A Randomized Controlled Trial of β-Blockers Versus Endoscopic Band Ligation for Primary Prophylaxis: A Large Sample Size is Required to Show a Difference in Bleeding Rates

Primary prophylaxis with nonselective -blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective -blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, 12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 ± 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or -blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 ± 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and -blocker therapy.     

Clinical Outcomes with β-Blockers for Myocardial Infarction: A Meta-analysis of Randomized Trials

BackgroundDebate exists about the efficacy of β-blockers in myocardial infarction and their required duration of usage in contemporary practice.MethodsWe conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating β-blockers in myocardial infarction enrolling at least 100 patients. The primary outcome was all-cause mortality. Analysis was performed stratifying trials into reperfusion-era (> 50% undergoing reperfusion or receiving aspirin/statin) or pre-reperfusion-era trials.ResultsSixty trials with 102,003 patients satisfied the inclusion criteria. In the acute myocardial infarction trials, a significant interaction (P_interaction = .02) was noted such that β-blockers reduced mortality in the pre-reperfusion (incident rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.79-0.94) but not in the reperfusion era (IRR 0.98; 95% CI, 0.92-1.05). In the pre-reperfusion era, β-blockers reduced cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.97), and angina (IRR 0.88; 95% CI, 0.82-0.95), with no difference for other outcomes. In the reperfusion era, β-blockers reduced myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] = 209) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB = 26) at the expense of increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) (number needed to treat to harm [NNTH] = 79), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH = 90), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73), with no benefit for other outcomes. Benefits for recurrent myocardial infarction and angina in the reperfusion era appeared to be short term (30 days).ConclusionsIn contemporary practice of treatment of myocardial infarction, β-blockers have no mortality benefit but reduce recurrent myocardial infarction and angina (short-term) at the expense of increase in heart failure, cardiogenic shock, and drug discontinuation. The guideline authors should reconsider the strength of recommendations for β-blockers post myocardial infarction.     

Comparative Effects of Different Doses of Ribavirin Plus Interferon-α2b for Therapy of Chronic Hepatitis C: Results of a Controlled, Randomized Trial

Compared to either drug alone, therapy with the combination of ribavirin and interferon- leads to improved rates of response in patients with chronic hepatitis C. Side effects often mandate downward dose adjustment or cessation of therapy, and the optimal dose of ribavirin has not been established. The aim of this study was to learn whether 600 mg ribavirin per day would prove as efficacious as 1000–1200 mg/day when combined with interferon (3 million units thrice weekly) for therapy of patients previously treated with standard interferon who had failed to respond or who had relapsed. We enrolled 69 patients with chronic hepatitis C and compensated liver disease: 45 were men, 65 were Caucasian, 48 were infected with genotype 1 hepatitis C virus. By random assignment, 35 received 600 mg ribavirin/day (group A), whereas the other 34 received 1000 mg (75 kg body wt) or 1200 mg/day (>75 kg body wt) (group B). At baseline, the two groups were well matched for demographic and laboratory features. In both groups, mean serum levels of alanine aminotransferase (ALT) and hepatitis C viral (HCV) RNA levels fell promptly and remained significantly lower than baseline throughout 24 weeks of therapy. There was no significant difference in mean levels of ALT or HCV RNA during therapy or at the end of follow-up (24 weeks after cessation of therapy). At the end of 24 weeks of posttherapy follow-up, 12 patients in each group had undetectable HCV RNA in serum, whereas 11 (31%) in group A and 9 (26.5%) in group B had normal serum ALT levels. The lower doses of ribavirin (group A) were tolerated better. %In conclusion, in previous nonresponders or relapsers to interferon done, combination therapy with interferon-_2b (3 MU thrice weekly) + 600 mg ribavirin/day is tolerated better and is as effective as interferon plus higher (standard) doses of ribavirin (1000–1200 mg/day).     

Assessment of Target Organ Damage in the Evaluation and Follow‐Up of Hypertensive Patients: Where Do We Stand?

Hypertension is associated with damage to the heart, kidneys, and vascular tree. Assessment of target organ damage (TOD) allows better prediction of cardiovascular risk than conventional risk assessment. Regression of TOD during antihypertensive treatment, which depends on the blood pressure (BP) reduction and the specific ancillary properties of each drug, may indirectly indicate that BP is well controlled. It is unclear whether regression of TOD during treatment is associated with favorable outcome and should be used as a surrogate endpoint. There is evidence that regression of left ventricular hypertrophy and albuminuria are associated with a favorable outcome. However, recent studies cast doubts on this evidence. Thus, assessment of TOD is important to define cardiovascular risk, but, so far, regression of TOD cannot be regarded as a major surrogate therapeutic target. The present paper will provide a critical overview of the data available in the literature.     

Comparing Cardiac Magnetic Resonance–Guided Versus Angiography-Guided Treatment of Patients With Stable Coronary Artery Disease: Results From a Prospective Randomized Controlled Trial

Objectives

The purpose of this study was the prospective and randomized evaluation of cardiovascular endpoints and quality of life in patients with stable coronary artery disease comparing a cardiac magnetic resonance (CMR)–based management strategy with a coronary angiography–based approach.

Study Design and Rationale of “A Multicenter,Open-Labeled,Randomized Controlled Trial Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema”: MIMO Trial

Purpose

Morphine has been used for several decades in cases of acute pulmonary edema (APE) due to the anxiolytic and vasodilatory properties of the drug. The non-specific depression of the central nervous system is probably the most significant factor for the changes in hemodynamics in APE. Retrospective studies have shown both negative and neutral effects in patients with APE and therefore some authors have suggested benzodiazepines as an alternative treatment. The use of intravenous morphine in the treatment of APE remains controversial.

Methods

The MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE. The MIMO trial will evaluate as a primary endpoint whether intravenous morphine administration improves clinical outcomes defined as in-hospital mortality. Secondary endpoint evaluation will be mechanical ventilation, cardiopulmonary resuscitation, intensive care unit admission rate, intensive care unit length of stay, and hospitalization length.

Conclusions

In the emergency department, morphine is still used for APE in spite of poor scientific background data. The data from the MIMO trial will establish the effect—and especially the risk—when using morphine for APE.

     

Results of a Randomized Controlled Trial of a Peer Mentor HIV/STI Prevention Intervention for Women Over an 18 Month Follow-Up

Despite numerous behavioral interventions designed for women, rates of HIV and STIs are increasing. Interventions are needed that reach a large number of at-risk individuals. This study was a randomized clinical trial of a HIV/STI behavioral intervention conducted in Baltimore, MD, USA. Heterosexual women (n = 169) completed a baseline and three semiannual follow-up visits. Participants were randomized into a standard of care comparison condition or a Peer Mentor condition. At the 6-month follow-up, Peer Mentors were less likely to have multiple sex partners [AOR: 0.28 (95% CI: 0.13, 0.63)]. At the 18 month follow-up assessment, Peer Mentors increased their condom use during vaginal [AOR: 0.47 (95% CI: 0.25, 0.87)] and anal sex [AOR: 0.24 (95% CI: 0.09, 0.68)] as well as with main [AOR: 0.41 (95% CI: 0.21, 0.77)] and non-main partners [AOR: 0.33 (95% CI: 0.14, 0.79)]. Peer education is a sustainable approach to change risky sexual behaviors.     

OPPORTUNITY?: A Randomized Clinical Trial of Growth Hormone on Outcome in Hemodialysis Patients

Background: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY™ Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients.Hypothesis: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile.Design/Measurements: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 μg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V ≥1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy.Conclusions: The OPPORTUNITY™ Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.Adult end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (MHD) experience high mortality and morbidity with diminished quality of life (1,2). Death and hospitalization rates in MHD patients correlate strongly with indicators of low protein mass, as indicated by low serum albumin and decreased fat-free, edema-free body mass (i.e., lean body mass [LBM]), as well as chronic inflammation (3,4). This is an important association because protein-energy wasting (PEW) occurs in approximately 40% of MHD patients (5). The possibility that improved measures of PEW may lead to decreased mortality or morbidity was recently underscored by several cross-sectional and longitudinal evaluations of cohorts containing up to 58,000 MHD patients who were followed for up to 2 yr. These studies showed that both higher serum albumin and body weight and an increase in these measures are strongly associated with greater survival (6,7). However, there are no prospective, randomized, clinical trials (RCTs) that have confirmed or even assessed whether a pharmacologic intervention that improves indicators of PEW prolongs survival and/or reduces morbidity, including hospitalization, in MHD patients. Thus, major unmet medical needs and important questions exist concerning whether PEW causes mortality and morbidity in MHD patients and whether a treatment that reduces PEW will reduce their high mortality and morbidity.Growth hormone (GH) has extensive metabolic and, in particular, protein anabolic effects (8), a number of which have also been demonstrated in MHD or chronic peritoneal dialysis patients (9–23). Most of these studies were performed on small numbers of patients. A recent phase 2 RCT involving 139 MHD patients indicated that the GH-treated patients underwent improvement in LBM, serum transferrin, exercise capacity, and a tendency (P = 0.076) for serum albumin to rise (9). Based on these data, a decision was made to conduct a more definitive prospective RCT in hypoalbuminemic MHD patients.     

The Impact of the ISCHEMIA Trial on Clinical Practice: an Interventionist’s Perspective

Cardiovascular Drugs and Therapy - The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial is the latest in a series of studies evaluating...     

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double–Blind,Randomized, Placebo–Controlled Trial

Background and objectives

Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD.

Design, setting, participants, & measurements

We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics.

Results

CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD–induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01).

Conclusions

Dietary CF ingestion mitigates acute HD–induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.     

Effects of Transdermal Tulobuterol in Pediatric Asthma Patients on Long-Term Leukotriene Receptor Antagonist Therapy: Results of a Randomized,Open-Label,Multicenter Clinical Trial in Japanese Children Aged 4–12 Years

BackgroundFew studies have examined the efficacy or safety of a transdermal β2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients.MethodsIn this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events.ResultsThirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group.ConclusionsThese results suggest that short-term use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.     

Effect of Training on Primary Care Residents’ Performance in Brief Alcohol Intervention: A Randomized Controlled Trial

Background Brief alcohol interventions (BAI) reduce alcohol use and related problems in primary care patients with hazardous drinking behavior. The effectiveness of teaching BAI on the performance of primary care residents has not been fully evaluated. Methods A cluster randomized controlled trial was conducted with 26 primary care residents who were randomized to either an 8-hour, interactive BAI training workshop (intervention) or a lipid management workshop (control). During the 6-month period after training (i.e., from October 1, 2003 to March 30, 2004), 506 hazardous drinkers were identified in primary care, 260 of whom were included in the study. Patients were interviewed immediately and then 3 months after meeting with each resident to evaluate their perceptions of the BAI experience and to document drinking patterns. Results Patients reported that BAI trained residents: conducted more components of BAI than did controls (2.4 vs 1.5, p = .001); were more likely to explain safe drinking limits (27% vs 10%, p = .001) and provide feedback on patients’ alcohol use (33% vs 21%, p = .03); and more often sought patient opinions on drinking limits (19% vs 6%, p = .02). No between-group differences were observed in patient drinking patterns or in use of 9 of the 12 BAI components. Conclusions The BAI-trained residents did not put a majority of BAI components into practice, thus it is difficult to evaluate the influence of BAI on the reduction of alcohol use among hazardous drinkers. Dr. Chossis died May 10, 2007. A poster on this study was presented at the 2006 RSA Annual Scientific Meeting held in Baltimore, Maryland, June 26, 2006.     

Optimizing Pre-Exposure Antiretroviral Prophylaxis Adherence in Men Who Have Sex with Men: Results of a Pilot Randomized Controlled Trial of “Life-Steps for PrEP”

Antiretroviral pre-exposure prophylaxis (PrEP) has been demonstrated to decrease HIV acquisition in multiple efficacy trials, but medication adherence is critical, and was suboptimal in several studies. Fifty HIV-uninfected at risk men who have sex with men (MSM) were randomized to a cognitive behavioral intervention condition or a time and session-matched comparison counseling intervention. The experimental intervention entailed four nurse-delivered initial and two booster sessions based on Life-Steps, an ART treatment adherence intervention. The comparison condition provided information and supportive counseling. The primary analyses compared adherence (Wisepill and tenofovir plasma levels) at 3 and 6 months. Fifty-eight MSM were screened to enroll 50 participants. Median age was 38.2 years old, 86% were white; 64% had completed college. Wisepill adherence was high in both groups, and not statistically different. Plasma tenofovir levels were significantly higher in the intervention group at 6 months using mean substitution analysis (i.e., computing missing variables) (p = 0.037), however, in the completer analyses (i.e., using only those completing all study visits), there were no statistically significant differences between randomization conditions. Medication adherence was high across a cognitive-behavioral (Life-Steps) and time-matched counseling intervention for PrEP adherence, with some evidence suggesting superiority of Life-Steps in this pilot RCT. Further evaluation in a fully powered efficacy trial is warranted to assess the robustness of this intervention.     

Formoterol Delivered via the Dry Powder Aerolizer® Inhaler Versus Albuterol MDI and Placebo in Mild-to-Moderate Asthma: A Randomized,Double-Blind,Double-Dummy Trial

The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 µg and 24 µg (Foradil) delivered via Aerolizer inhaler with four times daily albuterol (salbutamol) 180 µg delivered via metered dose inhaler (MDI) and placebo. A total of 554 adolescents and adults (ages 12–75 years) with mild-to-moderate asthma were randomized to this 12-week, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study. Twelve-hour spirometry measurements were taken at weeks 0, 4, 8, and 12. A total of 484 patients completed the study (122, 116, 127, and 119 given formoterol 12 µg, formoterol 24 µg, albuterol, and placebo, respectively). For the primary efficacy variable, the forced expiratory volume in 1 second (FEV₁), both formoterol 12 µg and 24 µg were statistically superior to placebo at all time points on all test days (p ≤ 0.017) and to albuterol at most time points on all test days (p ≤ 0.001). The onset of improvement in FEV₁ was rapid, with 15% increase within 5 min in 57%, 71%, and 65% of formoterol 12 µg, formoterol 24 µg, and albuterol patients, respectively. Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables: FEV₁ area under the curve, percentage of predicted FEV₁, forced vital capacity and forced expiratory flow, asthma symptom scores, and peak expiratory flows. In conclusion, both formoterol doses were superior to placebo in all lung function measurements. Overall, compared with albuterol, both formoterol doses produced superior bronchodilation. Formoterol and albuterol were safe and well-tolerated.