Participant recruitment into a randomised controlled trial of exercise therapy for people with multiple sclerosis

The success of a clinical trial is often dependant on whether recruitment targets can be met in the required time frame. Despite an increase in research into the benefits of exercise in people with multiple sclerosis (PwMS), no trial has reported detailed data on effective recruitment strategies for large-scale randomised controlled trials. The main purpose of this report is to provide a detailed outline of recruitment strategies, rates and estimated costs in the Exercise Intervention for Multiple Sclerosis (ExIMS) trial to identify best practices for future trials involving multiple sclerosis (MS) patient recruitment

Design and Baseline Characteristics of Participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) Trial of Dulaglutide's Cardiovascular Effects

DigitalThe aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.Ciencias Médicas y de la Salu

Spironolactone for heart failure with preserved ejection fraction

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Nine-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ∼4 years of intensive versus standard glycemic control in participants with type 2 diabetes and other cardiovascular risk factors had a neutral effect on the composite cardiovascular outcome, increased cardiovascular and total mortality, and reduced nonfatal myocardial infarction. Effects of the intervention during prolonged follow-up were analyzed

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

OBJECTIVERandomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality.RESEARCH DESIGN AND METHODSParticipants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C 7%.CONCLUSIONSThese analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD

Association of 3 different antihypertensive medications with hip and pelvic fracture risk in older adults secondary analysis of a randomized clinical trial

IMPORTANCE On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. OBJECTIVE To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. DESIGN, SETTING, AND PARTICIPANTS Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. MAIN OUTCOMES AND MEASURES Hip and pelvic fracture hospitalizations. RESULTS A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0%female; and 49.9%white non-Hispanic, 31.2%African American, and 19.1%other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95%CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95%CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95%CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95%CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. CONCLUSIONS AND RELEVANCE These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications

Assessment of atherosclerotic carotid plaque volume with multidetector computed tomography angiography

Purpose The amount of atherosclerotic plaque and its components (calcifications, fibrous tissue, and lipid core) could be better predictors of acute events than the now currently used degree of stenosis. Therefore, we evaluated a dedicated software tool for volume measurements of atherosclerotic carotid plaque and its components in multidetector computed tomography angiography (MDCTA) images. Materials and Methods Data acquisition was approved by the Institutional Review Board and all patients gave written informed consent. MDCTA images of 56 carotid arteries were analyzed by three observers. Plaque volumes were assessed by manual drawing of the outer vessel contour. The luminal boundary was determined based on a Hounsfield-Unit (HU) threshold. The contribution of different components was measured by the number of voxels within defined ranges of HU-values (calcification >130 HU, fibrous tissue 60–130 HU, lipid core <60 HU). Interobserver variability (IOV) was assessed. Results Plaque volume was 1,259 ± 621 mm3. The calcified, fibrous and lipid volumes were 238 ± 252 mm3, 647 ± 277 mm3 and 376 ± 283 mm3, respectively. IOV was moderate with interclass correlation coefficients (ICC) ranging from 0.76 to 0.99 and coefficients of variation (COV) ranging from 3% to 47%. Conclusion Atherosclerotic carotid plaque volume and plaque component volumes can be assessed with MDCTA with a reasonable observer variability

Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail:a post hoc analysis

Abstract Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. Results Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82–0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80–0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87–0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82–0.99) p = 0.028]. Conclusions These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. Clinical Trial Registration: https://www.clinicaltrials.gouv . Unique Identifier NCT01394952)

The Global Risk Approach Should Be Better Applied in French Hypertensive Patients: A Comparison between Simulation and Observation Studies

The prediction of the public health impact of a preventive strategy provides valuable support for decision-making. International guidelines for hypertension management have introduced the level of absolute cardiovascular risk in the definition of the treatment target population. The public health impact of implementing such a recommendation has not been measured.We assessed the efficiency of three treatment scenarios according to historical and current versions of practice guidelines on a Realistic Virtual Population representative of the French population aged from 35 to 64 years: 1) BP≥160/95 mm Hg; 2) BP≥140/90 mm Hg and 3) BP≥140/90 mm Hg plus increased CVD risk. We compared the eligibility following the ESC guidelines with the recently observed proportion of treated amongst hypertensive individuals reported by the Etude Nationale Nutrition Santé survey. Lowering the threshold to define hypertension multiplied by 2.5 the number of eligible individuals. Applying the cardiovascular risk rule reduced this number significantly: less than 1/4 of hypertensive women under 55 years and less than 1/3 of hypertensive men below 45 years of age. This was the most efficient strategy. Compared to the simulated guidelines application, men of all ages were undertreated (between 32 and 60%), as were women over 55 years (70%). By contrast, younger women were over-treated (over 200%).The global CVD risk approach to decide for treatment is more efficient than the simple blood pressure level. However, lack of screening rather than guideline application seems to explain the low prescription rates among hypertensive individuals in France. Multidimensional analyses required to obtain these results are possible only through databases at the individual level: realistic virtual populations should become the gold standard for assessing the impact of public health policies at the national level