Randomized Clinical Trials of Neurally Mediated Syncope

Evidence for therapy of neurally mediated syncope is generally weak. Many drugs have been used for the treatment of vasovagal syncope (beta-blockers, disopyramide, scopolamine, clonidine, theophylline, fludrocortisone, ephedrine, dihydroergotamine, etilefrine, midodrine, clonidine, serotonin reuptake inhibitors, enalapril). In general, although the results have been satisfactory in uncontrolled trials or short-term controlled trials, the majority of long-term placebo-controlled prospective trials have not been able to show a benefit of the active drug over placebo. Only two well-designed double-blind placebo-controlled randomized trials have been performed—one for etilefrine and the other for atenolol—and both were unable to show a superiority of the active drug versus placebo. Four randomized clinical trials of pacing therapy—three positive and one negative—have been performed in patients affected by vasovagal syncope. The relationship between carotid sinus hypersensitivity and spontaneous, otherwise unexplained, syncope has been demonstrated. Cardiac pacing appears to be beneficial in carotid sinus syndrome; its efficacy has been demonstrated by two randomized controlled trials and confirmed by several pre-post comparative studies, one controlled trial, and one prospective observational study. There is evidence and general agreement that cardiac pacing is useful in patients with cardioinhibitory or mixed carotid sinus syndrome. Usefulness of the treatment is less well established and divergence of opinion exists with regard to cardiac pacing in patients with cardioinhibitory vasovagal syncope. The evidence fails to support the efficacy of beta-blocking drugs. As yet there are insufficient data to support the use of any other pharmacologic therapy for vasovagal syncope. (J Cardiovasc Electrophysiol, Vol. 14, pp. S64-S69, September 2003, Suppl.)     

Glutamine Supplementation in Intensive Care Patients: A Meta-Analysis of Randomized Clinical Trials

The role of glutamine (GLN) supplementation in critically ill patients is controversial. Our aim was to analyze its potential effect in patients admitted to intensive care unit (ICU).We performed a systematic literature review through Medline, Embase, Pubmed, Scopus, Ovid, ISI Web of Science, and the Cochrane-Controlled Trials Register searching for randomized clinical trials (RCTs) published from 1983 to 2014 and comparing GLN supplementation to no supplementation in patients admitted to ICU. A random-effect meta-analysis for each outcome (hospital and ICU mortality and rate of infections) of interest was carried out. The effect size was estimated by the risk ratio (RR).Thirty RCTs were analyzed with a total of 3696 patients, 1825 (49.4%) receiving GLN and 1859 (50.6%) no GLN (control groups). Hospital mortality rate was 27.6% in the GLN patients and 28.6% in controls with an RR of 0.93 (95% CI = 0.81–1.07; P = 0.325, I² = 10.7%). ICU mortality was 18.0 % in the patients receiving GLN and 17.6% in controls with an RR of 1.01 (95% CI = 0.86–1.19; P = 0.932, I² = 0%). The incidence of infections was 39.7% in GLN group versus 41.7% in controls. The effect of GLN was not significant (RR = 0.88; 95% CI = 0.76–1.03; P = 0.108, I² = 56.1%).These results do not allow to recommend GLN supplementation in a generic population of critically ills. Further RCTs are needed to explore the effect of GLN in more specific cohort of patients.     

BMI,Infarct Size,and Clinical Outcomes Following Primary PCI: Patient-Level Analysis From 6 Randomized Trials

ObjectivesThe aim of this study was to examine the association between body mass index (BMI), infarct size (IS) and clinical outcomes.BackgroundThe association between obesity, IS, and prognosis in patients undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction is incompletely understood.MethodsAn individual patient-data pooled analysis was performed from 6 randomized trials of patients undergoing pPCI for ST-segment elevation myocardial infarction in which IS (percentage left ventricular mass) was assessed within 1 month (median 4 days) after randomization using either cardiac magnetic resonance (5 studies) or ^99mTc sestamibi single-photon emission computed tomography (1 study). Patients were classified as normal weight (BMI <25 kg/m²), overweight (25 kg/m² ≤BMI <30 kg/m²), or obese (BMI ≥30 kg/m²). The multivariable models were adjusted for age, sex, hypertension, hyperlipidemia, current smoking, left main or left anterior descending coronary artery infarct, baseline TIMI (Thrombolysis In Myocardial Infarction) flow grade 0 or 1, prior myocardial infarction, symptom–to–first device time, and study.ResultsAmong 2,238 patients undergoing pPCI, 644 (29%) were normal weight, 1,008 (45%) were overweight, and 586 (26%) were obese. BMI was not significantly associated with IS, microvascular obstruction, or left ventricular ejection fraction in adjusted or unadjusted analysis. BMI was also not associated with the 1-year composite risk for death or heart failure hospitalization (adjusted hazard ratio: 1.21 [95% confidence interval: 0.74 to 1.71] for overweight vs. normal [p = 0.59]; adjusted hazard ratio: 1.21 [95% confidence interval 0.74 to 1.97] for obese vs. normal [p = 0.45]) or for death or heart failure hospitalization separately. Results were consistent when BMI was modeled as a continuous variable.ConclusionsIn this individual patient-data pooled analysis of 2,238 patients undergoing pPCI for ST-segment elevation myocardial infarction, BMI was not associated with IS, microvascular obstruction, left ventricular ejection fraction, or 1-year rates of death or heart failure hospitalization.     

Yoga for Asthma? A Systematic Review of Randomized Clinical Trials

Objective. The objective of this systematic review was to assess the effectiveness of yoga as a treatment option for asthma. Method. Seven databases were searched from their inception to October 2010. Randomized clinical trials (RCTs) and non-randomized clinical trials (NRCTs) were considered, if they investigated any type of yoga in patients with asthma. The selection of studies, data extraction, and validation were performed independently by two reviewers. Results. Six RCTs and one NRCT met the inclusion criteria. Their methodological quality was mostly poor. Three RCTs and one NRCT suggested that yoga leads to a significantly greater reduction in spirometric measures, airway hyperresponsivity, dose of histamine needed to provoke a 20% reduction in forced expiratory volume in the first second, weekly number of asthma attacks, and need for drug treatment. Three RCTs showed no positive effects compared to various control interventions. Conclusions. The belief that yoga alleviates asthma is not supported by sound evidence. Further, more rigorous trials are warranted.     

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.     

Fortune of Reversals: How Randomized Clinical Trials Shape Medical Practice

Digestive Diseases and Sciences -     

Diabetes Mellitus and Acute Coronary Syndrome: Lessons From Randomized Clinical Trials

Diabetes mellitus is a major independent risk factor for acute coronary syndrome (ACS). In addition, diabetic patients with ACS suffer from increased mortality compared to their nondiabetic peers. Driven by multiple pathophysiological disturbances, such patients are predisposed to a proinflammatory, prothrombotic state, which may lead to plaque rupture. To counteract this more complex biology, several therapies and strategies have emerged, with some having unique preferential benefits in this population. Antiplatelet agents such as aspirin and clopidogrel have long been standard of care. Dose adjustment of these therapies remains the subject of continued research. Along with medical therapy, ACS diabetic patients preferentially benefit from primary percutaneous intervention compared to fibrinolysis. However, with advances in reperfusion techniques, the optimal strategy has yet to be determined. With these differences in ACS treatment responses, diabetic individuals may not just be a high-risk group, but may actually constitute a fundamentally different population, requiring dedicated clinical trials and individualized treatment regimens.     

Feasibility of Double-Blind Clinical Trials with Oral Diacetylmorphine: A Randomized Controlled Phase II Study in an Inpatient Setting

The aim of this study was to evaluate the feasibility of conducting double-blind controlled randomized clinical trials using twice-a-day immediate-release oral diacetylmorphine (DAM) in heroin-dependent patients, by means of measuring the capacity of oral DAM to block opiate withdrawal and clinicians' ability to distinguish it from morphine and methadone. This was a randomized, phase II, double-blind, multicenter pilot study comparing immediate-release oral DAM, slow-release oral morphine and oral methadone administered twice a day during 10 days. Forty-five heroin-dependent patients were randomly assigned to these three treatment groups in an inpatient regime. Patients were stabilized with a mean of 350 mg (SD = 193) of immediate-release oral DAM, 108 mg (SD = 46.2) of slow-release oral morphine and 40 mg (SD = 17.9) of methadone. No statistically significant differences were found between any studied medication in clinical outcome. Neither patients nor clinicians were able to identify the administered medication. This study shows the feasibility of double-blind clinical trials using b.i.d. immediate-release oral DAM allowing further phase III clinical trials in the process of introducing oral DAM as a medication for heroin-dependent patients not responding to standard maintenance treatments.     

Incident Stroke Events in Clinical Trials of Antihypertensive Drugs in Cardiovascular Disease Patients: A Network Meta-analysis of Randomized Controlled Trials

Antihypertensive drugs are commonly used in cardiovascular diseases (CVD), less is known about the comparative effectiveness of different antihypertensive drugs on stroke events in CVD patients. We searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science for randomized controlled trails comparing the different antihypertensive drugs for stroke events in CVD patients from inception until November, 2022. Pairwise and network meta-analysis were performed to compare of different antihypertensive drugs for the incidence of stroke events in CVD patients. The protocol was registered on the PROSPERO database (CRD42022375038). 33 trials involving 141,217 CVD patients were included. The incidence of stroke in CVD patients for each antihypertensive drugs was placebo (3.0%), ACEI (2.4%), ARB (4.1%), CCB (1.8%), β blocker (1.3%), and diuretic (3.6%). Antihypertensive drug was significantly reducing stroke events in CVD patients when compared with placebo (OR 0.82; 95% CI 0.75 to 0.89). Specifically, ACEI (OR 0.82; 95% CI, 0.69-0.97), ARB (OR 0.87; 95% CI, 0.77-0.98), CCB (OR 0.69; 95% CI, 0.54-to 0.87), and diuretic (OR 0.74; 95% CI, 0.57-0.95) were significantly reducing stroke events in CVD patients when compared with placebo. Network meta-analysis suggested CCB and diuretic ranked the first and second in reducing the incidence of stroke events in CVD patients with the SUCRA value of 90.9% and 73.8%. CCB and diuretic had the greatest possibility to reduce the incidence of stroke events in CVD patients, while, ACEI was the worst antihypertensive agents in reducing the incidence of stroke events in CVD patients.     

Effects of ACEIs Versus ARBs on Proteinuria or Albuminuria in Primary Hypertension: A Meta-Analysis of Randomized Trials

Although angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) belong to a family of therapies that block the renin–angiotensin system and are suggested to improve proteinuria/albuminuria, it is unclear which is more effective.To compare the effects of ACEIs and ARBs on proteinuria in primary hypertension by performing a meta-analysis covering randomized controlled trials (RCTs).We systematically searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1990 to November 2014. Eligible studies were RCTs of ACEI therapy versus ARB therapy that reported the albumin excretion rate (AER), albumin (Alb), and urinary albumin excretion (UAE) as outcomes.Seventeen RCTs, including 17,951 patients (without limit of race, age, or sex) with a mean duration of 62.6 weeks, were included. Pooled analysis suggested that ACEIs and ARBs showed no significant differences in AER/Alb/UAE/24-h urine protein/24-h urine total protein in a comparison of 10 trials (SMD 0.09; 95% CI –0.18–0.36; P = 0.52). No significant differences were observed in urinary protein/creatinine ratio (UPCR)/urinary albumin/creatinine ratio (UACR), or albumin/creatinine ratio (ACR) in 7 trials (SMD 0.15; 95% CI –1.88–2.19; P = 0.88). The total outcome of ACEIs and ARBs also showed no significant difference (SMD 0.13; 95% CI –1.03–1.29; P = 0.83). The efficacies of ACEIs and ARBs in controlling blood pressure as a secondary indicator were also similar (SMD –0.50; 95% CI –1.58–0.58; P = 0.37).Based on a meta-analysis of 17 randomized controlled trials including 17,951 patients, we found that ACEIs and ARBs can reduce urine protein levels, improve blood pressure, and were similarly effective in terms of reducing urinary protein excretion.     

Quality of Life After Surgery or Surveillance for Asymptomatic Primary Hyperparathyroidism: A Meta-Analysis of Randomized Controlled Trials

A number of studies have investigated the effects of surgery on symptoms and quality of life in patients with hyperparathyroidism. However, the results are inconsistent. We conducted this meta-analysis to quantitatively assess changes in quality of life among patients with asymptomatic primary hyperparathyroidism.Different databases were searched for randomized controlled trials comparing surgery with surveillance. Quality of life was measured by the Short Form-36 general health survey. The pooled random-effects estimates of standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated.Three trials involving 294 participants were included. At 1 year, patients undergoing parathyroidectomy had significantly better physical role functioning (SMD, 0.31; 95% CI 0.04–0.57; P = 0.02) and emotional role functioning (SMD, 0.29; 95% CI 0.02–0.55; P = 0.03). At 2 years, the surgery group had significantly better emotional role functioning (SMD, 0.35; 95% CI 0.02–0.67; P = 0.04) than the surveillance group. Furthermore, compared with baseline, emotional role functioning improved after surgery (SMD, 0.31; 95% CI 0.02–0.60; P = 0.04), whereas emotional role functioning tended to get worse in patients assigned to medical surveillance (SMD, −0.27; 95% CI −0.55 to 0.02; P = 0.07).Although Short Form-36 is a generic instrument, our results suggest that parathyroidectomy may be associated with better quality of life, especially in the emotional aspects of well-being.     

Side Effects of Phytoestrogens: A Meta-analysis of Randomized Trials

Background

Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown.

Methods

Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials.

Results

We identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P = .2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P = .003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups.

Conclusions

Based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies.