Bayesian network meta-regression hierarchical models using heavy-tailed multivariate random effects with covariate-dependent variances.

Network meta-analysis (NMA) is gaining popularity in evidence synthesis and network meta-regression allows us to incorporate potentially important covariates into network meta-analysis. In this article, we propose a Bayesian network meta-regression hierarchical model and assume a general multivariate t distribution for the random treatment effects. The multivariate t distribution is desired for heavy-tailed random effects and converges to the multivariate normal distribution when the degrees of freedom go to infinity. Moreover, in NMA, some treatments are compared only in a single study. To overcome such sparsity, we propose a log-linear regression model for the variances of the random effects and incorporate aggregate covariates into modeling the variance components. We develop a Markov chain Monte Carlo sampling algorithm to sample from the posterior distribution via the collapsed Gibbs technique. We further use the deviance information criterion and the logarithm of the pseudo-marginal likelihood for model comparison. A simulation study is conducted and a detailed analysis from our motivating case study is carried out to further demonstrate the proposed methodology.

Biphasic Postnatal Umbilical Cord Shortening.

INTRODUCTION: Variations in postnatal length of refrigerated, unfixed umbilical cords were studied over time to elucidate natural changes and times of stability. METHODS: Length was measured in 132 cords following severance, repeated at varying timed intervals and studied by analysis of variance and regression analysis. RESULTS: Data show immediate rapid initial phase shortening (mean 4.2+/-3.9 cm SD); an interval of lengthening; stable length at hours 3-4 following severance, a slower second phase shortening (mean 1.5+/-0.7 cm SD) beginning at 5 hours and peaking at 12 hours; and gradual lengthening to stable length after 23 hours. Overall, there was a significant net mean decrease of 3.49+/-2.29 cm SD. Shortening was greatest for intact long cord segments (p=0.0001), as much as 11 cm. Two highly significant models for predicting umbilical cord length at delivery (OL) were determined using the post-delivery lengths (Length) measured at different times following delivery (Hours), as follows:At ≤ 3 hours following delivery: OL=1.02xLength cm+1.11xHoursAt >3 hours following delivery: OL=1.07xLength+0.44xHours-0.01x(Hours)2. CONCLUSION: Cord lengths stabilized between hours 3-4 and after 23 hours following severance. Phase one shortening resembles vasoconstriction; phase two resembles rigor mortis. The models allow prediction of the original umbilical cord length at delivery, regardless of the time of measurement.

Bayesian inference for network meta-regression using multivariate random effects with applications to cholesterol lowering drugs.

Low-density lipoprotein cholesterol (LDL-C) has been identified as a causative factor for atherosclerosis and related coronary heart disease, and as the main target for cholesterol- and lipid-lowering therapy. Statin drugs inhibit cholesterol synthesis in the liver and are typically the first line of therapy to lower elevated levels of LDL-C. On the other hand, a different drug, Ezetimibe, inhibits the absorption of cholesterol by the small intestine and provides a different mechanism of action. Many clinical trials have been carried out on safety and efficacy evaluation of cholesterol lowering drugs. To synthesize the results from different clinical trials, we examine treatment level (aggregate) network meta-data from 29 double-blind, randomized, active, or placebo-controlled statins +/$-$ Ezetimibe clinical trials on adult treatment-naïve patients with primary hypercholesterolemia. In this article, we propose a new approach to carry out Bayesian inference for arm-based network meta-regression. Specifically, we develop a new strategy of grouping the variances of random effects, in which we first formulate possible sets of the groups of the treatments based on their clinical mechanisms of action and then use Bayesian model comparison criteria to select the best set of groups. The proposed approach is especially useful when some treatment arms are involved in only a single trial. In addition, a Markov chain Monte Carlo sampling algorithm is developed to carry out the posterior computations. In particular, the correlation matrix is generated from its full conditional distribution via partial correlations. The proposed methodology is further applied to analyze the network meta-data from 29 trials with 11 treatment arms.

Comparative analysis of retrograde intrarenal surgery and modified ultra-mini percutaneous nephrolithotomy in management of lower pole renal stones (1.5-3.5 cm).

BACKGROUND: To compare the safety and efficacy of retrograde intrarenal surgery (RIRS) and modified Ultra-mini percutaneous nephrolithotomy (UMP) in semi-supine combined lithotomy position for the management of 1.5-3.5 cm lower pole renal stones (LPSs). METHODS: A total of 63 patients with 1.5-3.5 cm LPSs who underwent RIRS (n = 33) or modified UMP (n = 30) in diameter between January 2017 and January 2019 were analyzed retrospectively. Modified UMP was performed in semi-supine combined lithotomy position and a 9.5/11.5 F ureteral access sheath (UAS) was inserted during the procedure in order to maintain low pelvic pressure and to facilitate the removal of stone fragments. Base-line parameters, stone characteristics, illness condition, operation time, postoperative hemoglobin (Hb) drop, postoperative creatinine (Cr) elevation, length of hospital stay, length of postoperative hospital stay, stone-free rate (SFR) and complications were compared between the two groups. RESULTS: There were no significant differences between the two groups in base-line parameters, stone characteristics and illness condition. The mean operating time of RIRS group was longer than UMP group (95.61 ± 21.9 vs. 55.0 ± 16.1 min, p < 0.001). The mean postoperative Hb drop was less in RIRS group (7.42 ± 4.7 vs. 15.70 ± 9.8 g/L, p < 0.001). The length of hospital stay and postoperative hospital stay for RIRS were shorter than UMP (4.76 ± 1.1 vs. 5.83 ± 0.8 d, p < 0.001, 2.97 ± 0.9 vs. 4.07 ± 0.9 d, p < 0.001). The Early SFR was higher in UMP group (54.5 vs. 80.0%, p < 0.050) while SFR at 1-month and 3-months postoperatively was similar in both groups (p = 0.504, p = 0.675). There were no significant differences between the two groups in complications (p = 0.228). CONCLUSION: For patients with 1.5-3.5 cm LPSs, both modified UMP and RIRS are safe and viable. The modified UMP technique was used in this study, application semi-supine combined lithotomy position and the retention of UAS can improve the surgical efficiency and maintain low pressure perfusion in the kidney, which resulted in superior treatment efficacy. Therefore, we highly recommend this technique for LPSs with heavy stone burdens.

Influence of metabolic syndrome factors and insulin resistance on the efficacy of ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome and atherosclerotic coronary heart disease risk.

BACKGROUND: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).

Bayesian inference for multivariate meta-analysis Box-Cox transformation models for individual patient data with applications to evaluation of cholesterol-lowering drugs.

In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the deviance information criterion is used to select the best transformation model. Because the model is quite complex, we develop a novel Monte Carlo Markov chain sampling scheme to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol-lowering drugs where the goal is to jointly model the three-dimensional response consisting of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) (LDL-C, HDL-C, TG). Because the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately; however, a multivariate approach would be more appropriate because these variables are correlated with each other. We carry out a detailed analysis of these data by using the proposed methodology.

Does Relocation of Lower Pole Stone During Retrograde Intrarenal Surgery Improve Stone-Free Rate? A Prospective Randomized Study.

Purpose: The aim of this study was to compare the stone-free rate (SFR) of in situ treatment vs relocation and lithotripsy for lower pole stones of less than 2 cm following retrograde intrarenal surgery (RIRS). Methods: This prospective randomized study was undertaken from June 2019 to May 2020 in patients undergoing RIRS for lower pole renal stones less than 2 cm in diameter. Patients were randomized into two groups: in situ lithotripsy group and relocation lithotripsy group. The in situ lithotripsy group underwent laser lithotripsy for lower pole stones without relocation of the calculus, and the relocation lithotripsy group had their stones relocated to a favorable location using a tipless Nitinol basket, followed by laser lithotripsy. Laser lithotripsy was achieved using the holmium:YAG (Ho:YAG) laser (120 W) with a 200-µm laser fiber. A Double-J stent was placed in all patients at the end of the procedure. Patient demographics, stone characteristics, operative outcomes, and complications were evaluated. The SFR was determined at 1 month postoperatively with a kidney, ureter, and bladder radiograph (KUB) and ultrasound KUB. Results: Sixty-eight patients were included in the study: in situ group (n = 35) and relocation group (n = 33). The mean stone size and stone density were similar between the groups. The total operative duration, lasing duration, and total energy used were similar between the groups. At the 1-month follow-up, the complete SFR was 85.7% and 91% in the in situ lithotripsy and relocation lithotripsy groups, respectively (p = 0.506). Conclusions: Relocation followed by subsequent laser lithotripsy was associated with similar SFRs as with in situ laser lithotripsy for lower pole renal calculi less than 2 cm in diameter following RIRS using the Ho:YAG laser.

Predictive Factors for the Peri-operative Outcome of Ureteroscopic Lithotripsy for Proximal Ureteric Stones.

BACKGROUND: Proximal ureteric stones are considered one of challenging location for lithotripsy using semirigid ureteroscopes. Aim of the study was to assess clinical and radiological characteristics associated with outcome of lithotripsy using semirigid ureteroscope for proximal ureteric stones. METHODS: Prospective observational study was done on patients who underwent semirigid ureteroscopic lithotripsy for proximal ureteric stone. Stone and ureteral mormphomeric parameters were documented from computed tomography urogram. Stone free status and complication rates were studied. To determine predictive factors for outcomes, multivariate regression analysis and receiver operative curve were used. RESULTS: One hundred patients were included in study. Demographic characteristics, stone size, density and mode of lithotripsy had no impact on stone free rate or complications. The mean ureteral wall thickness(p = 0.002), distance of stone from pelvi-ureteric junction(p = 0.005), degree of hydronephrosis(p = 0.0001) and peri-ureteric fat stranding (p = 0.038) were found to have significant association with stone free rate on univariate analysis. On multivariate analysis, mild hydronephrosis(p = 0.003) and distance of stone from pelvi-ureteric junction(p = 0.022) were significant for stone free rate. CONCLUSIONS: Mean ureteral wall thickness, stone distance from pelvi-ureteric junction, presence of peri-ureteric fat stranding and hydronephrosis affect stone free rate on univariate analysis. On multivariate analysis for stone free rate, stone distance from pelvi-ureteric junction and mild hydronephrosis were significant. There was no significant impact of any stone or ureteral morphometry on complication rate.

Prostatic Urethral Length as a Predictor for Surgery in Benign Prostatic Hyperplasia.

BACKGROUND: Benign prostatic hyperplasia is associated with structural and morphological changes including elongation of prostatic urethral length. The aim of our study was to assess whether prostatic urethral length could predict need of surgery in patients with benign prostatic hyperplasia. METHODS: This prospective observational study was conducted over a 12-months duration. All the patients who presented with lower urinary tract symptoms secondary to benign prostatic hyperplasia were evaluated with International Prostate Severity Score, serum Prostate Specific Antigen, Transrectal Ultrasound was done to measure prostatic urethral length, prostate volume, Intravesical prostatic protusion and Post-void Residual Urine. Patients not responding to medical treatment and complications secondary to benign prostatic hyperplasia underwent surgery. Logistic regression analysis was performed to identify risk factors associated with surgery. RESULTS: A total of 153 patients were included in the study. Eighty-three (54.2%) patients underwent surgery during the study period. Prostate volume, intravesical prostatic protrusion, post-void residual volume, serum prostate specific antigen, and prostatic urethral length were significantly higher in the surgical group. The mean prostatic urethral length in the surgical group was 39.47 + 10.2 mm and in the nonsurgical group was 26.20 + 6.72 mm (p <0.0001). According to the ROC curve-based prediction of surgery, the area under the curve for PUL was 0.866 and the best cutoff value was 31.5mm (81% sensitivity and 84.3% specificity). CONCLUSIONS: BPH patients with longer PUL may require surgical management. PUL measured by TRUS may be a predicting factor for the need of surgery in BPH Keywords: Benign prostatic hyperplasia; lower urinary tract symptoms; prostatic urethral length.

Meta-analysis methods and models with applications in evaluation of cholesterol-lowering drugs.

In this paper, we propose a class of multivariate random effects models allowing for the inclusion of study-level covariates to carry out meta-analyses. As existing algorithms for computing maximum likelihood estimates often converge poorly or may not converge at all when the random effects are multi-dimensional, we develop an efficient expectation-maximization algorithm for fitting multi-dimensional random effects regression models. In addition, we also develop a new methodology for carrying out variable selection with study-level covariates. We examine the performance of the proposed methodology via a simulation study. We apply the proposed methodology to analyze metadata from 26 studies involving statins as a monotherapy and in combination with ezetimibe. In particular, we compare the low-density lipoprotein cholesterol-lowering efficacy of monotherapy and combination therapy on two patient populations (naïve and non-naïve patients to statin monotherapy at baseline), controlling for aggregate covariates. The proposed methodology is quite general and can be applied in any meta-analysis setting for a wide range of scientific applications and therefore offers new analytic methods of clinical importance.

metapack: An R Package for Bayesian Meta-Analysis and Network Meta-Analysis with a Unified Formula Interface.

Meta-analysis, a statistical procedure that compares, combines, and synthesizes research findings from multiple studies in a principled manner, has become popular in a variety of fields. Meta-analyses using study-level (or equivalently aggregate) data are of particular interest due to data availability and modeling flexibility. In this paper, we describe an R package metapack that introduces a unified formula interface for both meta-analysis and network meta-analysis. The user interface-and therefore the package-allows flexible variance-covariance modeling for multivariate meta-analysis models and univariate network meta-analysis models. Complicated computing for these models has prevented their widespread adoption. The package also provides functions to generate relevant plots and perform statistical inferences like model assessments. Use cases are demonstrated using two real data sets contained in metapack.

Response by sex to statin plus ezetimibe or statin monotherapy: a pooled analysis of 22,231 hyperlipidemic patients.

BACKGROUND: Despite documented benefits of lipid-lowering treatment in women, a considerable number are undertreated, and fewer achieve treatment targets vs. men. METHODS: Data were combined from 27 double-blind, active or placebo-controlled studies that randomized adult hypercholesterolemic patients to statin or statin+ezetimibe. Consistency of treatment effect among men (n = 11,295) and women (n = 10,499) was assessed and percent of men and women was calculated to evaluate the between-treatment ability to achieve specified treatment levels between sexes. RESULTS: Baseline lipids and hs-CRP were generally higher in women vs. men. Between-treatment differences were significant for both sexes (all p < 0.001 except apolipoprotein A-I in men = 0.0389). Men treated with ezetimibe+statin experienced significantly greater changes in LDL-C (p = 0.0066), non-HDL-C, total cholesterol, triglycerides, HDL-C, apolipoprotein A-I (all p < 0.0001) and apolipoprotein B (p = 0.0055) compared with women treated with ezetimibe+statin. The odds of achieving LDL-C < 100 mg/dL, apolipoprotein B < 90 mg/dL and the dual target [LDL-C < 100 mg/dL & apoliprotein B < 90 mg/dL] was significantly greater for women vs. men and the odds of achieving hs-CRP < 1 and < 2 mg/L and dual specified levels of [LDL-C < 100 mg/dL and hs-CRP < 2 mg/L] were significantly greater for men vs. women. Women reported significantly more gall-bladder-related, gastrointestinal-related, and allergic reaction or rash-related adverse events (AEs) vs. men (no differences between treatments). Men reported significantly more CK elevations (no differences between treatments) and hepatitis-related AEs vs. women (significantly more with ezetimibe+simvastatin vs. statin). CONCLUSIONS: These results suggest that small sex-related differences may exist in response to lipid-lowering treatment and achievement of specified lipid and hs-CRP levels, which may have implications when managing hypercholesterolemia in women.

Low incidence of paradoxical reductions in HDL-C levels in dyslipidemic patients treated with fenofibrate alone or in combination with ezetimibe or ezetimibe/simvastatin.

BACKGROUND: Fibrates have been reported to cause paradoxical decreases in HDL-C in certain patients. DESIGN AND METHODS: This post-hoc analysis explored the frequency/magnitude of HDL-C reductions in a pooled database of mixed dyslipidemic patients (LDL-C:3.4-5.7 mmol/L;TG:1.7-5.7 mmol/L) receiving placebo (PBO), fenofibrate (FENO), ezetimibe plus FENO (EZE+FENO), or EZE/simvastatin plus FENO (EZE/SIMVA+FENO) for 12 weeks. RESULTS: PBO-treated patients had the highest incidence of HDL-C reductions from baseline (45%) compared with patients taking FENO (14%), EZE+FENO (9%), or EZE/SIMVA+FENO (9%). Reductions <30% reflected natural variability since the largest reduction in HDL-C approached 30% in the PBO group. Only 3 patients exhibited HDL-C reductions ≥30% (i.e., 2 patients in the FENO group and 1 in the EZE+FENO group). There were no differences in demographic/biochemical characteristics between patients with and without HDL-C reductions. CONCLUSIONS: The incidence of paradoxical HDL-C reductions was low in mixed dyslipidemic patients receiving FENO alone or combined with EZE or EZE/SIMVA.

Comparative Study of Percutaneous Nephrolithotomy in Supine and Prone Positions.

BACKGROUND: The aim of the study is the compare efficacy and safety of percutaneous nephrolithotomy in supine and prone positions. Percutaneous nephrolithotomy is conventionally performed in prone position but in recent years numbers of supine percutaneous nephrolithotomies is increasing globally. METHODS: The hospital based cross-sectional observational study was conducted in the Department of Urology, Bir Hospital from July 2018 to January 2020. A total of 81 consecutive patients undergoing percutaneous nephrolithotomy were divided into two groups, with 38 patients in Supine (Group 1) and 43 patients in Prone (Group 2) positions, respectively. Patient's demographics, access time, operative duration, stone free rate, radiation dose and duration, irrigation fluid volume, post-operative hemoglobin drop and complications were compared. RESULTS: Demographic and stone characteristics were comparable in both groups. Supine Group (Group 1) had significantly shorter operative duration than Prone Group (Group 2), 44.63 ± 12.44minsvs 53.02 ±12.67mins (p< 0.04). The mean radiation duration was 99.11 ± 61.17secs in Group 1 and 108.40 ± 51.65 secs in Group 2 (p=0.46), respectively. Although the mean radiation dose was lower in Group 1 (375.1µGym2) than in Group 2 (465.7 µGym2), it was not statistically significant(p=0.24). The stone free rate at 1 month duration were comparable with 92.1% and 93.02% in Group 1 and Group 2 respectively (p=0.16). Overall complication rates were similar in both groups (15.7% in Group 1 vs 16.2% in Group 2), respectively. None of the patients in both groups had complications higher than Clavien IIIa. CONCLUSIONS: PCNL in supine position has significantly shorter operative time with similar complications and stone free rates as compared to prone position.

Monopolar Transurethral Resection of Prostate for Benign Prostatic Hyperplasia in Patients With and Without Preoperative Urinary Catheterization: A Prospective Comparative Study.

Background A significant proportion of patients undergo surgery for benign prostatic hyperplasia following acute urinary retention. Studies have reported conflicting results of improvement following transurethral surgery in these patients. Objective To compare perioperative complications and postoperative voiding parameters in patients undergoing monopolar transurethral resection of prostate with and without preoperative Foley catheterization. Methods A prospective non-randomized study was conducted in patients undergoing monopolar transurethral resection of prostate for symptomatic benign prostatic hyperplasia. Patients were divided into those with Foley catheterization preoperatively (n=52), and those without catheters (n=90). Change in hemoglobin level, the resected volume of prostate, complications and the need for postoperative catheterization were compared. Postoperative symptoms score using International Prostate Symptom Score, maximum flow rate and post-void residual volume were assessed at three months follow up. Results The mean operative duration, length of stay and resected volume were higher in those patients with catheters; however, no significant differences were noted for mean hemoglobin level change and need for postoperative recatheterization. Three patients in each group required recatheterization and, all were catheter-free at one week postoperatively. Complications developed in 16.1% (n=23) with most of them being Clavien I. Patients with catheters had a lower postoperative maximum flow rate than those without it (16.90 vs 19.75 mL/sec). Patients with catheters had a significantly better postoperative quality of life and symptom score. Conclusion Monopolar transurethral resection of prostate in patients with preoperative per-urethral Foley catheter for acute urinary retention had similar postoperative voiding parameters with comparable complication rates to those without a catheter.

Elevated high sensitivity C-reactive protein levels in aging men with low testosterone.

OBJECTIVE: We examined baseline data from a lipid treatment study to assess the relationship between testosterone (T) and the cardiovascular inflammatory marker, high sensitivity C-reactive protein (hsCRP). METHODS: The baseline T, hsCRP, lipid, glycemic, and anthropometric data were obtained from 467 men (mean age: 52 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4 to 4.9 mmol/l and triglycerides < or = 4.0 mmol/l. The baseline hsCRP levels were examined across the following T subgroups: <6.9 nmol/l (moderate to severe hypogonadism), 6.9 to <10.4 nmol/l (mild to moderate hypogonadism), 10.4 to <15 nmol/l (low-normal T), and > or = 15 nmol/l (normal T). RESULTS: The median hsCRP levels were significantly (p = 0.041) different across the four T subgroups; patients in the lower T subgroups had higher median hsCRP levels than patients in the higher T subgroups. The percentage of men with elevated hsCRP (>2 mg/l) was also significantly (p = 0.038) different across the four T subgroups; 83% of men with T < 6.9 nmol/l had elevated hsCRP compared with 40% with T > or = 15 nmol/l. CONCLUSIONS: This analysis demonstrated an inverse relationship between serum T and hsCRP in aging men. Urologists need to be aware that low T levels may not only adversely affect sexual function but also may worsen cardiovascular risk in aging, hypogonadal men.

Increased occurrence of marked elevations of lipoprotein(a) in ageing, hypercholesterolaemic men with low testosterone.

OBJECTIVE: We previously examined the inverse relationship between total serum testosterone (T) and the occurrence of the metabolic syndrome in ageing men using baseline data from two lipid treatment studies. We further examined baseline data from a subset of US men participating in one of these two studies to assess the relationship between T and the cardiovascular risk factor lipid, lipoprotein(a) [Lp(a)]. METHODS: Baseline T, lipid, glycaemic and anthropometric data were obtained from 107 men (mean age: 55 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4-4.9 mmol/l and triglycerides < or = 4.0 mmol/l. Baseline Lp(a) levels were examined across the following baseline T subgroups: <15 nmol/l (low/low-normal T) and > or = 15 nmol/l (normal T). RESULTS: There was an overall trend for a higher incidence of clinically significant Lp(a) elevations in men with low T; 17.1% of men in the low/low-normal T subgroup had an Lp(a) level > or = 3 times the upper limit of normal compared to 8.1% in the normal T subgroup. CONCLUSIONS: The data from this descriptive analysis suggest that ageing men with low serum T levels may have an increase in marked elevations in Lp(a), which would be expected to be associated with a significant increase in their cardiovascular event risk.

Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?

BACKGROUND: Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL. RESULTS: Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels <150 or ≥150 mg/dL. CONCLUSIONS: When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels. TRIAL REGISTRATION: (Registered at clinicaltrials.gov: Clinical trial # NCT00276484).

Ezetimibe/simvastatin 10/20 mg versus rosuvastatin 10 mg in high-risk hypercholesterolemic patients stratified by prior statin treatment potency.

OBJECTIVE: This post-hoc analysis compared the lipid-altering efficacy of Ezetimibe/Simvastatin 10/20 mg (EZ/Simva) versus Rosuvastatin 10 mg (Rosuva) in patients stratified by statin potency/dose prior to randomization. METHODS: Patients with elevated low-density lipoprotein cholesterol (LDL-C) despite prior statin treatment (n=618) were randomized 1:1 to EZ/Simva 10/20 mg or Rosuva 10 mg for 6 weeks. Percent change from baseline in lipids and attainment of lipid targets were assessed within each subgroup (low potency n=369, high potency n=249). Consistency of the treatment effect across subgroups was evaluated by testing for treatment-by-subgroup interaction. No multiplicity adjustments were made. RESULTS: Significant treatment-by-subgroup interaction occurred for LDL-C (p=0.013), total cholesterol (p=0.025), non-HDL-C (p=0.032), and apolipoprotein B (p=0.016) with greater between-treatment differences in favor of EZ/Simva observed in patients from the high potency stratum vs low potency stratum. Individual and triple target attainment was higher for Eze/Simva compared with Rosuva in both strata. CONCLUSIONS: Compared with Rosuva, switching to EZ/Simva provided greater reductions in LDL-C, total cholesterol, non-HDL-C and apolipoprotein B and higher target attainment in patients on prior statin treatment, regardless of potency, although patients treated with higher potency statins prior to randomization experienced greater between treatment differences in favor of EZ/Simva. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT00479713.

Bayesian flexible hierarchical skew heavy-tailed multivariate meta regression models for individual patient data with applications.

A flexible class of multivariate meta-regression models are proposed for Individual Patient Data (IPD). The methodology is well motivated from 26 pivotal Merck clinical trials that compare statins (cholesterol lowering drugs) in combination with ezetimibe and statins alone on treatment-naïve patients and those continuing on statins at baseline. The research goal is to jointly analyze the multivariate outcomes, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG). These three continuous outcome measures are correlated and shed much light on a subject's lipid status. The proposed multivariate meta-regression models allow for different skewness parameters and different degrees of freedom for the multivariate outcomes from different trials under a general class of skew t-distributions. The theoretical properties of the proposed models are examined and an efficient Markov chain Monte Carlo (MCMC) sampling algorithm is developed for carrying out Bayesian inference under the proposed multivariate meta-regression model. In addition, the Conditional Predictive Ordinates (CPOs) are computed via an efficient Monte Carlo method. Consequently, the logarithm of the pseudo marginal likelihood and Bayesian residuals are obtained for model comparison and assessment, respectively. A detailed analysis of the IPD meta data from the 26 Merck clinical trials is carried out to demonstrate the usefulness of the proposed methodology.