Statins: pleiotropic, but less than previously thought

This editorial refers to ‘Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evi-dence from randomized trials’, by K. Rahimi et al., doi:10.1093/eurheartj/ehs005 Statins are undoubtedly the mainstay in the treatment of hyperlip-idaemia. They are used in primary and secondary prevention of cardiovascular disease.1,2 It is therefore not surprising that statins rank very high among the most successful drugs in the history of medicine. For example, atorvastatin has raked in around US$130 billion for Pfizer during its 14 years on the market, making it cur-rently the world’s bestselling drug.3 Recent studies show that statins possess powerful pleiotropic effects that are independent of their effects on lipids and lipoproteins.4 The pleiotropic effects of statins are credite

A Systematic Review and Metaanalysis on the Effects of Garlic Preparations on Blood Pressure in Individuals With Hypertension

BACKGROUND Many patients prefer herbal medications to conventional drugs. Limited trial evidence suggests that garlic preparations reduce high blood pressure (BP). METHODS We searched electronic databases through March 2014 to identify all randomized controlled trials that compared a garlic preparation to placebo in hypertensive patients. Trials were required to report BP values at baseline and after a follow-up of at least 4 weeks. RESULTS Nine double-blind trials with 482 individuals fulfilled our inclusion criteria. Included trials were rather small, and the quality of the majority of included trials was moderate. Follow-up ranged from 8 to 26 weeks. All trials reported office BP measurements. Systolic BP and diastolic BP (SBP and DBP) were more effectively reduced in individuals treated with garlic preparations than in individuals treated with placebo. However, heterogeneity was high (weighted mean difference (WMD) for SBP was −9.1mm Hg; 95% confidence interval (CI), −12.7 to −5.4; P for heterogeneity = 0.0006; and I 2 = 71%; WMD for BP was −3.8mm Hg; 95% CI, −6.7 to −1.0; P for heterogeneity = 0.00001; I 2 = 80%). When analyses were restricted to higher-quality trials using intention-to-treat analysis or to trials with concealed treatment allocation and standardized and blinded BP measurement, effect sizes for SBP but not for DBP were lower and heterogeneity disappeared. CONCLUSIONS Although evidence from this review suggests that garlic preparations may lower BP in hypertensive individuals, the evidence is not strong. A well-conducted and powered trial of longer duration is needed to confirm these finding

Clinical outcomes of stents versus balloon angioplasty in non-acute coronary artery disease: A meta-analysis of randomized controlled trials

Aims To evaluate whether stents as compared to balloon angioplasty reduce mortality in patients with non-acute coronary artery disease. Methods and results We identified randomized controlled trials comparing stents to balloon angioplasty for the treatment of non-acute coronary artery disease by searching major medical databases from 1979 to March 2002. Two independent reviewers selected and extracted data from trials that had to report data on death and myocardial infarction. Nineteen trials, with a total of 8004 patients, fulfilled our inclusion criteria. For 1000 patients treated with stents rather than balloon angioplasty, 3 (95% CI 0-6), 5 (95% CI 0-9), and 6 (95% CI -1-12) additional lives were saved at 30 days, 6 and 12 months. At 12 months, for 1000 patients treated with stents rather than balloon angioplasty 46 (95% CI 25-66) additional target vessel revascularizations were avoided, but 25 (95% CI 15-34) additional bleeding complications with need for blood transfusion or surgical intervention occurred. In sensitivity analysis 11 (95% CI 2-20) and 2 (95% CI -4-7) deaths were avoided per 1000 patients treated with stents rather than PTCA in trials that routinely used compared to trials that did not use glycoprotein IIb/IIIa inhibitors. Conclusion In non-acute coronary disease stents may reduce overall mortality, but this benefit seems to be limited to stents used in conjunction with glycoprotein IIb/IIIa inhibitors. Stents compared to PTCA reduce target vessel revascularizations, but increase the risk of bleeding complication

Clinical Outcomes of Primary Stenting versus Balloon Angioplasty in Patients with Myocardial Infarction: A Meta-analysis of Randomized Controlled Trials

PURPOSE: To examine whether primary stenting as compared with primary balloon angioplasty reduces clinical outcomes in patients with myocardial infarction. METHODS: Major medical databases from 1979 to March 2002 were searched for randomized controlled trials that compared primary stenting with balloon angioplasty in patients with myocardial infarction. Two independent reviewers selected and extracted data from identified trials. The outcomes were mortality at 30 days, 6 months, and 12 months; recurrent events; and bleeding. RESULTS: Nine trials with a total of 4433 patients fulfilled the inclusion criteria. The odds ratios for mortality after stenting as compared with balloon angioplasty were 1.17 (95% confidence interval [CI]: 0.78 to 1.74) at 30 days, 1.07 (95% CI: 0.76 to 1.52) at 6 months, and 1.09 (95% CI: 0.80 to 1.50) at 12 months (P for heterogeneity Ͼ0.1 for each comparison). The odds ratios for reinfarction after stenting as compared with balloon angioplasty were 0.52 (95% CI: 0.31 to 0.87) at 30 days, 0.67 (95% CI: 0.45 to 1.00) at 6 months, and 0.67 (95% CI: 0.45 to 0.99) at 12 months; for target vessel revascularization, they were 0.46 (95% CI: 0.34 to 0.61) at 30 days, 0.42 (95% CI: 0.35 to 0.51) at 6 months, and 0.48 (95% CI: 0.39 to 0.59) at 12 months (P for heterogeneity Ͼ0.1 for all estimates with the exception of reinfarction at 12 months where P ϭ 0.08). The odds ratio for postinterventional bleeding complications after stenting as compared with balloon angioplasty was 1.34 (95% CI: 0.95 to 1.88; P for heterogeneity Ͼ0.1). CONCLUSION: Compared with balloon angioplasty, primary stenting is not associated with lower mortality, but is associated with a lower risk of reinfarction and target vessel revascularization. Am J Med. 2004;116:253-262. ©2004 by Excerpta Medica Inc. I n patients with myocardial infarction, balloon angioplasty reduces short-term death, nonfatal myocardial infarction, and stroke when compared with thrombolytic reperfusion (1). Still, the clinical efficacy of balloon angioplasty is limited by the development of late restenosis in up to 50% of patients, and by recurrent myocardial infarction in 3% to 5% of patients (2-5). Primary stenting may offer additional benefits. However, a recent meta-analysis of clinical trials found no difference in mortality and reinfarction rates among patients undergoing stenting or balloon angioplasty (6). We conducted a meta-analysis based on published and unpublished trial data to investigate whether primary stenting as compared with balloon angioplasty reduces mortality, recurrent events, and the risk of bleeding in patients with myocardial infarction. METHODS Data Search and Trial Selection We searched MEDLINE, EMBASE, Pascal, Index Medicus, the Cochrane Library, and abstracts from cardiology conferences from 1979 to March 2002 to identify all randomized controlled trials that compared primary stenting with balloon angioplasty in patients with myocardial infarction. We used the following search terms: angioplasty transluminal percutaneous coronary, stents, randomized controlled trials, clinical trials, coronary artery dilatation, transluminal coronary angioplasty, and random. We also searched all references of relevant articles for additional trials. If necessary, authors of identified trials were contacted for additional information

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions

Accuracy of drug advertisements in medical journals under new law regulating the marketing of pharmaceutical products in Switzerland

<p>Abstract</p> <p>Background</p> <p>New legal regulations for the marketing of pharmaceutical products were introduced in 2002 in Switzerland. We investigated whether claims in drug advertisements citing published scientific studies were justified by these studies after the introduction of these new regulations.</p> <p>Methods</p> <p>In this cross-sectional study, two independent reviewers screened all issues of six major Swiss medical journals published in the year 2005 to identify all drug advertisements for analgesic, gastrointestinal and psychopharmacologic drugs and evaluated all drug advertisements referring to at least one publication. The pharmaceutical claim was rated as being supported, being based on a potentially biased study or not to be supported by the cited study according to pre-specified criteria. We also explored factors likely to be associated with supported advertisement claims.</p> <p>Results</p> <p>Of 2068 advertisements 577 (28%) promoted analgesic, psychopharmacologic or gastrointestinal drugs. Among them were 323 (56%) advertisements citing at least one reference. After excluding multiple publications of the same drug advertisement and advertisements with non-informative references, there remained 29 unique advertisements with at least one reference to a scientific study. These 29 advertisements contained 78 distinct pairs of claims of analgesic, gastrointestinal and psychopharmacologic drugs and referenced studies. Thirty-seven (47%) claims were supported, 16 (21%) claims were not supported by the corresponding reference, and 25 (32%) claims were based on potentially biased evidence, with no relevant differences between drug groups. Studies with conflict of interest and studies stating industry funding were more likely to support the corresponding claim (RR 1.52, 95% CI 1.07–2.17 and RR 1.50, 95% CI 0.98–2.28) than studies without identified conflict of interest and studies without information on type of funding.</p> <p>Conclusion</p> <p>Following the introduction of new regulations for drug advertisement in Switzerland, 53% of all assessed pharmaceutical claims published in major medical journals are not supported by the cited referenced studies or based on potentially biased study information. In light of the discrepancy between the new legislation and the endorsement of these regulations, physicians should not trust drug advertisement claims even when they seem to refer to scientific studies.</p

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE)

OBJECTIVES Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist. DESIGN Repeated cross sectional study. SETTING Swiss, German and Canadian research ethics committees (RECs). PARTICIPANTS RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292). PRIMARY AND SECONDARY OUTCOME MEASURES The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship. CONCLUSIONS In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BACKGROUND We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research

Premature Discontinuation of Pediatric Randomized Controlled Trials : A Retrospective Cohort Study

Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.Peer reviewe

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi