Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized,Double-blind,and Placebo-controlled Trial

Purpose

The purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment.

A retrospective meta-analysis of the efficacy and tolerability of fenofibrate 300 mg/d on high-density lipoprotein cholesterol levels in randomized, double-blind, comparative studies conducted in Japan

Background

Low levels of plasma high-density lipoprotein cholesterol (HDL-C) represent an important risk factor for coronary heart disease (CHD). Increasing HDL-C by 1 mg/dL decreases the incidence of CHD by 2% to 3%. Fenofibrate increases HDL-C by ∼23%, to ≥40 mg/dL, and may be effective in preventing CHD.

Objective

The aim of this study was to assess the effects of fenofibrate on HDL-C in patients treated for 12 weeks in 3 randomized, double-blind, comparative studies conducted in Japan. Changes in total cholesterol (TC) and triglycerides (TG), effects on HDL-C and apolipoprotein (apo) A-I and A-II by TG level, and effects on serum lipid levels by type of hyperlipidemia were the secondary end points.

Methods

Changes in HDL-C levels, as well as TC and TG levels, were analyzed in patients who received fenofibrate 300 mg/d for 12 weeks. Patients aged 20 to 80 years with mean TC ≥220 mg/dL (hypercholesterolemia), TG ≥150 mg/dL (hypertriglyceridemia), or both (combined hyperlipidemia) were considered assessable.

Results

In this retrospective meta-analysis conducted at Grelan Pharmaceutical Co. Ltd. (Tokyo, Japan), data from 263 patients (137 women, 126 men; mean [SD] age, 56.0 [10.8] years; range, 25-79 years) were included. The mean (SD) HDL-C level increased significantly, from 46.1 (0.9) mg/dL to 55.9 (1.0) mg/dL after 12 weeks of treatment with fenofibrate (P<0.001). Serum TC and TG decreased significantly (both P<0.001). HDL-C elevation was greater in patients with TG ≥150 mg/dL than in patients with TG<150 mg/dL, although apo A-I and A-II changes were the same in both groups. HDL-C increased in every type of hyperlipidemia, 14.9% in hypercholesterolemia, 22.0% in hypertriglyceridemia, and 33.5% in combined hyperlipidemia. Baseline HDL-C levels were <40 mg/dL in 93 patients (group 1) and ≥40 mg/dL in 170 patients (group 2). Mean HDL-C levels increased significantly in both groups during the treatment period, from 32.6 (0.6) mg/dL to 42.6 (1.0) mg/dL in group 1 and from 53.5 (0.9) mg/dL to 63.1 (1.1) mg/dL in group 2 (both P<0.001). One patient (0.3%) of the 331 included in the tolerability analysis experienced a serious adverse effect (jaundice).

Conclusion

In this study of patients with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia, 12-week treatment with fenofibrate 300 mg/d was effective and generally well tolerated, with the possible exception of transient changes in aminotransferases. HDL-C was increased in all patients to ∼40 mg/dL, the target level.     

Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV,Prospective, US,Multicenter, Randomized,Double-blind,Superiority Trial

Purpose

Results from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18–80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia.

Methods

This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg.

Findings

A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m²) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was –38.1% for pitavastatin 4 mg and –26.4% for pravastatin 40 mg; the difference in median percent change between treatments was –12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non–HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis.

Implications

Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.     

Short-Term Effects of Extended-Release Niacin With and Without the Addition of Laropiprant on Endothelial Function in Individuals With Low HDL-C: A Randomized,Controlled Crossover Trial

Background

Reduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation.

Objective

This study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C.

Methods

Asymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2.

Results

Eighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD.

Conclusions

In these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291.     

Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes: An open-label, crossover study

Background:

Plasma lipid abnormalities commonly persist in patients with diabetic dyslipidemia in spite of statin monotherapy.

Objective:

The aim of this study was to determine whether fenofibrate plus low-dose nicotinic acid adequately improves the lipoprotein profile in patients with diabetic dyslipidemia who are being treated with a statin.

Methods:

In this open-label, crossover study, patients with type 2 diabetes mellitus who were receiving statin treatment were enrolled at the Lipid Clinic of the Veterans Affairs Medical Center, Dallas, Texas, and administered simvastatin 20 mg/d for 8 weeks. At the end of the 8-week period, fenofibrate 160 mg/d was added for 8 weeks, followed by the addition of extended-release nicotinic acid 1 g/d for an additional 8 weeks. The first subject was recruited on September 25, 2003, and the last subject was recruited on September 28, 2004. Liver function tests, creatine phosphokinase activity, and blood glucose levels were assessed every 4 weeks to assess tolerability. Levels of fasting plasma lipids and lipoprotein cholesterol were measured every 8 weeks on 3 consecutive days in each patient; C-reactive protein, lipoprotein pattern, and glycosylated hemoglobin levels were assessed once every 8 weeks. Plasma levels of total cholesterol, triglycerides, very-low-density lipoprotein plus intermediate-density lipoprotein cholesterol (VLDL+IDL-C), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B were also measured.

Results:

Twenty-six patients were enrolled in the study and 20 patients (18 men, 2 women; mean [SD] age, 58.8 [6.5] years) completed it. The mean plasma triglyceride level was significantly decreased (−29.2%; P= 0.004) and the mean HDL-C level was significantly increased (+13.5%; P < 0.001) with 3-drug treatment (simvastatin + fenofibrate + extended-release nicotinic acid) compared with simvastatin monotherapy. Significant reductions in plasma levels of VLDL+IDL-C (−35.7%; P = 0.001), VLDL+IDL-apolipoprotein B (−30%; P = 0.005), non-HDL-C (−12.9%; P = 0.001), and total-apolipoprotein B (−17.9%; P < 0.001) were seen with the 3-drug treatment compared with simvastatin alone. Compared with simvastatin monotherapy, simvastatin + fenofibrate-treated (2-drug treatment) patients had significantly lower plasma levels of triglycerides (−24.9%; P = 0.014) and significantly higher levels of HDL-C (+5.4%; P = 0.008). Significant reductions were also seen in levels of VLDL+IDL-C (−28.6%; P = 0.004), VLDL+IDL-apolipoprotein B (−26.7%; P < 0.001), non-HDL-C (−9.1 %; P= 0.004), and total-apolipoprotein B (−12.3%; P < 0.001) in the 2-drug treatment group compared with the simvastatin monotherapy group. The administration of 3-drug treatment was associated with improved responses in all lipoprotein fractions, although only the increase in HDL-C level was statistically significant (+7.7%; P = 0.008) compared with 2-drug treatment.

Conclusions:

Treatment with the 3-drug regimen was associated with a significant reduction in triglyceride levels compared with simvastatin monotherapy. However, there was not a significant incremental reduction in triglyceride levels when nicotinic acid was added to the 2-drug treatment, suggesting that the triglyceride-lowering effect of fenofibrate + nicotinic acid is not cumulative. To obtain clinically meaningful responses, particularly for the treatment of elevated HDL-C, higher doses of nicotinic acid might be required.     

Effects of Aggressive Statin Therapy on Patients With Coronary Saphenous Vein Bypass Grafts: A Systematic Review and Meta-Analysis of Randomized,Controlled Trials

Objectives

The aim of this study was to investigate the effectiveness and safety of aggressive statin versus moderate statin therapy on patients with saphenous vein grafts (SVGs) in randomized, controlled trials (RCTs).

Methods

We searched MEDLINE (1980–June 2012), the Cochrane Controlled Trials Register, EMBASE, Science Citation Index, and PubMed (to June 2012), and found 10 relevant RCTs, including 7 substudy analyses from a Post-CABG trial, and 1 pooled analysis of the PROVE-IT TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators) and A to Z trial. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes; phase Z of the A to Z trial.

Results

A total of 6645 of participants, ages ranging from 21 to 75 years old, were treated with coronary artery bypass graft (CABG) and were followed for 2 to 5 years. Eight studies showed that aggressive statin therapy had lower LDL-C levels and a decrease of 39% in graft atherosclerotic progression, 12% in new occlusions, and 19% in new lesions more than moderate statin therapy. Three reports indicated that aggressive statin therapy lowered the risk of repeated myocardial infarction more than moderate statin therapy for coronary revascularization (95% CI, 0.66–0.95; risk ratio [RR] = 0.80; and 95% CI, 0.66–0.85; RR = 0.75) and lowered the risk of cardiac death as well (95% CI, 0.64–1.08; RR = 0.83). Aggressive statin therapy had safety similar to that of moderate statin therapy except for a slight increase in myopathic events and aminotransferase levels. Seventy percent to 90% of patients took statin treatment as prescribed in long-term.

Conclusions

Compared with moderate statin therapy, long-term aggressive statin lowered the LDL-C level significantly, further decreased the atherosclerotic progression of SVG, reduced the risks of repeated myocardial infarction and coronary revascularization after CABG, and revealed similar patient compliance and statin-related adverse effects but slightly increased myopathy events and aminotransferase levels.     

A Randomized,Double-Blind Study of Fenofibric Acid Plus Rosuvastatin Compared With Rosuvastatin Alone in Stage 3 Chronic Kidney Disease

Background

Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve lipid parameters.

Objective

This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout.

Methods

Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8.

Results

FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, −38.0% vs −22.4%, P < 0.001; week 16, −42.6% vs −29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R).

Conclusions

The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.     

Evaluation of the Efficacy and Safety of a Hydrochlorothiazide to Chlorthalidone Medication Change in Veterans With Hypertension

Background

There are few data available examining the clinical impact of switching patients from hydrochlorothiazide (HCTZ) to chlorthalidone for blood pressure management.

Objectives

The goal of this study was to compare within-patient clinic blood pressure readings, serum electrolyte levels, and renal function markers before and after a medication change from HCTZ to chlorthalidone in a veteran population.

Methods

This was a retrospective, pre- and postmeasure, self-controlled study. Veterans Affairs Ann Arbor Healthcare System patients switched from HCTZ to chlorthalidone between January 1, 2001, and January 31, 2012, who had at least 1 follow-up clinic blood pressure reading recorded between 2 and 8 weeks from the date of the medication change were included in the study. Mean pre- and postmeasure values for systolic and diastolic clinic blood pressures, serum potassium, serum sodium, serum calcium, serum creatinine, and blood urea nitrogen were compared by using a 2-tailed, paired t test with a significance level (α) of 0.05.

Results

Of the 40 patients included in the study 95% were male, 65% were white, and the mean age was 64.9 (10.8) years. Both mean systolic (–15.8 mm Hg [95% CI, 8.9 to 22.6], P < 0.0001) and mean diastolic (–4.2 mm Hg [95% CI, 1.5 to 6.9], P = 0.0035) blood pressures showed statistically and clinically significant reductions after the medication change. A statistically significant decrease in mean sodium (–1.1 mmol/L [95% CI, 0.4 to 1.9], P = 0.003) and an increase in mean serum creatinine (0.06 mg/dL [95% CI, –0.09 to –0.02], P = 0.002) was observed; however, these changes may not be viewed as clinically significant by many practitioners. No statistically significant changes were observed in any of the other outcomes examined. Most patients (38 of 40) were taking at least 1 additional antihypertensive agent; 73% of patients were using ≥3 antihypertensive agents at the time of the medication change.

Conclusions

In patients with hypertension already taking HCTZ, switching to chlorthalidone seems to further reduce systolic and diastolic blood pressures without any clinically significant changes in renal function or electrolyte levels.     

Successful Discharge of Children with Gastroenteritis Requiring Intravenous Rehydration

Background

Emergency Department (ED) revisits are very common in children with gastroenteritis administered intravenous rehydration.

Study Objectives

To determine if bicarbonate values are associated with ED revisits in children with gastroenteritis.

Methods

We conducted a secondary analysis of prospectively collected data, which included children >3 months of age with gastroenteritis treated with intravenous rehydration. Regression analysis was employed to determine whether, among discharged children, bicarbonate independently predicts revisits within 7 days (primary outcome) and successful discharge (secondary outcome). The latter composite outcome measure was defined as discharge at the index visit and the absence of a revisit requiring intravenous rehydration.

Results

Of 226 potentially eligible children, 174 were discharged and were included in the primary outcome analysis. Of the eligible children, 18% (30/174) had a revisit that was predicted by a higher baseline bicarbonate (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.0–1.3; p = 0.03), absence of a primary care provider (OR 7.8; 95% CI 1.2–51.0; p = 0.03), and ondansetron administration (OR 2.4; 95% CI 1.0–5.5; p = 0.05). Bicarbonate was not associated with successful discharge. Negatively associated independent predictors of successful discharge were volume of intravenous fluids administered (OR 0.84/10 mL/kg increase; 95% CI 0.76–0.93; p < 0.001), and baseline clinical dehydration score (OR 0.75/unit increase; 95% CI 0.58–0.97; p < 0.001). Revisits requiring intravenous rehydration and hospitalization were associated with higher bicarbonate values (21.2 ± 4.6 mEq, p = 0.001, and 22.3 ± 5.0 mEq/L, p < 0.001, respectively).

Conclusion

Lower serum bicarbonate values at the time of intravenous rehydration are not associated with unfavorable outcomes after discharge.     

Pharmacokinetics and Pharmacodynamics of Subcutaneous Recombinant Parathyroid Hormone (1–84) in Patients With Hypoparathyroidism: An Open-Label,Single-Dose,Phase I Study

Background

Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1–84 (rhPTH[1–84]) is being developed for the treatment of hypoparathyroidism.

Objective

The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1–84) in patients with hypoparathyroidism.

Methods

This was an open-label, dose-escalating study of single subcutaneous administration of 50 µg and then 100 µg of rhPTH(1–84). Enrolled patients (age range, 25–85 years) had ≥12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses ≥1000 mg/d of oral calcium and ≥0.25 µg/d of active vitamin D (oral calcitriol). The patient’s prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1–84) administration. Each patient received a single 50-µg rhPTH(1–84) dose, had at least a 7-day washout interval, and then received a single 100-µg rhPTH(1–84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate.

Results

After administration of rhPTH(1–84) 50 µg (n = 6) and 100 µg (n = 7), the approximate t_½ was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~12 hours. The median AUC was similar with calcitriol and rhPTH(1–84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123–227 pg · h/mL; rhPTH[1–84], 101–276 pg · h/mL), calcium (calcitriol, 3.3–3.7 mg · h/dL; rhPTH[1–84], 3.3–7.6 mg · h/dL), and magnesium (calcitriol, 0.7–0.9 mg · h/dL; rhPTH[1–84], 1.3–2.8 mg · h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1–84) (calcitriol, −1.0 to 0.8 mg · h/dL; rhPTH[1–84], −21.3 to −26.5 mg · h/dL). Compared with calcitriol, rhPTH(1–84) 50 µg reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1–84) 100 µg reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1–84) 50 µg increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1–84) 100 µg increased them by 45% and 42%. Urine cyclic adenosine monophosphate–to–creatinine ratio increased with rhPTH(1–84) by 2.3-fold (50 µg) and 4.4-fold (100 µg) compared with calcitriol.

Conclusions

PTH replacement therapy with rhPTH(1–84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hypoparathyroidism.     

Atorvastatin in stable angina patients lowers CCL2 and ICAM1 expression: Pleiotropic evidence from plasma mRNA analyses

Objective

Statin pleiotropy is still an evolving concept, and the lack of clarity on this subject is due at least in part to the lack of a definitive biomarker for statin pleiotropy. Using plasma mRNA analysis as a novel research tool for the non-invasive in vivo assessment of gene expression in vascular beds, we hypothesised that atorvastatin lowers the plasma mRNA level from statin pleiotropy-target genes, and the reduction is independent of the reduction of low-density lipoprotein cholesterol (LDL-C).

Design and methods

Forty-four patients with stable angina received atorvastatin therapy (20 mg/day, 10 weeks). Plasma chemokine (C-C motif) ligand 2 (CCL2) and intercellular adhesion molecule-1 (ICAM1) mRNA levels and their protein concentrations (MCP-1, sICAM-1) were analysed before and after the treatment. Plasma vascular adhesion molecule-1 (sVCAM-1) concentrations were also analysed.

Results

Atorvastatin lowered plasma mRNA levels (CCL2: − 31.76%, p = 0.037; ICAM1: − 34.09%, p < 0.001) and MCP-1 protein concentration (− 18.88%, p = 0.008) but did not lower sICAM-1 and sVCAM-1 protein concentrations, and the decreases appeared to be independent from the lowering of LDL-C. The plasma mRNA levels correlated with their protein concentrations following statin treatment only.

Conclusion

Our results significantly strengthen the clinical evidence in support of statin pleiotropy. Furthermore, this unique simultaneous measurement of plasma mRNAs and their protein concentrations offers an advanced non-invasive in vivo assessment of the circulation pathology.     

Assessment of apoB dyslipoproteinemia in Korean population

Objectives

There is sparse data on apoB dyslipoproteinemia in Asian population. The purpose of this study was to assess apoB dyslipoproteinemia and to compare the LDL-C, non-HDL and apoB for risk assessment with percentile equivalent cut off in Korean population.

Methods

With 1193 Korean adult subjects, the prevalence and characteristics of different types of dyslipoproteinemias were analyzed in each age and gender group. The percentile values of direct LDL-C, calculated LDL-C, non HDL-C, HDL-C, apoAI, apoB and apoB/apoAI ratio were estimated.

Results

The prevalences of normoapoB–hyperTG, hyperapoB–normoTG and hyperapoB–hyperTG dyslipoproteinemia were 6.9, 8.9 and 10.9% in men and 3.7, 6.4 and 2.8% in women. The 40th percentile of direct LDL-C, calculated LDL-C, non-HDL-C and apo B were 108, 104.2, 126 and 85 mg/dl, respectively. The individual above optimal cut off was significantly underestimated with LDL-C than with non-HDL and apoB, in groups with adverse risk factors.

Conclusions

This study firstly shows the prevalence of various types of dyslipoproteinemias in Asian population. The percentile values of Korean population were similar to those of NHANES. Integration of lipid markers is needed for making clinical decisions and further research involving various populations and methodologies should be performed.     

Pharmacokinetics of Pilsicainide Hydrochloride for Injection in Healthy Chinese Volunteers: A Randomized,Parallel-Group,Open-Label,Single-Dose Study

Background

Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation.

Objective

The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride.

Methods

This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration–time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs.

Results

Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m²) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean C_max was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) μg/mL, respectively; AUC_0–24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · μg/mL; and AUC_0–∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · μg/mL. The ranges for t_½z, CL, and V_z were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC_0–24 values in the 0.50-mg/kg dose group (P = 0.044), and V_z showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters.

Conclusions

Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC_0–24 and AUC_0–∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.     

Immature/total granulocyte ratio: A promising tool to assess the severity and the outcome of post-cardiac arrest syndrome

Background

The immature/total granulocyte (I/T-G) ratio increases during severe systemic inflammatory response syndrome. This study evaluated the I/T-G ratio as a predictor of poor outcome after out-of-hospital cardiac arrest (OHCA).

Methods

We conducted a pilot prospective cohort study of patients who were admitted in our intensive care unit (ICU) during a one-year period after post-OHCA resuscitation. I/T-G ratio measurements were obtained from blood samples collected on admission using flow cytometry and the outcomes were ICU mortality and post-cardiac arrest syndrome.

Results

Among the 130 patients (76% male, median age 54 [46–67] years), the median I/T-G ratio was 0.85 [0.42–1.98]%. The I/T-G ratio was poorly correlated with the SOFA score and lactate level on day 1 (r = 0.25, p = 0.005 and r = 0.5, p < 0.001, respectively). Patients with high I/T-G ratios were more likely to develop post-resuscitation shock (37% vs. 58%, p = 0.02). Patients dying from post-resuscitation shock had a higher I/T-G ratio than patients dying from neurological causes (2 [1–4]% vs. 1.2 [0.6–1.2]%, p = 0.02). The area under the ROC curve based on the I/T-G ratio was 0.82 for predicting ICU mortality.

Conclusion

The I/T-G ratio appears to be an accurate predictor of poor outcome. However, the added clinical value of this marker and the possible involvement of immature granulocytes in the pathophysiology of post-cardiac arrest syndrome remain to be investigated.     

Ambulatory Blood Pressure Response to Once-Daily Fimasartan: An 8-Week,Multicenter, Randomized,Double-Blind,Active-Comparator,Parallel-Group Study in Korean Patients With Mild To Moderate Essential Hypertension

Background

Fimasartan, a selective angiotensin II type 1 receptor blocker, was approved in Korea for the treatment of patients with mild to moderate hypertension.

Objective

The aim of this study was to evaluate the 24-hour blood pressure (BP) profiles before and after 8-week treatment with fimasartan and to compare them with those of valsartan.

Methods

A multicenter, randomized, double-blind, active-controlled, parallel-group study was conducted using ambulatory BP monitoring (ABPM). Korean patients with mild to moderate essential hypertension were enrolled and randomly received once-daily oral fimasartan 60 or 120 mg or valsartan 80 mg for 8 weeks. ABPM was performed before and after 8-week treatment, and clinic BP was also measured. Based on ABPM data, trough-to-peak ratio and smoothness index were derived. Tolerability was monitored throughout the study.

Results

Ninety-two patients were enrolled (mean [SD] age, 54.1 [8.2] years; weight, 67.9 [10.2] kg). After 8 weeks, 24-hour, daytime, and nighttime mean ambulatory systolic and diastolic BPs (SBP and DBP, respectively) were significantly decreased in all 3 treatment groups (range: SBP, –9.2 to –15.6 mm Hg; DBP, –5.0 to –10.7 mm Hg; P <0.0001–<0.05). The global trough-to-peak ratios of ambulatory DBP in the fimasartan groups were 0.74 (60 mg/d) and 0.81 (120 mg/d)—45.1% and 58.8% higher, respectively, than the ratio of 0.51 in the valsartan group. Fimasartan 60 mg/d was associated with 53.5% (SBP) and 68.3% (DBP) greater smoothness index scores compared with those with valsartan 80 mg/d (SBP, 1.52 vs. 0.99; DBP, 1.38 vs. 0.82). The decrease in clinic-measured DBP was significantly greater in the fimasartan 60-mg/d group compared with that in the valsartan 80-mg/d group (–14.0 vs –8.7 mm Hg; P = 0.0380). Fimasartan was well tolerated; headache was the most common adverse event.

Conclusion

Once-daily fimasartan effectively maintained a BP-reduction profile over the full 24-hour dosing interval; this profile was comparable to or slightly better than that of once-daily valsartan. Fimasartan was well tolerated; headache was the most common adverse event. ClinicalTrials.gov identifier: NCT00922441.     

Utilization and Yield of Chest Computed Tomographic Angiography Associated with Low Positive D-dimer Levels

Background

It is unclear to what degree broadly applied D-dimer testing combined with a low threshold for imaging with even minimally positive results may be contributing to the utilization of chest computed tomographic angiography (CTA).

Study Objectives

To determine what proportion of chest CTAs for suspected pulmonary embolism (PE) were performed in the setting of minimally elevated D-dimer levels, and to determine the prevalence of PE in those patients when stratified by clinical risk.

Methods

Retrospective chart review of all patients who had chest CTA for the evaluation of suspected PE during the years 2002–2006 in a suburban community teaching hospital emergency department.

Results

There were 1136 eligible patient visits, of which 353 (31.1%) were found to have D-dimer levels in the low positive range (0.5–0.99 μg/mL). Of these 353 patients, 9 (2.6%; 95% confidence interval [CI] 0.9–4.2%) were diagnosed with PE. There were also 109 patients (9.6%) who had normal D-dimer levels (<0.5 μg/mL). Two of these 109 (1.8%; 95% CI 0–4.2%) were diagnosed with PE. When stratified by the Pulmonary Embolism Rule-out Criteria, 99 of 353 patients with low positive D-dimer levels (28.0%; 95% CI 23.4–32.7%), and 14 of 109 with normal D-dimer levels (12.8%; 95% CI 6.6–19.1%) were classified as low risk, none of whom had PE.

Conclusions

Nearly one-third of all chest CTAs were done for patients with minimally elevated D-dimer levels, and another 9.6% for patients with normal D-dimer levels with very low yield. Further research to define clinical criteria identifying patients with minimal risk of PE despite low positive D-dimer levels represents an opportunity to improve both patient safety and utilization efficiency of chest CTA.     

Statins do not improve short-term survival in an oriental population with sepsis

Objectives

The aim of this study was to define the effect of statin on 30-day mortality in an oriental population with sepsis.

Design

We conducted a retrospective study on patients with sepsis at National Taiwan University Hospital from 2001 to 2002. The effects of statins on 30-day mortality were evaluated based on clinical settings. Log-rank test and Cox regression analysis were performed using the proportional hazards assumption.

Results

A total of 763 episodes of sepsis were reviewed; 454 consecutive patients were considered eligible. Among them, 104 (22.9%) took a statin at least 30 days before admission and during sepsis course, whereas the other 350 control (77.1%) did not. There was no significant difference of 30-day sepsis-related mortality between groups (19.2% vs 18.9%, P = .952). Statin treatment was not associated with decreased mortality at 30 days (P = .853; risk ratio, 0.95; 95% confidence interval, 0.53-1.68).

Conclusion

Short-term, sepsis-related mortality in a septic Taiwanese population was not reduced with statin treatment in our study. We concluded that statin therapy may have little effect on the survival of sepsis in oriental people, particularly in Taiwanese.     

Amoxicillin-associated interference in an HPLC–EC assay for urinary fractionated metanephrines: Potential pitfall in pheochromocytoma biochemical diagnosis

Objective

Measurement of urinary fractionated metanephrines represents a first-line test for the biochemical diagnosis of pheochromocytoma. The high performance liquid chromatography coupled to electrochemical detection (HPLC–EC) assays used in the routine clinical laboratory can be subjected to analytical interferences by the presence of drugs or their metabolites. In this paper we describe the interference on urinary normetanephrine (uNMN) caused by amoxicillin.

Design and methods

Two pediatric patients suspected of pheochromocytoma had very high uNMN levels (2543 and 4227 μg/g Cr respectively; upper reference value: 339 μg/g Cr). Amoxicillin interference was assessed by comparison for co-elution with uNMN and by LC–MS/MS analysis.

Results

After amoxicillin interference was suspected and the therapy was stopped uNMN levels returned to normal (149 and 214 μg/g Cr respectively). Chromatograms obtained by HPLC–EC clearly showed that amoxicillin co-elutes with uNMN. Patients' uNMN levels measured by LC–MS/MS were in the normal range.

Conclusion

Amoxicillin is responsible for analytical interference on HPLC–EC assay for uNMN. This finding can be of help in distinguishing true-positive from false-positive results in the course of a biochemical diagnosis for pheochromocytoma.     

Efficacy of Addition of Transcutaneous Electrical Nerve Stimulation to Standardized Physical Therapy in Subacute Spinal Spasticity: A Randomized Controlled Trial

Objective

To study the immediate and short-term efficacy of adding transcutaneous electrical nerve stimulation (TENS) to standardized physical therapy on subacute spasticity within 6 months of spinal cord injury.

Design

Randomized controlled trial for 3 weeks.

Setting

A university hospital.

Participants

Subjects (N=16) with clinically determined spasticity were randomly assigned to either the experimental group (n=8) or the control group (n=8).

Intervention

Sixty-minute sessions of TENS over the bilateral common peroneal nerves before 30 minutes of physical therapy for the experimental group and 30 minutes of physical therapy alone for the control group. All patients in both groups had access to standardized rehabilitation care.

Main Outcome Measures

The composite spasticity score, which included 3 subscores (ankle jerk, muscle tone, and ankle clonus scores), was used as the primary end point to assess plantar flexor spasticity. These subscores were designated as secondary end points. Serial evaluations were made at baseline before study entry and immediately after the first and last sessions in both groups.

Results

On analysis for immediate effects, there was a significant reduction only in the composite spasticity score (mean difference, 1.75; 99% confidence interval [CI], 0.47–3.03; P=.002) in the experimental group, but no significant reduction was observed in all outcome variables in the control group. A significant difference in the composite spasticity score (1.63; 99% CI, 0.14–3.11; P=.006) was observed between the 2 groups. After 15 sessions of treatment, a significant reduction was determined in the composite spasticity score (2.75; 99% CI, 1.31–4.19; P<.001), the muscle tone score (1.75; 99% CI, 0.16–3.34; P=.006), and the ankle clonus score (0.75; 99% CI, 0.18–1.32; P=.003) in the experimental group, whereas none of the outcome variables revealed a significant reduction in the control group. The between-group difference was significant only for the composite spasticity score (2.13; 99% CI, 0.59–3.66; P=.001) and the muscle tone score (1.50; 99% CI, 0.15–2.85; P=.005) after 15 intervention sessions.

Conclusion

Addition of TENS to standardized physical therapy had synergistically antispastic action, providing more effective reduction of clinical spasticity.     

Differences in clinical chemistry values according to the use of two laxatives for colonoscopy

Objectives

Polyethylene glycol–electrolyte lavage solutions (PEG–ELSs) and sodium phosphate formulations (NaPs) are two major colon cleansing laxatives used in preparation for endoscopic examinations of the gastrointestinal tract. PEG–ELSs are osmotically balanced preparations, whereas NaPs are hyperosmotic purgatives. This study aimed to evaluate the effects of these two laxatives on routine chemistry tests.

Design and methods

We retrospectively reviewed 9366 clinical records of patients who had health checkups with or without colonoscopy from July 2010 to June 2011. We compared the values of 19 clinical chemistry parameters in the NaPs group (n = 3239) and the PEG–ELSs group (n = 1279) with those of controls (without colonoscopy, n = 4848).

Results

Compared with controls, the NaPs group had higher mean values of inorganic phosphate, sodium, chloride, creatinine, total protein, AST, and ALT, and lower mean values of calcium and potassium, exceeding acceptable biases. Notably, inorganic phosphate showed the largest % bias (51.14%). In the PEG–ELSs laxative group, higher mean values of inorganic phosphorus, creatinine, uric acid, AST, and total bilirubin and a lower mean value of potassium were observed compared with controls, exceeding acceptable biases. The effects of NaPs on inorganic phosphate, calcium, and electrolyte levels exceeded those of PEG–ELSs.

Conclusions

PEG–ELSs rather than NaPs are recommended as the first choice for bowel preparation, taking safety concerns and the reliability of laboratory values into account. Blood chemistry data from blood samples drawn after the ingestion of laxatives for colonoscopy should be interpreted with caution.