Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway.

Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S. aureus the formation of haem involves the conversion of coproporphyrinogen III into coproporphyrin III by coproporphyrin synthase HemY, insertion of iron into coproporphyrin III via ferrochelatase HemH, and oxidative decarboxylation of Fe-coproporphyrin III into protohaem IX by Fe-coproporphyrin oxidase/dehydrogenase HemQ. Together, this route represents a transitional pathway between the classic pathway and the more recently acknowledged alternative biosynthesis machinery. The role of the haem biosynthetic pathway in the survival of the bacterium was investigated by testing for inhibitors of HemY. Analogues of acifluorfen are shown to inhibit the flavin-containing HemY, highlighting this protein as a suitable target for the development of drugs against S. aureus. Moreover, the presence of a transitional pathway for haem biosynthesis within many Gram positive pathogenic bacteria suggests that this route has the potential not only for the design of antimicrobials but also for the selective discrimination between bacteria operating different routes to the biosynthesis of haem.

Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study.

OBJECTIVES: Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent. METHODS: Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks. RESULTS: Significantly greater (p < 0.05) reductions in LDL-C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ∼10-14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced ß-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable. CONCLUSION: Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe.

Achievement of LDL-C goals depends on baseline LDL-C and choice and dose of statin: an analysis from the VOYAGER database.

BACKGROUND: Reducing low-density lipoprotein cholesterol (LDL-C) levels decreases cardiovascular risk in direct proportion to the decrease in LDL-C. DESIGN: The aim of this study was to assess the importance of baseline LDL-C and choice and dose of statin in achievement of LDL-C goals of 100 and 70 mg/dl, using a novel statistical model. The analysis included 30,102 patient exposures to rosuvastatin 10-40 mg or atorvastatin 10-80 mg from 31 direct comparative trials in the VOYAGER database. METHODS: For each statin dose, percentage goal achievement was plotted for 20 equally large subgroups defined by baseline LDL-C. Logistic regression analysis was then performed for each statin dose to estimate the percentage of patients reaching target. Best-fit logistic regression curves were plotted 'pair-wise', comparing each rosuvastatin dose with equal or higher doses of atorvastatin. RESULTS: LDL-C <100 mg/dl was achieved by 53.7-85.5% of patients on rosuvastatin 10-40 mg and 43.3-80.0% of those on atorvastatin 10-80 mg, whereas LDL-C <70 mg/dl was achieved by 4.5-44.0% of rosuvastatin-treated patients and 6.5-41.4% of those on atorvastatin. Similar differences in efficacy favouring rosuvastatin over equal or double doses of atorvastatin were observed across the range of baseline LDL-C levels for both LDL-C goals, being more pronounced at higher baseline values. CONCLUSIONS: Baseline LDL-C and choice and dose of statin are important for LDL-C goal achievement. The present analysis may allow prediction of individual patient response to different statins at different doses.

Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either <70 mg/dl or ≥ 50% reduction in high-risk patients: results from VOYAGER.

OBJECTIVE: Guidelines published in 2011 by the European Atherosclerosis Society and the European Society of Cardiology recommend a goal of either low-density lipoprotein cholesterol (LDL-C) <70 mg/dl (~1.8 mmol/l) or ≥ 50% reduction in LDL-C for patients at very high cardiovascular risk. The aim of this study was to determine the percentage of high-risk patients from the VOYAGER individual patient data meta-analysis treated with rosuvastatin 10-40 mg, atorvastatin 10-80 mg or simvastatin 10-80 mg who achieved this goal. METHODS: We analysed 25,075 patient exposures from high-risk patients. Paired comparisons were made between each rosuvastatin dose and an equal or higher dose of either atorvastatin or simvastatin, with a series of meta-analyses that included only randomised studies that directly compared rosuvastatin and its comparator treatments. RESULTS: As statin dose increased, higher percentages of patients achieved LDL-C <70 mg/dl or ≥ 50% LDL-C reduction. A greater percentage achieved this goal with rosuvastatin 10-40 mg (43.8-79.0%) than with equal or double milligram doses of atorvastatin (16.1-65.2%) or simvastatin (0-39.7%). Paired comparisons showed statistically significant differences for: rosuvastatin 10 mg vs. atorvastatin 10-20 mg and simvastatin 10-20 mg; rosuvastatin 20 mg vs. atorvastatin 20-40 mg and simvastatin 20-80 mg; and rosuvastatin 40 mg vs. atorvastatin 40-80 mg and simvastatin 40-80 mg (all p < 0.001). CONCLUSION: These data from VOYAGER highlight the importance of an effective statin at an appropriate dose to achieve treatment goals for LDL-C in patients with very high cardiovascular risk.

Effect of rosuvastatin on the echolucency of the common carotid intima-media in low-risk individuals: the METEOR trial.

BACKGROUND: The echolucency of the carotid intima-media is related to increased cardiovascular risk factor levels, morbidity, and mortality. The aim of this study was to assess the effect of statins on the echolucency of the common carotid intima-media in a low-risk population. METHODS: Data from the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin study were used. Ultrasound images from the far walls of the left and right common carotid arteries were used for evaluation of the echolucency of the carotid intima-media, measured by grayscale median (GSM). Low GSM values reflect echolucent structures, whereas high values reflect echogenic structures. The primary end point was the difference in the annual rate of change in GSM between rosuvastatin and placebo. RESULTS: Two-year change in GSM did not significantly differ between rosuvastatin and placebo in the total population, with a mean difference in the rate of change in GSM of 1.13 (95% confidence interval, -1.00 to 3.25). The effect of rosuvastatin differed across quintiles of baseline GSM values (P for interaction = .01). In the lowest quintile (n = 175) (i.e., in those with the most echolucent intima-media), the difference in the rate of change in GSM between rosuvastatin and placebo was 4.18 (95% confidence interval, -0.23 to 8.58). Increases in GSM were significantly related to decreasing low-density lipoprotein cholesterol levels in the lowest quintile (ß = 0.76; 95% confidence interval, 0.26 to 1.25). CONCLUSIONS: Treatment with rosuvastatin did not affect the echolucency of the arterial wall in all low-risk individuals. However, a potential effect of rosuvastatin on the echolucency of the common carotid intima-media is most likely to be found in individuals with echolucent arterial walls at baseline.

Biologically implausible carotid intima-media thickness measurement values: effects on rate of change over time.

OBJECTIVE: Carotid intima-media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT. METHODS: Data were used from the METEOR (Measuring Effects on Intima-media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT. RESULTS: The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups). LIMITATION: This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening, CONCLUSION: Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change.

Sample size requirements in trials using repeated measurements and the impact of trial design.

OBJECTIVE: Sample size calculations for clinical trials generally use expected changes between groups, and variances obtained from the literature. However, this approach neglects the impact of differences in trial design. We studied the effects of variations in trial design on the required sample size. METHODS: Data were used from the METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) trial in which carotid intima-media thickness (CIMT) measurements were performed twice at baseline, at 6, 12 and 18 months, and twice at the end of 2-year study treatment. A sample size formula for continuous outcome measures that incorporates between- and within-individual variance components was used to evaluate the impact of differences in the length of follow-up, and the number of CIMT examinations. RESULTS: Trial designs with a shorter duration of follow-up have increased within-individual variance and require larger sample sizes to detect the same treatment effect. Reduction in the number of examinations within a trial with a given duration, i.e. by using single rather than duplicate baseline and end-of-study scans or by not performing intermediate scans, also increased the required sample size to maintain the same power. CONCLUSION: A longer trial duration and/or more frequent examinations within a trial which has repeated measures of an outcome variable substantially increase study power and reduce the required sample size. In situations where the costs of recruiting, retaining and examining individual participants are known, the sample size, study length and number of examinations can be balanced to optimize the trial design relative to costs or other study objectives.

Multiple imputation of missing repeated outcome measurements did not add to linear mixed-effects models.

OBJECTIVE: To assess the added value of multiple imputation (MI) of missing repeated outcomes measures in longitudinal data sets analyzed with linear mixed-effects (LME) models. STUDY DESIGN AND SETTING: Data were used from a trial on the effects of Rosuvastatin on rate of change in carotid intima-media thickness (CIMT). The reference treatment effect was derived from a complete data set. Scenarios and proportions of missing values in CIMT measurements were applied and LME analyses were used before and after MI. The added value of MI, in terms of bias and precision, was assessed using the mean-squared error (MSE) of the treatment effects and coverage of the 95% confidence interval. RESULTS: The reference treatment effect was -0.0177 mm/y. The MSEs for LME analysis without and with MI were similar in scenarios with up to 40% missing values. Coverage was large in all scenarios and was similar for LME with and without MI. CONCLUSION: Our study empirically shows that MI of missing end point data before LME analyses does not increase precision in the estimated rate of change in the end point. Hence, MI had no added value in this setting and standard LME modeling remains the method of choice.

Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender.

BACKGROUND: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk. METHODS AND RESULTS: We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT. For each subject, circumferential information on the maximum CIMT of the left and right carotid arteries was obtained for the common carotid, bifurcation, and internal carotid artery segments. In each segment (common, bifurcation, internal), mixed modelling was used to study the differences in CIMT between angles, sides, gender, age, race, and studies. Each segment showed a different circumferential CIMT pattern. In all segments there were statistically significant differences between maximum CIMT across circumferential angles (p < 0.001); on average CIMT was highest in the posteromedial wall of the bifurcation and internal carotid segments and in the anterolateral wall of the common carotid segment. This asymmetric circumferential pattern was found to be identical in men and women, in young and old age, in different race groups, and across the studies. CONCLUSIONS: We confirmed the asymmetrical helix-like distribution of atherosclerosis in the carotid arteries and expand the evidence by showing that the atherosclerotic configuration is similar across populations with different vascular risks and across gender, age, and race. This has implications for future design of carotid ultrasound studies, as the angle of insonation is an important predictor of maximum CIMT.

Extensive or restricted ultrasound protocols to measure carotid intima-media thickness: analysis of completeness rates and impact on observed rates of change over time.

BACKGROUND: Ultrasound protocols to measure carotid intima-media thickness (CIMT) vary considerably with regard to carotid sites and angles that are assessed. Measurements from the carotid bifurcation and internal carotid artery are thought to be affected by large numbers of missing data. Actual published quantification of completeness rates and the relation with cardiovascular risk factors, however, is scarce. Also, it is currently unknown whether extensive ultrasound protocols including assessment of the carotid bifurcation and internal carotid artery add information in detecting rate of change in CIMT induced by drug therapy. These issues were addressed in this study using data from Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR). METHODS: In METEOR, carotid ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and twice after 24 months of study treatment. B-mode ultrasound images were obtained from the near and far walls of the left and right common carotid artery, bifurcation, and internal carotid artery at five predefined angles. Completeness of CIMT data was assessed by carotid site and by angle. A site was considered complete when any of the five angles was measured. The relation between completeness at baseline and cardiovascular risk factors was assessed using logistic regression analyses. Ultrasound protocols with a reduced number of carotid sites and angles were retrospectively constructed, and differences in the rate of change in maximum CIMT between ultrasound protocols were compared. RESULTS: At each visit, CIMT measurements from all 12 carotid sites were available for >94% of the participants. Incompleteness was the highest for near wall of the internal carotid artery and for the extreme angles (60° and 300°). Of 12 risk factors examined, higher body mass index was related to incompleteness. Ultrasound protocols with a reduced number of angles resulted in similar estimates for the differences in rate of change in maximum CIMT. However, reductions in the number of sites gave results in the same direction but with different magnitudes and larger standard errors. CONCLUSIONS: High levels of complete data can be obtained with extensive ultrasound protocols that include measurement from the carotid bifurcation and internal carotid artery. A high body mass index contributes to incompleteness of CIMT measurements. Extensive ultrasound protocols are required to obtain the highest precision to observe a treatment effect and to fully cover the degree of atherosclerotic burden.

Algorithms to measure carotid intima-media thickness in trials: a comparison of reproducibility, rate of progression and treatment effect.

BACKGROUND: Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials differ considerably. The best CIMT protocol would be one that combines high reproducibility, a large and precise estimate of the rate of CIMT progression and a large and precise estimate of the treatment effect. We performed a post-hoc analysis to determine the best algorithm for determining CIMT using data from the METEOR study, a randomized double-blind, placebo-controlled study of the effect of rosuvastatin on CIMT progression in 984 low coronary heart disease risk individuals with increased CIMT. METHODS: CIMT information was collected from two walls (near and far wall), three segments (common carotid, bifurcation and internal carotid artery), five different angles (for the right carotid artery - 60, 90, 120, 150, and 180 degrees on the Meijer's carotid arc; for the left - 300, 270, 240, 210, and 180 degrees) of two sides (left and right carotid artery), resulting in possibly (2 × 3 × 5 × 2 =) 60 measurements. On the basis of combinations of these measurements, we built 66 different ultrasound protocols to estimate a CIMT for each individual (22 protocols for mean common CIMT, 44 protocols for mean maximum CIMT). For each protocol we assessed reproducibility [intraclass correlation (ICC), mean difference of duplicate scans], 2-year progression rate in the placebo group with its corresponding standard error and treatment effect (difference in CIMT progression between rosuvastatin and placebo) and its corresponding standard error. RESULTS: Data of duplicate ultrasound examinations at baseline and end of study were available for 688 participants (70% of 984). The ICC based on duplicate baseline examinations ranged from 0.81 to 0.95. CIMT progression rates in the placebo group ranged from 0.0046 to 0.0177 mm/year, with SE ranging from 0.00134 to 0.00337. Treatment effects ranged from 0.0141 to 0.0388 mm/year. The protocols with highest reproducibility, highest CIMT progression/precision ratio and highest treatment effect/precision ratio were those measuring both near and far wall for at least two angles. CONCLUSION: Ultrasound protocols that include CIMT measurements at multiple angles of both near and far wall give the best balance between reproducibility, rate of CIMT progression, treatment effect and their associated precision in this low-risk population with subclinical atherosclerosis.

Effect of number of ultrasound examinations on the assessment of carotid intima-media thickness changes over time: the example of the METEOR study.

OBJECTIVE: To evaluate the effect of the number and positioning during follow-up of ultrasound examinations on the rate of change in carotid intima-media thickness (CIMT) using METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) as an example. METHODS: METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced progression of 2-year change in CIMT among low-risk patients with subclinical atherosclerosis. In the full METEOR protocol, ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and then twice at the end of study at 24 months. For the present study, 17 study designs were retrospectively constructed with varying number and position of ultrasound examinations during the study. Differences in the rate of change in maximum CIMT between these study designs were compared. RESULTS: Variations in frequency of ultrasound visits gave results in the same direction and magnitude for the change in maximum CIMT for both groups (i.e. nonsignificant change for rosuvastatin and significant progression for placebo, and a significant difference between treatments). However, standard errors were larger when the number of exams reduced. This finding was consistent over different lengths of follow-up, sample sizes, and with CIMT measurements made on different locations. CONCLUSION: Protocols with different number and timing of ultrasound examinations minimally affect the direction and magnitude of treatment effects on the rate of change in CIMT. However, reductions in exam frequency increase standard errors of rates of change, suggesting larger sample sizes would be required to have the same level of statistical power.

The use of plaque score measurements to assess changes in atherosclerotic plaque burden induced by lipid-lowering therapy over time: the METEOR study.

AIM: To evaluate whether plaque scoring measurements are able to track changes in atherosclerotic plaque burden over time and to study whether this is affected by lipid-lowering therapy. METHODS: Data used were from METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin), a randomized controlled trial of rosuvastatin 40 mg among 984 low-risk patients with modest carotid intima-media thickening (CIMT). In this analysis, duplicate ultrasound images from 12 carotid sites were collected at the baseline and end of the study from 495 European patients and were evaluated for plaque presence and severity. Plaques were scored from near and far walls of the 12 sites (0= none; 1= minimal; 2= moderate; 3= severe) and plaque scores (PS) were combined into two summary measures for each examination. The MeanMaxPS is the mean over the 12 carotid sites of the maximum score at each site and the MaxMaxPS reflects the most severe lesion at any site. RESULTS: Baseline MeanMaxPS and MaxMaxPS were 0.31 (SD: 0.20) and 1.15 (SD: 0.51), respectively. Changes in MeanMaxPS and MaxMaxPS significantly differed between rosuvastatin and placebo (mean difference: -0.03 [SE: 0.01; p =0.016] and -0.09 [SE: 0.04; p =0.027], respectively). In contrast to rosuvastatin, which demonstrated no change from the baseline, placebo showed significant progression in MeanMaxPS and MaxMaxPS (p =0.002; both). CONCLUSION: The plaque-scoring method proved capable of assessing the change in atherosclerotic plaque burden over time and proved useful to evaluate lipid-lowering in asymptomatic individuals with a low risk of cardiovascular disease and subclinical atherosclerosis.

Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER).

Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention.

Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database.

The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coefficient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.

Does baseline carotid intima-media thickness modify the effect of rosuvastatin when compared with placebo on carotid intima-media thickness progression? The METEOR study.

BACKGROUND: Many studies have used carotid intima-media thickness (CIMT) measurement to study atherosclerosis and the efficacy of interventions. The placebo-controlled Measuring Effects on intima-media Thickness: an Evaluation Of Rosuvastatin (METEOR) study showed significant reduction in the progression rate of maximum CIMT with 2 years of lipid treatment in asymptomatic individuals with subclinical atherosclerosis. DESIGN: The present post-hoc subgroup analysis of METEOR was carried out to determine whether the effect of rosuvastatin treatment varied according to baseline CIMT level. METHODS: To assess the relationship between efficacy of treatment with rosuvastatin versus placebo and baseline CIMT, we analyzed the effects on the primary CIMT endpoint in participants stratified by baseline quartiles of CIMT (Q1-Q4) using all individuals with a baseline reading and at least one post-baseline CIMT reading. Statistical analysis was carried out using a multilevel repeated-measures linear mixed effects model. RESULTS: In total, 876 participants were included in the analysis. In all quartiles, progression of mean maximum CIMT was significantly slower in rosuvastatin-treated individuals as compared with placebo controls. Although the magnitude of the treatment effect appeared larger in those with the highest baseline CIMT, statistical testing indicated that the magnitude of the treatment effect did not vary significantly with levels of baseline CIMT. CONCLUSION: This subgroup analysis of the METEOR study showed that in middle-aged adults with sub-clinical atherosclerosis, rosuvastatin treatment resulted in significant reduction in mean maximum CIMT progression in four quartiles of baseline CIMT, with no evidence for difference in benefit across levels of baseline CIMT.

Toxic epidermal necrolysis and neutropaenia: complications of omeprazole.

Worldwide, proton pump inhibitors (PPI) are one of the most frequently prescribed drugs; however, up to 70% of patients taking these drugs have no appropriate indication. Although PPI are relatively well tolerated, they are not free from side-effects and several life-threatening complications are associated with them. In the present report, a 43-year-old woman presented to her general practitioner with an erythematous rash over her face and chest, having been started on omeprazole for chronic abdominal bloating. Over the next 24 h she became increasingly unwell and was admitted to hospital with shortness of breath, pyrexia and the rash spreading over her back, arms and legs. Vesicles had now started to appear within the erythematous regions over her upper body and within 24 h the rash became confluent and desquamative, spreading to involve her entire body. A diagnosis of toxic epidermal necrolysis (TEN) was made. Despite supportive treatment within a critical care setting, she became neutropaenic and her skin loss became more extensive, resulting in 95% epidermal detachment. This case highlights that TEN is a life-threatening condition associated with a high incidence of morbidity and mortality. Optimal management requires early diagnosis and transfer to a specialized unit. Clinicians need to be aware that PPI are not free from side-effects and that their routine prescription should be strongly discouraged.

A primer on screening data management.

A drug discovery startup company or academic lab entering the screening arena faces numerous challenges as it tries to manage the large quantity of data generated by a typical drug discovery screening campaign. Although there are sophisticated off-the-shelf software solutions available, their use requires substantial forethought and attention to detail if the data they capture are to be of sufficient quality to serve the various purposes to which it will be put. For newcomers to the field of screening data management in particular, the problem is compounded by a lack of literature covering the practical aspects of managing screening data. The authors provide some practical advice based on their experience of using a commercially available software suite. They discuss issues ranging from the organizational aspects to examples of how the form and content of metadata can have a big impact on whether results can be easily queried, pivoted, and reported. It is also hoped that their experiences might provide an opportunity for reflection to data management practitioners operating in established environments.

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.

CONTEXT: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. OBJECTIVE: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. INTERVENTION: Participants received either a 40-mg dose of rosuvastatin or placebo. MAIN OUTCOME MEASURES: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. RESULTS: Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was -0.0014 (95% CI, -0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was -0.0038 (95% CI, -0.0064 to -0.0013) mm/y for the common carotid artery sites (P<.001), -0.0040 (95% CI, -0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, -0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, -0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). CONCLUSIONS: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225589