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In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Many patients with heart failure have a normal or near-normal left ventricular ejection fraction. 1 – 4 Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction. 5 – 8 However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less. 1 , 2 , 9 The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .

Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target. The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF. Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age ≥50 years, left ventricular ejection fraction ≥45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide ≥100 pg/mL or N-terminal pro–B-type natriuretic peptide ≥360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. TOPCAT is designed to assess definitively the role of spironolactone in the management of HF-PEF.

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.

Prior randomized trials suggested that revascularization of diabetic patients by coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty. The introduction of drug-eluting stents (DESs) calls into question the relevance of past studies to the current era. The FREEDOM Trial is designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients. The FREEDOM Trial is a multicenter, open-label prospective randomized superiority trial of PCI versus CABG in at least 2000 diabetic patients in whom revascularization is indicated. Consenting diabetic patients with multivessel disease will be randomized on a 1:1 basis to either CABG or multivessel stenting using DESs and observed at 30 days, 1 year, and annually for up to 5 years. At the discretion of the primary physician or interventionalists, patients randomized to the PCI/DES arm will receive any approved DESs. The primary outcome measure is the composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Patients will be observed for a mean of 4 years. At present, coronary revascularization with CABG surgery is the treatment of choice in diabetic patients with multivessel coronary artery disease. Drug-eluting stents have shown promising preliminary results in the diabetic population. The FREEDOM Trial is an international study designed to define the optimal revascularization strategy for the diabetic patient with multivessel coronary disease.

Background The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. Purpose The purpose of this report is to describe our Network’s experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than ‘crisis’ resolution as trial endpoints, and alternative statistical analysis strategies. Methods The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. Results Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. Limitations While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. Lessons learned Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. Conclusions A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

Patients with prior stroke represent a substantial proportion of patients presenting with acute ST-segment elevation myocardial infarction (STEMI). However, the impact of prior stroke on prognosis has not been rigorously examined in the reperfusion era. The baseline characteristics, treatments, and clinical outcomes of patients with prior stroke enrolled in the Magnesium in Coronaries (MAGIC) trial were evaluated and compared to those of patients without prior stroke. MAGIC enrolled 6213 patients with STEMI, of whom 558 (9.0%) had prior stroke. Patients with prior stroke were more likely to have a history of hypertension (88.0% vs 70.3%), diabetes (19.9% vs 14.5%), myocardial infarction (38.2% vs 25.1%), and congestive heart failure (15.6% vs 9.7%). The mean Thrombolysis in Myocardial Infarction Risk Score was higher in patients with prior stroke compared to those without prior stroke (4.37 vs 3.93, P < .0001). Patients with prior stroke were less likely to receive reperfusion therapy, even among those considered eligible at presentation (66.3% vs 80.6%, P < .0001). Compared to patients without prior stroke, inhospital stroke (3.0% vs 1.0%, P < .0001), severe congestive heart failure (23.3% vs 18.2%, P = .003), and 30-day mortality (21.0% vs 14.7%, P < .0001) were higher among patients with prior stroke. On multivariable analysis, prior stroke was independently associated with a significantly higher risk of death at 30 days (odds ratio 1.44, P = .0023). Patients with prior stroke who present with STEMI are at very high risk for short-term morbidity and mortality. Aggressive treatment of these patients appears warranted.

Although researched extensively over several decades, the prevalence, costs and reasons for depression among women during the middle years remain a challenge to public health. A vast literature is distilled into two predominant schools of thought, each with profoundly different implications for research and clinical practice. One school (the estrogen-deficiency perspective) holds that depression is associated with or triggered by endocrine changes in women around 50 years of age (menopause). A second school (the social-circumstances perspective) holds that depression is related to social circumstances encountered frequently by women during their fourth and fifth decades. Employing data from a randomly selected cohort of 2,500 premenopausal women sampled in Massachusetts, this paper shows that: \\bullet depression is associated with a surgical menopause and may even be a cause rather than a consequence of this surgery for this atypical group of women; \\bullet depression is not associated with the natural changes from pre- to immediately postmenopause; and \\bullet the most marked increases in depression are associated with multiple causes of worry and multiple roles among currently married women (including paid work, adolescent children, ailing husbands, and aging parents or parents-in-law). Some implications of these findings are discussed in the context of a rapidly aging population.