Design Issues in Randomized Clinical Trials of Maintenance Therapies.

A potential therapeutic strategy for patients who respond (or have stable disease) on a fixed-duration induction therapy is to receive maintenance therapy, typically given for a prolonged period of time. To enable patients and clinicians to make informed treatment decisions, the designs of phase III randomized clinical trials (RCTs) assessing maintenance strategies need to be such that their results will provide clear assessment of the relevant risks and benefits of these strategies. We review the key aspects of maintenance RCT designs. Important design considerations include choice of first-line and second-line therapies, minimizing between-arm differences in follow-up schedules, and choice of the primary endpoint. In order to change clinical practice, RCTs should be designed to accurately isolate and quantify the clinical benefit of maintenance as compared with the standard approach of fixed-duration induction followed by the second-line treatment at progression. To accomplish this, RCTs need to utilize an overall survival (or quality of life) endpoint or, in settings where this is not feasible, endpoints that incorporate the effects of the subsequent line of therapy (eg, time from randomization to second progression or death). Toxicity and symptom information over both the study treatment (maintenance) and the second-line treatment should also be collected and reported.

Duration of Dual Antiplatelet Therapy After Coronary Stenting: A Review of the Evidence.

The duration of dual antiplatelet therapy (DAPT) after coronary stenting has been evaluated in randomized studies with apparently conflicting results. Although longer exposure associates with more bleeding complications, late stent thrombosis (ST) and myocardial infarction are reduced. In addition, as new drug-eluting stents carry a lower risk of ST compared with the first-generation drug-eluting stents and possibly even bare-metal stents, a shift toward better protection from ST may have an effect on the duration and intensity of DAPT. Whether the duration of DAPT should be shorter or longer than the currently recommended 6 to 12 months is analyzed in this review, drawing on lessons from the most recent studies.

Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association.

Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.

Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights From Randomized Controlled Trials.

RATIONALE: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.

Assessing the relative efficacy of new drugs: an emerging opportunity.

The increasing availability of individual-level data from clinical trials could allow the relative efficacy of new drugs to be assessed in a robust, cost-effective and timely way.

Long-Term Safety of Drug-Eluting and Bare-Metal Stents: Evidence From a Comprehensive Network Meta-Analysis.

BACKGROUND: Previous meta-analyses have investigated the relative safety and efficacy profiles of different types of drug-eluting stents (DES) and bare-metal stents (BMS); however, most prior trials in these meta-analyses reported follow-up to only 1 year, and as such, the relative long-term safety and efficacy of these devices are unknown. Many recent studies have now reported extended follow-up data. OBJECTIVES: This study sought to investigate the long-term safety and efficacy of durable polymer-based DES, bioabsorbable polymer-based biolimus-eluting stents (BES), and BMS by means of network meta-analysis. METHODS: Randomized controlled trials comparing DES to each other or to BMS were searched through MEDLINE, EMBASE, and Cochrane databases and proceedings of international meetings. Information on study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. RESULTS: Fifty-one trials that included a total of 52,158 randomized patients with follow-up duration ≥3 years were analyzed. At a median follow-up of 3.8 years, cobalt-chromium everolimus-eluting stents (EES) were associated with lower rates of mortality, definite stent thrombosis (ST), and myocardial infarction than BMS, paclitaxel-eluting stents (PES), and sirolimus-eluting stents (SES) and less ST than BES. Phosphorylcholine-based zotarolimus-eluting stents had lower rates of definite ST than SES and lower rates of myocardial infarction than BMS and PES. The late rates of target-vessel revascularization were reduced with all DES compared with BMS, with cobalt-chromium EES, platinum chromium-EES, SES, and BES also having lower target-vessel revascularization rates than PES. CONCLUSIONS: After a median follow-up of 3.8 years, all DES demonstrated superior efficacy compared with BMS. Among DES, second-generation devices have substantially improved long-term safety and efficacy outcomes compared with first-generation devices.

Rapid response systems: a systematic review and meta-analysis.

INTRODUCTION: Although rapid response system teams have been widely adopted by many health systems, their effectiveness in reducing hospital mortality is uncertain. We conducted a meta-analysis to examine the impact of rapid response teams on hospital mortality and cardiopulmonary arrest. METHOD: We conducted a systematic review of studies published from January 1, 1990, through 31 December 2013, using PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and the Cochrane Library. We included studies that reported data on the primary outcomes of ICU and in-hospital mortality or cardiopulmonary arrests. RESULTS: Twenty-nine eligible studies were identified. The studies were analysed in groups based on adult and paediatric trials that were further sub-grouped on methodological design. There were 5 studies that were considered either cluster randomized control trial, controlled before after or interrupted time series. The remaining studies were before and after studies without a contemporaneous control. The implementation of RRS has been associated with an overall reduction in hospital mortality in both the adult (RR 0.87, 95 % CI 0.81-0.95, p<0.001) and paediatric (RR=0.82 95 % CI 0.76-0.89) in-patient population. There was substantial heterogeneity in both populations. The rapid response system team was also associated with a reduction in cardiopulmonary arrests in adults (RR 0.65, 95 % CI 0.61-0.70, p<0.001) and paediatric (RR=0.64 95 % CI 0.55-0.74) patients. CONCLUSION: Rapid response systems were associated with a reduction in hospital mortality and cardiopulmonary arrest. Meta-regression did not identify the presence of a physician in the rapid response system to be significantly associated with a mortality reduction.

Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis.

BACKGROUND AND PURPOSE: Elevated blood pressure is common in acute stage of ischemic stroke and the strategy to manage this situation is not well established. We therefore conducted a meta-analysis of randomized controlled trials comparing active blood pressure lowering and control groups in early ischemic stroke. METHODS: Pubmed, EMBASE, and Clinicaltrials.gov from January 1966 to March 2015 were searched to identify relevant studies. We included randomized controlled trials with blood pressure lowering started versus control within 3 days of ischemic stroke onset. The primary outcome was unfavorable outcome at 3 months or at trial end point, defined as dependency or death, and the key secondary outcome was recurrent vascular events. Pooled relative risks and 95% confidence intervals were calculated using random-effects model. RESULTS: The systematic search identified 13 randomized controlled trials with 12 703 participants comparing early blood pressure lowering and control. Pooling the results with the random-effects model showed that blood pressure lowering in early ischemic stroke did not affect the risk of death or dependency at 3 months or at trial end point (relative risk, 1.04; 95% confidence interval, 0.96-1.13; P=0.35). Also, blood pressure lowering also had neutral effect on recurrent vascular events, as well as on disability or death, all-cause mortality, recurrent stroke, and serious adverse events. CONCLUSIONS: This meta-analysis suggested blood pressure lowering in early ischemic stroke had a neutral effect on the prevention of death or dependency.

Best (but oft-forgotten) practices: designing, analyzing, and reporting cluster randomized controlled trials.

Cluster randomized controlled trials (cRCTs; also known as group randomized trials and community-randomized trials) are multilevel experiments in which units that are randomly assigned to experimental conditions are sets of grouped individuals, whereas outcomes are recorded at the individual level. In human cRCTs, clusters that are randomly assigned are typically families, classrooms, schools, worksites, or counties. With growing interest in community-based, public health, and policy interventions to reduce obesity or improve nutrition, the use of cRCTs has increased. Errors in the design, analysis, and interpretation of cRCTs are unfortunately all too common. This situation seems to stem in part from investigator confusion about how the unit of randomization affects causal inferences and the statistical procedures required for the valid estimation and testing of effects. In this article, we provide a brief introduction and overview of the importance of cRCTs and highlight and explain important considerations for the design, analysis, and reporting of cRCTs by using published examples.

Evolving therapies for myocardial ischemia/reperfusion injury.

The damage inflicted on the myocardium during acute myocardial infarction is the result of 2 processes: ischemia and subsequent reperfusion (ischemia/reperfusion injury). During the last 3 decades, therapies to reduce ischemic injury (mainly reperfusion strategies) have been widely incorporated into clinical practice. The remarkable reduction in death rates achieved with these therapies has resulted in a shift in emphasis from efforts to reduce mortality to a focus on tackling the downstream consequence of survival: post-infarction heart failure. Infarct size is the main determinant of long-term mortality and chronic heart failure, and thus, the possibility of limiting the extent of necrosis during an ST-segment elevation myocardial infarction is of great individual and socioeconomic value. After the great success of therapies to reduce ischemic injury, the time has come to focus efforts on therapies to reduce reperfusion injury, but in the recent few years, few interventions have successfully passed the proof-of-concept stage. In this review, we examine the past, present, and future therapies to reduce ischemia/reperfusion injury.