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of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evi-dence from randomized trials’, by K. Rahimi et al., doi:10.1093/eurheartj/ehs005 Statins are undoubtedly the mainstay in the treatment of hyperlip-idaemia.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

Impact of Baseline Echocardiography on Treatment Outcome in Primary Care Patients With Newly Detected Arterial Hypertension: A Randomized Trial

Background: The objective of this study was to test whether baseline echocardiography in newly detected hypertension improves left ventricular mass index and blood pressure control. This is a randomized trial with primary care patients. Methods: After routine clinical work-up 177 consecutive patients with newly detected hypertension were randomized according to result of their echocardiogram (echo group and control group). Treating physicians were encouraged to prescribe angiotensin II receptor antagonist therapy for patients with evidence of hypertensive target organ damage. Mean blood pressure (BP) and echocardiographic left ventricular mass index were measured at baseline and after 6 months of therapy in both groups. Results: More patients with hypertensive target organ damage were identified in the echo group as compared to the control group (58 of 91 [64%] v 42 of 86 [49%] patients (difference 15%, 95% CI 1%-29%). In the echo group, 41 patients (45%) received angiotensin II receptor antagonist therapy as compared to 27 patients (31%) in the control group (difference 14%, 95% CI 0-28%). After 6 months, there were no differences in mean left ventricular mass index, mean diastolic 24-h ambulatory BP monitoring, or mean systolic and diastolic office BP between the two groups. Conclusions: In patients with newly detected hypertension, baseline echocardiography detects more patients with hypertensive target organ damage, but does not lead to a reduction in left ventricular mass index or improved BP control after 6 months of therap

Testing the HTA Core Model: Experiences from two pilot projects

Objectives: The aim of this study was to analyze and describe process and outcomes of two pilot assessments based on the HTA Core Model, discuss the applicability of the model, and explore areas of development. Methods: Data were gathered from HTA Core Model and pilot Core HTA documents, their validation feedback, questionnaires to investigators, meeting minutes, emails, and discussions in the coordinating team meetings in the Finnish Office for Health Technology Assessment (FINOHTA). Results: The elementary structure of the HTA Core Model proved useful in preparing HTAs. Clear scoping and good coordination in timing and distribution of work would probably help improve applicability and avoid duplication of work. Conclusions: The HTA Core Model can be developed into a platform that enables and encourages true HTA collaboration in terms of distribution of work and maximum utilization of a common pool of structured HTA information for national HTA report

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

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

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

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