Everolimus-eluting bioresorbable stent vs. durable polymer everolimus-eluting metallic stent in patients with ST-segment elevation myocardial infarction: results of the randomized ABSORB ST-segment elevation myocardial infarction-TROFI II trial.

AIMS Patients with ST-segment elevation myocardial infarction (STEMI) feature thrombus-rich lesions with large necrotic core, which are usually associated with delayed arterial healing and impaired stent-related outcomes. The use of bioresorbable vascular scaffolds (Absorb) has the potential to overcome these limitations owing to restoration of native vessel lumen and physiology at long term. The purpose of this randomized trial was to compare the arterial healing response at short term, as a surrogate for safety and efficacy, between the Absorb and the metallic everolimus-eluting stent (EES) in patients with STEMI. METHODS AND RESULTS ABSORB-STEMI TROFI II was a multicentre, single-blind, non-inferiority, randomized controlled trial. Patients with STEMI who underwent primary percutaneous coronary intervention were randomly allocated 1:1 to treatment with the Absorb or EES. The primary endpoint was the 6-month optical frequency domain imaging healing score (HS) based on the presence of uncovered and/or malapposed stent struts and intraluminal filling defects. Main secondary endpoint included the device-oriented composite endpoint (DOCE) according to the Academic Research Consortium definition. Between 06 January 2014 and 21 September 2014, 191 patients (Absorb [n = 95] or EES [n = 96]; mean age 58.6 years old; 17.8% females) were enrolled at eight centres. At 6 months, HS was lower in the Absorb arm when compared with EES arm [1.74 (2.39) vs. 2.80 (4.44); difference (90% CI) -1.06 (-1.96, -0.16); Pnon-inferiority <0.001]. Device-oriented composite endpoint was also comparably low between groups (1.1% Absorb vs. 0% EES). One case of definite subacute stent thrombosis occurred in the Absorb arm (1.1% vs. 0% EES; P = ns). CONCLUSION Stenting of culprit lesions with Absorb in the setting of STEMI resulted in a nearly complete arterial healing which was comparable with that of metallic EES at 6 months. These findings provide the basis for further exploration in clinically oriented outcome trials.

Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.

BACKGROUND Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. METHODS AND RESULTS Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively. CONCLUSIONS In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.

Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial

IMPORTANCE Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond 1 year provides ischemic event protection after DES, ischemic event risk is perceived to be less after BMS, and the appropriate duration of DAPT after BMS is unknown. OBJECTIVE To compare (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs 12 months of thienopyridine in patients treated with BMS taking aspirin and (2) treatment duration effect within the combined cohorts of randomized patients treated with DES or BMS as prespecified secondary analyses. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, randomized, double-blinded, placebo-controlled trial comparing extended (30-months) thienopyridine vs placebo in patients taking aspirin who completed 12 months of DAPT without bleeding or ischemic events after receiving stents. The study was initiated in August 2009 with the last follow-up visit in May 2014. INTERVENTIONS Continued thienopyridine or placebo at months 12 through 30 after stent placement, in 11,648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES. MAIN OUTCOMES AND MEASURES Stent thrombosis, MACCE, and moderate or severe bleeding. RESULTS Among 1687 patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5% vs 1.11% (n = 4 vs 9; hazard ratio [HR], 0.49; 95% CI, 0.15-1.64; P = .24), rates of MACCE were 4.04% vs 4.69% (n = 33 vs 38; HR, 0.92; 95% CI, 0.57-1.47; P = .72), and rates of moderate/severe bleeding were 2.03% vs 0.90% (n = 16 vs 7; P = .07), respectively. Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41% vs 1.32% (n = 23 vs 74; HR, 0.31; 95% CI, 0.19-0.50; P < .001), rates of MACCE were 4.29% vs 5.74% (n = 244 vs 323; HR, 0.73; 95% CI, 0.62-0.87; P < .001), and rates of moderate/severe bleeding were 2.45% vs 1.47% (n = 135 vs 80; P < .001). CONCLUSIONS AND RELEVANCE Among patients undergoing coronary stent placement with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938.

A randomised controlled trial: can acupuncture reduce drug requirement during analgosedation with propofol and alfentanil for colonoscopy? A study protocol.

BACKGROUND The number of colonoscopies tremendously increased in recent years and will further rise in the near future. Because of patients' growing expectation on comfort during medical procedures, it is not surprising that the demand for sedation also expands. Propofol in combination with alfentanil is known to provide excellent analgosedation, however, its use is associated with respiratory and cardiovascular depression. Acupuncture could be a technique to reduce drug requirement while providing the same level of sedation and analgesia. METHODS/DESIGN The study will be performed as a single centre, randomised, placebo controlled trial. 153 patients scheduled for propofol/alfentanil sedation during colonoscopy will be randomly assigned to receive electroacupuncture (P6, ST36, LI4), sham acupuncture, or placebo acupuncture. Following endoscopy patients and gastroenterologists have to fill in questionnaires about their sedation experiences. Additionally, patients have to accomplish the Trieger test before and after the procedure. Patient monitoring includes time adapted HR, SpO2, ECG, NIBP, exCO2, OAA/S, and the Aldrete score. The primary outcome parameter is the dosage of propofol necessary for an adequate level of sedation to tolerate the procedure (OAA/S < 4). Effectiveness of sedation, classified by satisfaction levels measured by questionnaires is the secondary outcome parameter. DISCUSSION Moderate to deep sedation using propofol is increasingly applied during colonoscopies with a high satisfaction level among patients despite well-known hemodynamic and respiratory side effects of this hypnotic agent. Acupuncture is known to attenuate gastrointestinal discomfort and pain. We hypothesize that the combination of conventional sedation techniques with acupuncture may result in equally satisfied patients with a lower risk of respiratory and hemodynamic events during colonoscopies. TRIAL REGISTRATION This trial is registered in the Nederland's Trial Register NTR 4325 . The first patient was randomized on 13 February 2014.

Continuous safety screens for randomized controlled clinical trials with blinded treatment information

Standard methods for testing safety data are needed to ensure the safe conduct of clinical trials. In particular, objective rules for reliably identifying unsafe treatments need to be put into place to help protect patients from unnecessary harm. DMCs are uniquely qualified to evaluate accumulating unblinded data and make recommendations about the continuing safe conduct of a trial. However, it is the trial leadership who must make the tough ethical decision about stopping a trial, and they could benefit from objective statistical rules that help them judge the strength of evidence contained in the blinded data. We design early stopping rules for harm that act as continuous safety screens for randomized controlled clinical trials with blinded treatment information, which could be used by anyone, including trial investigators (and trial leadership). A Bayesian framework, with emphasis on the likelihood function, is used to allow for continuous monitoring without adjusting for multiple comparisons. Close collaboration between the statistician and the clinical investigators will be needed in order to design safety screens with good operating characteristics. Though the math underlying this procedure may be computationally intensive, implementation of the statistical rules will be easy and the continuous screening provided will give suitably early warning when real problems were to emerge. Trial investigators and trial leadership need these safety screens to help them to effectively monitor the ongoing safe conduct of clinical trials with blinded data.^

A relaxation technique enhances psychological well-being and immune parameters in elderly people from a nursing home: A randomized controlled study

Background: The aging process involves a decline in immune functioning that renders elderly people more vulnerable to disease. In residential programs for the aged, it is vital to diminish their risk of disease, promote their independence, and augment their psychological well-being and quality of life. Methods: We performed a randomized controlled study, evaluating the ability of a relaxation technique based on Benson’s relaxation response to enhance psychological well-being and modulate the immune parameters of elderly people living in a geriatric residence when compared to a waitlist control group. The study included a 2-week intervention period and a 3-month follow-up period. The main outcome variables were psychological well-being and quality of life, biomedical variables, immune changes from the pre-treatment to post-treatment and follow-up periods. Results: Our findings reveal significant differences between the experimental and control groups in CD19, CD71, CD97, CD134, and CD137 lymphocyte subpopulations at the end of treatment. Furthermore, there was a decrease in negative affect, psychological discomfort, and symptom perception in the treatment group, which increased participants’ quality of life scores at the three-month follow-up. Conclusions: This study represents a first approach to the application of a passive relaxation technique in residential programs for the elderly. The method appears to be effective in enhancing psychological well-being and modulating immune activity in a group of elderly people. This relaxation technique could be considered an option for achieving health benefits with a low cost for residential programs, but further studies using this technique in larger samples of older people are needed to confirm the trends observed in the present study. Trial registration: International Standard Randomised Controlled Trial Number Register ISRCTN85410212.

A randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants

OBJECTIVE: Acute bronchiolitis is a common disorder of infants that often results in hospitalization. Apart from supportive care, no therapy has been shown to influence the course of the disease, except for a possible effect of nebulized hypertonic saline (HS). To determine whether this does have beneficial effects on length of stay in hospital or on severity scores, we undertook a double-blind, randomized, controlled trial in a pediatric department of a Portuguese hospital. METHODS: Previously healthy infants, younger than 12 months, hospitalized with mild-to-moderate acute viral bronchiolitis were randomized to receive either nebulized 3% (hypertonic, HS) or 0.9% (normal, NS) saline during their entire hospital stay. Primary endpoints were: length of hospital stay and severity scores on each day of hospitalization. Need for supplemental oxygen, further add-on medications and adverse effects were also analyzed. RESULTS: Sixty-eight patients completed the study (HS: 33; NS: 35). The median length of hospital stay did not differ between groups: HS: 5.6 ± 2.3 days; NS: 5.4 ± 2.1 days (P = 0.747). We found no difference between groups in severity scores from day 1 to day 4. There were no differences in need for supplemental oxygen or add-on medications. Patients in HS group had significantly more cough (46% vs. 20%, P = 0.025) and rhinorrhoe (58% vs. 31%, P = 0.30). CONCLUSION: This study does not support the use of nebulized HS over NS in therapy of hospitalized children with mild-to-moderate acute viral bronchiolitis

Efficacy of an Internet-based, individually tailored smoking cessation program: A randomized trial

Introduction: Self-help computer-based programs are easily accessible and cost-effective interventions with a great recruitment potential. However, each program is different and results of meta-analyses may not apply to each new program; therefore, evaluations of new programs are warranted. The aim of this study was to assess the marginal efficacy of a computer-based, individually tailored program (the Coach) over and above the use of a comprehensive Internet smoking cessation website. Methods: A two-group randomized controlled trial was conducted. The control group only accessed the website, whereas the intervention group received the Coach in addition. Follow-up was conducted by e-mail after three and six months (self-administrated questionnaires). Of 1120 participants, 579 (51.7%) responded after three months and 436 (38.9%) after six months. The primary outcome was self-reported smoking abstinence over four weeks. Results: Counting dropouts as smokers, there were no statistically significant differences between intervention and control groups in smoking cessation rates after three months (20.2% vs. 17.5%, p¼0.25, odds ratio (OR)¼1.20) and six months (17% vs. 15.5%, p¼0.52, OR¼1.12). Excluding dropouts from the analysis, there were statistically significant differences after three months (42% vs. 31.6%, p¼0.01, OR¼1.57), but not after six months (46.1% vs. 37.8%, p¼0.081, OR¼1.41). The program also significantly increased motivation to quit after three months and self-efficacy after three and six months. Discussion: An individually tailored program delivered via the Internet and by e-mail in addition to a smoking cessation website did not significantly increase smoking cessation rates, but it increased motivation to quit and self-efficacy.

Quality assurance experience with the randomized neuropathic bone pain trial (Trans-Tasman Radiation Oncology Group, 96.05)

Background and purpose: Trans-Tasman Radiation Oncology Group 96.05 is a prospective randomized controlled trial comparing a single 8 Gy with 20 Gy in five fractions of radiotherapy (RT) for neuropathic pain due to bone metastases. This paper summarizes the quality assurance (QA) activities for the first 234 patients (accrual target 270). Materials and methods: Independent audits to assess compliance with eligibility/exclusion criteria and appropriateness of treatment of the index site were conducted after each cohort of approximately 45 consecutive patients. Reported serious adverse events (SAEs) in the form of cord/cauda equina compression or pathological fracture developing at the index site were investigated and presented in batches to the Independent Data Monitoring Committee. Finally, source data verification of the RT prescription page and treatment records was undertaken for each of the first 234 patients to assess compliance with the protocol. Results: Only one patient was found conclusively not to have genuine neuropathic pain, and there were no detected 'geographical misses' with RT fields. The overall rate of detected infringements for other eligibility criteria over five audits (225 patients) was 8% with a dramatic improvement after the first audit. There has at no stage been a statistically significant difference in SAEs by randomization arm. There was a 22% rate of RT protocol variations involving ten of the 14 contributing centres, although the rate of major dose violations (more than +/- 10% from protocol dose) was only 6% with no statistically significant difference by randomization arm (P = 0.44). Conclusions: QA auditing is an essential but time-consuming component of RT trials, including those assessing palliative endpoints. Our experience confirms that all aspects should commence soon after study activation. Crown Copyright (C) 2003 Published by Elsevier Science Ltd. All rights reserved.

Prolotherapy injections, saline injections, and exercises for chronic low-back pain: A randomized trial

Objectives. To assess the efficacy of a prolotherapy injection and exercise protocol in the treatment of chronic nonspecific low back pain. Design. Randomized controlled trial with two- by- two factorial design, triple- blinded for injection status, and single- blinded for exercise status. Setting. General practice. Participants. One hundred ten participants with nonspecific low- back pain of average 14 years duration were randomized to have repeated prolotherapy ( 20% glucose/ 0.2% lignocaine) or normal saline injections into tender lumbo- pelvic ligaments and randomized to perform either flexion/ extension exercises or normal activity over 6 months. Main outcome measures: Pain intensity ( VAS) and disability scores ( Roland- Morris) at 2.5, 4, 6, 12, and 24 months. Results. Follow- up was achieved in 96% at 12 months and 80% at 2 years. Ligament injections, with exercises and with normal activity, resulted in significant and sustained reductions in pain and disability throughout the trial, but no attributable effect was found for prolotherapy injections over saline injections or for exercises over normal activity. At 12 months, the proportions achieving more than 50% reduction in pain from baseline by injection group were glucose- lignocaine: 0.46 versus saline: 0.36. By activity group these proportions were exercise: 0.41 versus normal activity: 0.39. Corresponding proportions for > 50% reduction in disability were glucose- lignocaine: 0.42 versus saline 0.36 and exercise: 0.36 versus normal activity: 0.38. There were no between group differences in any of the above measures. Conclusions. In chronic nonspecific low- back pain, significant and sustained reductions in pain and disability occur with ligament injections, irrespective of the solution injected or the concurrent use of exercises.

Controlled trial of hyperbaric oxygen treatment for alkali corneal burn in the rabbit

Purpose: To evaluate the efficacy of hyperbaric oxygen therapy in the treatment of alkali-induced corneal burns in an animal model. Methods: Twenty-four rabbits were randomized into a control group (n = 12) and hyperbaric oxygen treatment group (n = 12). After induction of anaesthesia, the alkali burn model was established by application of 1 N sodium hydroxide to one eye of each rabbit. The hyperbaric oxygen treatment group was treated each day for 21 days with hyperbaric oxygen at 2.4 Atmospheres Absolute (ATA) for 1 h. The eyes of the animals were examined daily for 2 weeks and then weekly until the end of the trial. The principal endpoint was that of perforation of the cornea at which time the animals were killed with a lethal dose of either intravenous or intraperitoneal barbiturate and the eyes immediately enucleated and fixed in 10% neutral buffered formalin. All animals in which complete healing took placed were also killed, the eyes removed, fixed and examined histologically. Photographs were taken of the rabbit's eyes at weekly intervals and the area of vascularization and epithelial defects in the hyperbaric and control groups were compared. Results: Equal numbers (seven) of the control and hyperbaric oxygen treated groups had perforated corneas and there was no statistical difference in the mean time to perforation (control 30.1 days; treated 30 days). There was also no statistical difference between the two groups with respect to epithelial defect size. Conclusion: Treatment with hyperbaric oxygen for 1 h daily for 21 days had no beneficial effect on alkali-induced corneal burns.

The Randomized Nitric Oxide Tocolysis Trial (RNOTT) for the treatment of preterm labor

Objective: This study was undertaken to assess the effectiveness of glyceryl trinitrate (GTN) patches in comparison with beta2 sympathornimetics (beta2) for the treatment of preterm labor. Study design: A multicenter, multinational, randomized controlled trial was conducted in tertiary referral teaching hospitals. Women in threatened preterm labor with positive fetal fibronectin or ruptured membranes between 24 and 35 weeks' gestation were recruited and randomly assigned to either beta2 or GTN with rescue beta2 tocolysis if moderate-to-strong contractions persisted at 2 hours. Obstetric and neonatal outcomes were assessed. Results: Two hundred thity-eight women were recruited and randomly assigned, 117 to beta2 and 121 to GTN. On a strict intention-to-treat basis, there was no significant difference in the time to delivery using Kaplan-Meier curves (P = .451). At 2 hours, 27% of women receiving beta2 had moderate or stronger contractions compared with 53% in the GTN group (P < .001). This led to 35% of women in the GTN group receiving rescue treatment. If delivery or requirement for beta2 rescue are regarded as treatment failure, then a significant difference was observed between the 2 arms (P = .0032). There were no significant differences in neonatal outcomes. Conclusion: GTN is a less efficacious tocolytic compared with beta2 sympathomimetics. (C) 2004 Elsevier Inc. All rights reserved.

Lithium for schizophrenia revisited: A systematic review and meta-analysis of randomized controlled trials

Background: Clinicians frequently use lithium to augment antipsychotic medication in schizophrenia. Therefore, we undertook a systematic review and meta-analysis of the use of lithium in the treatment of schizophrenia. Data sources and study selection: Randomized controlled trials examining lithium (as a sole or an adjunctive compound) in participants with schizophrenia or related disorders were searched in the register of the Cochrane Schizophrenia Group. No language restrictions were applied. The Boolean phrase [lithium* or lithicarb or eskalith or lithobid or lithane or cibalith-s or quilonum or hypnorex] was used to locate articles. The search strategy initially identified 90 references. The authors of the included studies were contacted to obtain original patient data. The data were combined in a meta-analysis. The main outcome parameters were the number of patients with a clinically significant response and the number of patients leaving the studies early. Results: The meta-analysis includes 20 studies (N = 611). The evidence shows that lithium as a sole agent is ineffective in the treatment of schizophrenia. Eleven trials examined the augmentation of antipsychotics with lithium. More patients who received lithium augmentation than those who received antipsychotics alone were classified as responders. However, the superiority was not consistent across different response thresholds, and when patients with prominent affective symptoms were excluded from the analysis, the advantage of lithium augmentation was not significant (p = .07). Significantly more patients taking lithium left the trials early, suggesting a lower acceptability of lithium augmentation compared with that of taking antipsychotics alone. Conclusion: Despite some evidence in favor of lithium augmentation, the overall results are inconclusive. A large trial of lithium augmentation of antipsychotic medications will be required in order to detect a benefit of small effect size in patients with schizophrenia who lack affective symptoms.