURN used serial intravascular ultrasound (IVUS) to measure coronary atheroma volume in 1039 patients before and after 24 months of treatment with rosuvastatin 40 mg or atorvastatin 80 mg. This post hoc analysis compared the relationship between baseline percent atheroma volume (PAV) and major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in patients with baseline PAV less than (n = 519) or greater than (n = 520) the median. Patients with a higher baseline PAV had a similar LDL-C compared with those with a lower baseline PAV at baseline (119.0 ± 29 vs. 121.0 ± 27 mg/dL, P = 0.09) and at follow-up (65.3 ± 23 vs. 65.8 ± 22 mg/dL, P = 0.47). In multivariable analysis, each standard deviation increase in baseline PAV was associated with a 28% increase in MACE [HR 1.28 (1.05, 1.57), P = 0.01]. Those with the highest quartile of baseline PAV (>41.8%) had a 2-year cumulative MACE rate of 12%, which was significantly higher (log-rank P = 0.001) than MACE rates of all lower PAV quartiles (MACE: quartile 3, 2, and 1 were 5.7, 7.9, and 5.1%, respectively). LDL-C levels at baseline [HR 0.96 (0.79, 1.18), P = 0.73] and on-treatment [HR 1.19 (0.83, 1.73), P = 0.35] were not associated with MACE. CONCLUSION: Following 2 years of high-intensity statin therapy, a baseline coronary atheroma volume predicted MACE, despite the achievement of very low on-treatment LDL-C levels.

Determination of lignans in Wuweizi by using magnetic bar microextraction and HPLC.

In this paper, a magnetic bar microextraction was developed to extract schisandrin A, schisantherin A, and deoxyschizandrin from Wuweizi. The analytes were determined by HPLC. A stainless-steel wire was inserted into the hollow of the hollow fiber to make the magnetic bar. The bar can be used to stir the extraction system and extract the analytes, and was isolated from the extract system by magnetic force. Several experimental parameters, including type and volume of extraction solvent, the number of magnetic bars, extraction temperature and time, stirring speed and NaCl concentration were investigated and optimized. The LODs for schisandrin A, schisantherin A, and deoxyschizandrin were 0.14, 0.06, and 0.10 g/mL, respectively. The recoveries were in the range of 70.90-106.67% and the RSDs were < 8.84%. Compared with ultrasound-assisted and Soxhlet extraction, when the present method was applied, the extraction time was shorter, the sample amount was smaller, and the consumption of organic solvent was lower.

Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis.

BACKGROUND: A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data. METHODS AND RESULTS: We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86-1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81-1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41-0.88). Substantial statistical heterogeneity was evident for the case-control studies (I(2)=66%, P=0.01), but not for the cohort studies (I(2)=0%, P=0.48) or randomized trials (I(2)=30%, P=0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results. CONCLUSIONS: We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.

Quality of life after the initial treatment of atrial fibrillation with cryoablation versus drug therapy.

BACKGROUND: The STOP AF First trial recently demonstrated that initial treatment with cryoballoon ablation (CBA) is safe and superior to antiarrhythmic drug (AAD) therapy for preventing atrial arrhythmia recurrence in patients with symptomatic atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the change in quality of life (QoL) and symptoms after first-line CBA vs AAD therapy. METHODS: Patients with symptomatic AF not previously receiving rhythm control therapy were randomized to AAD (class I or III) or CBA (Arctic Front Advance, Medtronic, Mounds View, MN). QoL was evaluated at baseline and at 6 and 12 months by using the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and the European Quality of Life-5 Dimensions questionnaires. A review of AF-associated symptoms was conducted at baseline and at 1, 3, 6, and 12 months. RESULTS: In total, 203 subjects received either CBA (n = 104 [51.2%]) or AAD therapy (n = 99 [48.8%]). Improvements in the AFEQT summary and subscale scores were significantly larger with CBA than with AAD therapy at 6 and 12 months (P < .02 for all). Clinically meaningful improvement (>5 points) in the AFEQT summary score from baseline to 12 months was observed in 96.0% (100) of patients in the CBA arm vs 72.2% (71) of patients in the AAD arm (P < .001). No significant between-group differences were observed in the change in the European Quality of Life-5 Dimensions index or visual analog scale scores. Overall, 54.4% (57) of the CBA group vs 29.7% (29) of the AAD group reported no AF-specific symptom recurrence after a 90-day blanking period (P = .0005). CONCLUSION: First-line CBA vs AAD therapy is associated with larger improvements in AF-specific QoL and a higher rate of symptom resolution.

Prospective Evaluation of the Correlation Between Gated Cardiac Computed Tomography Detected Vascular Fibrosis and Ease of Transvenous Lead Extraction.

BACKGROUND: Difficulty of lead extraction does not track well with procedural complications, but several small retrospective studies have lead fibrosis on computed tomography as an important indicator of difficult lead extraction. The purpose of the present study was to apply a standardized gated cardiac computed tomography (CT) protocol to assess fibrosis and study it prospectively to examine the need for powered sheaths and risk outcomes. METHODS: We performed a prospective, blinded, multicenter, international study at high-volume lead extraction centers and included patients referred for transvenous lead extraction with at least one lead with a dwell time >1 year and ability to receive a cardiac CT. The degree of fibrosis (as measured by amount of lead adherence to vessel wall) was graded on a scale of 1 to 4 by dedicated CT readers in 3 zones (vein entry to superior vena cava, superior vena cava, and right atrium to lead tip). The primary outcome of the study was number of extractions requiring powered sheaths at zone 2 for each fibrosis group. RESULTS: A total of 200 patients were enrolled in the trial with 196 completing full gated CT and lead extraction analysis. The primary endpoint of powered sheath (laser and mechanical) sheath use was significantly higher in patients with higher fibrosis seen on CT (scores 3+4; 67.8%) at the zone 2 compared to patients with lower fibrosis (scores 1+2; 38.6%; P<0.001). There were 5 major complications with 3 vascular lacerations all occurring in zone 2 in the study. CONCLUSIONS: Gated, contrasted CT can predict the need for powered sheaths by identification of fibrosis but did not identify an absolute low-risk cohort who would not need powered sheaths. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03772704.

Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

BACKGROUND: Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality. METHODS AND RESULTS: We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001). CONCLUSIONS: In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Bleeding, mortality, and antiplatelet therapy: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

BACKGROUND: The association between bleeding severity and cause of mortality in the non-acute setting is unclear. We sought to investigate the association between bleeding and mortality subtype, and assess whether this association differs in patients on dual antiplatelet therapy (DAPT) versus aspirin alone. METHODS: Using multivariable Cox proportional hazards survival regression, we examined the association between moderate or severe bleeding and all-cause, cardiovascular, and cancer mortality in 15,603 patients with cardiovascular disease or multiple risk factors enrolled in the CHARISMA trial. RESULTS: Patients with moderate or severe bleeding had a higher incidence of all-cause, cardiovascular, and cancer mortality (P < .001 for each). After multivariable adjustment, moderate/severe bleeding remained independently associated with not only all-cause mortality (adjusted hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.24-2.21) and cardiovascular mortality (HR 2.05, 95% CI 1.38-3.04) but also cancer mortality (HR 4.76, 95% CI 2.60-8.69). However, there was a significant interaction between bleeding and potency of antiplatelet therapy for all-cause (P = .002), cardiovascular (P = .02), and cancer mortality (P = .03); in subjects on aspirin alone, moderate/severe bleeding was associated with all-cause (HR 5.27, 95% CI 3.56-7.80), cardiovascular (HR 4.33, 95% CI 2.55-7.37), and cancer mortality (HR 9.01, 95% CI 4.41-18.43), but not in subjects on DAPT (all-cause: HR 1.48, 95% CI 0.93-2.34; cardiovascular: HR 1.04, 95% CI 0.58-1.86; and cancer mortality: HR 1.79, 95% CI 0.56-5.74). CONCLUSIONS: In stable patients, moderate or severe bleeding is associated with a significantly increased risk of all-cause, cardiovascular, and cancer mortality. However, this risk appeared different in subjects on single antiplatelet therapy versus DAPT.

Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial.

CONTEXT: Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins. OBJECTIVE: To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. INTERVENTIONS: Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. MAIN OUTCOME MEASURES: The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment. RESULTS: The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed. CONCLUSIONS: Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01105975.

Simultaneous determination of 9 environmental pollutants including bisphenol A in vegetable oil by solid phase extraction-liquid chromatography-tandem mass spectrometry.

In this study, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method with solid phase extraction was established for the simultaneous determination of bisphenol A, bisphenol F, bisphenol S, 4-nonylphenol, n-nonylphenol, octylphenol, n-octylphenol, perfluorooctane sulfonate acid and perfluorooctanoic acid in vegetable oil. The sample was extracted with ammonia acetonitrile solution (1 : 9, V/V) by ultrasonication. And the obtained extract was purified by using a PRIME HLB solid phase extraction column. The identification and quantification of the compounds was performed by liquid chromatography-tandem mass spectrometry in multiple reaction monitoring (MRM) mode. The internal standard method was used for quantitative analysis. Under optimal experimental conditions, the limits of quantitation of bisphenol A, bisphenol F, bisphenol S, 4-nonylphenol, n-nonylphenol, octylphenol and n-octylphenol in vegetable oil were 1.0 µg kg-1. The limits of quantitation of perfluorooctane sulfonic acid and perfluorooctanoic acid in vegetable oil were 0.1 µg kg-1. The average spiked recoveries of the method were in the range of 89.2-117.1% with the relative standard deviations (RSD) of 2.9-9.8% (n = 6). This method is sensitive, versatile and reproducible, and is suitable for the simultaneous determination of bisphenol A, bisphenol F, bisphenol S, 4-nonylphenol, n-nonylphenol, octylphenol, n-octylphenol, perfluorooctane sulfonate acid and perfluorooctanoic acid in vegetable oil.

Impact of an electronic medical record-based appointment order on outpatient cardiology follow-up after hospital discharge.

Outpatient follow-up after hospital discharge improves continuity of care and reduces readmissions, but rates of follow-up remain low. It is not known whether electronic medical record (EMR)-based tools improve follow-up. The aim of this study was to determine if an EMR-based order to secure cardiology follow-up appointments at hospital discharge would improve follow-up rates and hospital readmission rates. A pre-post interventional study was conducted and evaluated 39,209 cardiovascular medicine discharges within an academic center between 2012 and 2017. Follow-up rates and readmission rates were compared during 2 years prior to EMR-order implementation (pre-order era 2012-2013, n = 12,852) and 4 years after implementation (EMR-order era 2014-2017, n = 26,357). The primary endpoint was 90-day cardiovascular follow-up rates within our health system. In the overall cohort, the mean age of patients was 69.3 years [SD 14.7] and 60.7% (n = 23,827) were male. In the pre-order era, 90-day follow-up was 56.7 ± 0.4% (7286 of 12,852) and increased to 67.9 ± 0.3% (17,888 of 26,357, P < 0.001) in the EMR-order era. The use of the EMR follow-up order was independently associated with increased outpatient follow-up within 90 days after adjusting for patient demographics and payor status (OR 3.28, 95% CI 3.10-3.47, P < 0.001). The 30-day readmission rate in the pre-order era was 12.8% (1642 of 12,852) compared with 13.7% (3601 of 26,357, P = 0.016) in the EMR-order era. An EMR-based appointment order for follow-up appointment scheduling was associated with increased cardiovascular medicine follow-up, but was not associated with an observed reduction in 30-day readmission rates.

Smoking, clopidogrel, and mortality in patients with established cardiovascular disease.

BACKGROUND: Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown. METHODS AND RESULTS: We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15). CONCLUSIONS: Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.

The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease.

AIMS: We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease. METHODS AND RESULTS: This was a prospective observational study of 15 532 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who were randomly assigned to clopidogrel or placebo, and followed-up for a median of 28 months for the occurrence of the primary endpoint (cardiovascular death, myocardial infarction, or stroke), all-cause mortality, and bleeding complications. Compared with the highest BMI quartile, the primary endpoint, cardiovascular, and all-cause mortality all occurred more frequently among patients in the lowest BMI quartile (about a third lower). The relationship between continuous BMI and adverse cardiovascular outcomes were presented as two linear spline terms with 29 kg/m(2) as the cut-point for all-cause mortality. Lower BMI was associated with an increase in moderate and severe bleeding complications, largely accounted for by those receiving dual-antiplatelet agents with the highest tertile aspirin dose. CONCLUSION: Adverse cardiovascular events and bleeding complications occurred more frequently among individuals with or at-risk for atherothrombotic disease and low BMI. Further studies should be directed to these patients to improve outcomes.

Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study.

BACKGROUND: Atherothrombosis is a common condition affecting individuals worldwide. Its impact on different ethnic groups receiving evidence-based therapy is unclear. We aimed to determine if ethnicity is an independent predictor for cardiovascular events and bleeding complications in a contemporary clinical trial on antiplatelet therapy. METHODS: This was a prospective observational study of 15,603 patients enrolled in the CHARISMA trial followed up every 6 months for a median of 28 months. The primary efficacy end point was the first occurrence of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was bleeding. RESULTS: The cohort comprised 12,502 (80.1%) white, 486 (3.1%) black, 775 (5.0%) Asian, and 1,613 (10.3%) Hispanic patients. There was no difference in the occurrence of the primary composite end point among the 4 ethnic groups. Compared with Asians, cardiovascular and all-cause mortality occurred more frequently among black (adjusted hazard 2.19 and 2.04) and Hispanic (adjusted hazard, 1.83 and 1.69) patients. Although the occurrence of severe bleeding was similarly low among the 4 ethnic groups, Asian (adjusted hazard, 2.21) and black (adjusted hazard, 3.06) patients were more likely to have moderate bleeding complications than Hispanic patients. CONCLUSION: In this trial of individuals at risk of vascular events, ethnicity was not a significant, independent predictor of the primary composite cardiovascular event. However, ethnicity was a significant, independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics), and moderate bleeding complications (blacks and Asians).

Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome: A Secondary Analysis of the VISTA-16 Trial.

Importance: Higher baseline high-sensitivity C-reactive protein (hsCRP) levels after an acute coronary syndrome (ACS) are associated with adverse cardiovascular outcomes. The usefulness of serial hsCRP measurements for risk stratifying patients after ACS is not well characterized. Objective: To assess whether longitudinal increases in hsCRP measurements during the 16 weeks after ACS are independently associated with a greater risk of a major adverse cardiac event (MACE), all-cause death, and cardiovascular death. Design, Setting, and Participants: Secondary analysis of the double-blind, multicenter, randomized clinical Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial conducted between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012), which included 5145 patients from 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America assigned to receive varespladib or placebo on a background of atorvastatin treatment beginning within 96 hours of presentation with an ACS. The present study evaluated data from patients with available baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 after randomization to treatment or placebo. Statistical analysis was performed from June 15, 2018, through September 15, 2018. Main Outcomes and Measures: Outcomes were MACE (composite of cardiovascular death, myocardial infarction, nonfatal stroke, or unstable angina with documented ischemia requiring hospitalization), cardiovascular death, and all-cause death after adjustment for baseline clinical, treatment, and laboratory characteristics, including baseline hsCRP levels. Results: Among 4257 patients in this study, 3141 (73.8%) were men and the mean age was 60.3 years (interquartile range [IQR], 53.5-67.8 years). The median 16-week low-density lipoprotein cholesterol level was 64.9 mg/dL (IQR, 50.3-82.3 mg/dL), and the median hsCRP level was 2.4 mg/L (IQR, 1.1-5.2 mg/L). On multivariable analysis, higher baseline hsCRP level (hazard ratio [HR], 1.36 [95% CI, 1.13-1.63]; P = .001) and higher longitudinal hsCRP level (HR, 1.15 [95% CI, 1.09-1.21]; P < .001) were independently associated with MACE. Similar significant and independent associations were shown between baseline and longitudinal hsCRP levels and cardiovascular death (baseline: HR, 1.61 per SD [95% CI, 1.07-2.41], P = .02; longitudinal: HR, 1.26 per SD [95% CI, 1.19-1.34], P < .001) and between baseline and longitudinal hsCRP levels and all-cause death (baseline: HR, 1.58 per SD [95% CI, 1.07-2.35], P = .02; longitudinal: HR, 1.25 per SD [95% CI, 1.18-1.32], P < .001). Conclusions and Relevance: Initial and subsequent increases in hsCRP levels during 16 weeks after ACS were associated with a greater risk of the combined MACE end point, cardiovascular death, and all-cause death despite established background therapies. Serial measurements of hsCRP during clinical follow-up after ACS may help to identify patients at higher risk for mortality and morbidity.