Search

Author(s): Khan, Muhammad Shahzeb; Shahid, Izza; Asad, Nava; Greene, Stephen J; Khan, Safi U; Doukky, Rami; Metra, Marco; Anker, Stefan D; Filippatos, Gerasimos S; Fonarow, Gregg C; Butler, Javed | Abstract: AimsDiscontinuation or non-publication of trials may hinder scientific progress and violates the commitment made to research participants. We sought to identify the prevalence of discontinuation and non-publication of heart failure (HF) clinical trials.Methods and resultsWe conducted a cross-sectional search of ClinicalTrials.gov to identify all completed and discontinued HF clinical trials. We limited our search to only include trials that were completed by 31 December 2017. Trials were investigated to identify reasons for discontinuation. Informative termination was defined as trial termination due to safety or efficacy concerns. Data pertaining to the trial phase, funding, intervention, enrolment, and trial completion date were extracted for each trial. A total of 572 trials were included. Of these, 21% (nn=n118) were discontinued before completion. Patient accrual was the most frequently cited reason (nn=n42; 36%) for trial discontinuation, followed by informative termination (nn=n16; 14%) and funding (nn=n14; 12%). Overall, 24n780 patients were enrolled in trials that were terminated. Of trials that were completed and not terminated, nearly one-third (nn=n131/454; 29%) were not published. Seventy-nine (24%) trials were published within 12nmonths, 192 (59%) within 24nmonths, and 252 (78%) trials within 36nmonths.ConclusionsDiscontinuation and non-publication of HF trials is common. This raises ethical concerns towards participants who volunteer for research and are exposed to potential risks, inconvenience, and discomfort without furthering scientific progress.

Aims Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. Methods and results The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5–5.3, P = 0.018) for OSS and 2.8 (0.3–5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3–5.6, P = 0.028) for OSS and 2.9 (0.2–5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. Conclusion In iron-deficient patients with HF and left ventricular ejection fraction, Graphical Abstract

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in clinical practice. Radiofrequency and cryoballoon catheter ablation are therapeutic options in addition to antiarrhythmic drug therapy for the treatment of AF. Ablation is effective at reducing recurrent atrial arrhythmias and also in the reduction of AF burden. Besides arrhythmia control, improvement in quality of life and clinical outcomes are also desirable goals with AF treatment. Randomized clinical trials have evaluated ablation in several patient populations, including symptomatic patients as first-line or second-line therapy, asymptomatic patients, and patients with heart failure. These trials clarify the durability of ablation in arrhythmia control, clarify quality-of-life improvement, and identify patient populations in whom ablation may be expected to improve clinical outcomes. In this review, we summarize the major clinical trials involving ablation; discuss the strengths, weakness, and clinical implications of these trials; and highlight the knowledge gaps in our current understanding of AF ablation for future clinical studies., Graphical abstract

The VICTORIA trial showed Vericiguat once daily (titrated up to 10 mg) significantly reduced its primary end-point, the composite of death from cardiovascular causes or first hospitalization for heart failure, in 5050 class II-IV HFrEF patients (LVEF5,314 pg/mL) being almost significantly worse on Vericiguat with a HR of 1.16 (0.99-1.35). So the two major areas where Vericiguat may have received special notice appear to be less impressive when we look in detail at the trial results. How do we therefore place Vericiguat in the wake of VICTORIA? It is a proven therapy in a disease which still has residual high rates of clinical mortality and morbidity. It conveyed a benefit on top of other therapies, thus it should be not ignored and may indeed be a very effective therapy in some patients.

Purpose Two randomized controlled trials (RCTs), Mitra-Fr and Coapt, evaluating the benefit of percutaneous repair (PR) for heart failure (HF) patients with severe mitral regurgitation, have led to conflicting results. We aimed to evaluate the impact of these trial results on the cost-effectiveness of PR using effectiveness inputs from the two RCTs. Methods We developed a time varying Markov type model with three mutually exclusive health states: alive without HF hospitalisation, alive with HF hospitalisation, and dead. Clinically plausible extrapolations beyond observed data were obtained by developing parametric modelling for overall survival and HF hospitalisations using published data from each trial. We adopted the perspective of the French Health System and used a 30-year time horizon. Results were expressed as € / quality-adjusted life year (QALY) gained using utility inputs from literature. Findings Results are presented using treatment efficacy measures from Mitra-F and Coapt trials respectively. With the Mitra-Fr data, after annual discounting, the base case model generated an incremental 0.00387 QALY at a cost of €25,010, yielding an incremental cost effectiveness ratio (ICER) of €6,467,032 / QALY. The model was sensitive to changes made to model inputs. There was no potential of PR being cost-effective. With the Coapt data, the model generated 1.19 QALY gain at a cost of €26,130 yielding an ICER of €21,918 / QALY and at a threshold of >€50,000/QALY PR had a probability of 1 of being cost-effective. Implications Cost effectiveness results were conflicting; reconciling differences between trials is a priority and could promote optimal cost effectiveness analyses and resource allocation.

BACKGROUND The Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure (SBP) of ≤ 120 mm Hg (intensive treatment) reduced cardiovascular disease (CVD) events compared to SBP of ≤ 140 mm Hg (standard treatment); however, it is unclear if this effect is similar in all racial/ethnic groups. METHODS We analyzed SPRINT data within non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic subgroups to address this question. High-risk nondiabetic hypertensive patients (N = 9,361; 30% NHB; 11% Hispanic) 50 years and older were randomly assigned to intensive or standard treatment. Primary outcome was a composite of the first occurrence of a myocardial infarction, acute coronary syndrome, stroke, decompensated heart failure, or CVD death. RESULTS Average postbaseline SBP was similar among NHW, NHB, and Hispanics in both treatment arms. Hazard ratios (HRs) (95% confidence interval) (intensive vs. standard treatment groups) for primary outcome were 0.70 (0.57–0.86), 0.71 (0.51–0.98), 0.62 (0.33–1.15) (interaction P value = 0.85) in NHW, NHB, and Hispanics. CVD mortality HRs were 0.49 (0.29–0.81), 0.77 (0.37–1.57), and 0.17 (0.01–1.08). All-cause mortality HRs were 0.61 (0.47–0.80), 0.92 (0.63–1.35), and 1.58 (0.73–3.62), respectively. A test for differences among racial/ethnic groups in the effect of treatment assignment on all-cause mortality was not significant (Hommel-adjusted P value = 0.062) after adjustment for multiple comparisons. CONCLUSION Targeting a SBP goal of ≤ 120 mm Hg compared to ≤ 140 mm Hg led to similar SBP control and was associated with similar benefits and risks among all racial ethnic groups, though NHBs required an average of ~0.3 more medications. CLINICAL TRIALS REGISTRATION Trial Number NCT01206062, ClinicalTrials.gov Identifier at https://clinicaltrials.gov/ct2/show/NCT01206062.

Aims: Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to selexipag. Methods and results: Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to selexipag. Conclusions: These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.

Background This study assessed the association between heart failure (HF) medication (angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB), beta-blockers (BB), mineralocorticoid-receptor antagonists (MRA) and diuretics) and HF readmissions in a real-world unselected group of patients after a first hospital admission for HF. Furthermore we analysed readmission rates for ACEI versus ARB and for carvedilol versus β1-selective BB and we investigated the effect of HF medication in relation to time since discharge. Methods and findings Medication at discharge was determined with dispensing data from the Dutch PHARMO Database Network including 22,476 patients with HF between 2001 and 2015. After adjustment for age, gender, number of medications and year of admission no associations were found for users versus non-users of ACEI/ARB (hazard ratio, HR = 1.01; 95%CI 0.96–1.06), BB (HR = 1.00; 95%CI 0.95–1.05) and readmissions. The risk of readmission for patients prescribed MRA (HR = 1.11; 95%CI 1.05–1.16) or diuretics (HR = 1.17; 95%CI 1.09–1.25) was higher than for non-users. The HR for ARB relative to ACEI was 1.04 (95%CI 0.97–1.12) and for carvedilol relative to β1-selective BB 1.33 (95%CI 1.20–1.46). Post-hoc analyses showed a protective effect shortly after discharge for most medications. For example one month post discharge the HR for ACEI/ARB was 0.77 (95%CI 0.69–0.86). Although we did try to adjust for confounding by indication, probably residual confounding is still present. Conclusions Patients who were prescribed carvedilol have a higher or at least a similar risk of HF readmission compared to β1-selective BB. This study showed that all groups of HF medication -some more pronounced than others- were more effective immediately following discharge.

IntroductionColorectal cancer is one of the leading causes of cancer-related morbidity worldwide and it has been reported to be associated with poor lifestyle habits which include excess tobacco and alcohol intake as well as genetics and age factors. Probiotics such as the lactic acid bacteria and Bifidobacterium as well as probiotic containing foods (kombucha, kefir, miso etc) have received lots of attention as anticancer agents for prevention and treatment. The effects of the administration of probiotics to patients with colorectal cancer is the primary goal of this systematic review. The overall aim is to assess how the use of probiotics in patients with colorectal cancer helps in the management of colorectal cancer and its effect on the diversity of gut microbiota. The final systematic review will provide a comprehensive evidence base for the use and efficacy of probiotics in patient with colorectal cancer care.Methods and analysisThe systematic review, will be conducted by extensively searching different databases such as PubMed, Web of Science, Scopus, Wiley and ProQuest to identify randomised controlled trials (with no time frame) which relate to the administration of probiotics to patients with colorectal cancer. The search strategy will include words like colorectal cancer, probiotics, Bifidobacterium, clinical trials etc. A systematic search of databases was performed between 17 and 20 January 2020. Two reviewers will independently review the studies and also search the reference lists of the eligible studies to obtain more references. Data will be extracted from the eligible studies using standardised data extraction form. After assessing the risk of bias, qualitative analysis will be used to synthesise the systematic review.Ethics and disseminationThis is a protocol for a systematic review; therefore, it doesn’t require any ethics approval. We intend to disseminate the protocol in a peer reviewed journal.

ObjectiveTo identify and explore change processes explaining the effects of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention taking account of reach, amount of intervention received, delivery fidelity and patient and caregiver perspectives.DesignMixed methods process evaluation parallel to a randomised controlled trial using data from the intervention group (REACH-HF plus usual care).SettingFour centres in the UK (Birmingham, Cornwall, Gwent and York).ParticipantsPeople with heart failure with reduced ejection fraction (HFrEF) and their caregivers.MethodsThe REACH-HF intervention consisted of a self-help manual for patients with HFrEF and caregivers facilitated over 12 weeks by trained healthcare professionals. The process evaluation used multimodal mixed methods analysis. Data consisted of audio recorded intervention sessions; demographic data; intervention fidelity scores for intervention group participants (107 patients and 53 caregivers); qualitative interviews at 4 and 12 months with a sample of 19 patients and 17 caregivers.Outcome measuresQuantitative data: intervention fidelity and number, frequency and duration of intervention sessions received. Qualitative data: experiences and perspectives of intervention participants and caregivers.ResultsIntervention session attendance with facilitators was high. Fidelity scores were indicative of adequate quality of REACH-HF intervention delivery, although indicating scope for improvement in several areas. Intervention effectiveness was contingent on matching the intervention implementation to the concerns, beliefs and goals of participants. Behaviour change was sustained when shared meaning was established. Respondents’ comorbidities, socio-economic circumstances and existing networks of support also affected changes in health-related quality of life.ConclusionsBy combining longitudinal mixed methods data, the essential ingredients of complex interventions can be better identified, interrogated and tested. This can maximise the clinical application of research findings and enhance the capacity of multidisciplinary and multisite teams to implement the intervention.Trial registration numberISRCTN25032672; Pre-results.

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first‐in‐class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double‐blind, placebo‐controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time‐averaged proportional change in N‐terminal pro‐brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994889.

Background and objectivesStatins showed mixed results in heart failure (HF) patients. The benefits in major HF outcomes, including all-cause mortality and sudden cardiac death (SCD), have always been discordant across systematic reviews and meta-analyses. We intended to systematically identify and appraise the available evidence that evaluated the effectiveness of statins in clinical outcomes for HF patients.DesignSystematic review and meta-analysis.Data sourcesWe searched, until April 28, 2016: Medline, Embase, ISI Web of Science and EBM reviews (Cochrane DSR, ACP journal club, DARE, CCTR, CMR, HTA, and NHSEED), checked clinicaltrials.gov for ongoing trials and manually searched references of included studies.Eligibility criteria for selecting studiesWe identified 24 randomized clinical trials that evaluated the efficacy of statins for HF patients. All randomized clinical trials were assessed for risk of bias and pooled together in a meta-analysis. Pre-specified outcomes were sudden cardiac death, all-cause mortality, and hospitalization for worsening heart failure.ResultsStatins did not reduce sudden cardiac death (SCD) events in HF patients [relative risk (RR) 0.92, 95% confidence interval (CI) 0.70 to 1.21], all-cause mortality [RR 0.88, 95% CI 0.75 to 1.02] but significantly reduced hospitalization for worsening heart failure (HWHF) although modestly [RR 0.79, 95% CI 0.66 to 0.94]. Nevertheless, estimated predictive intervals were insignificant in SCD, all-cause mortality and HWHF [RR, 0.54 to 1.63, 0.64 to 1.19, and 0.54 to 1.15], respectively. An important finding was the possible presence of publication bias, small-study effects and heterogeneity of the trials conducted in HF patients.ConclusionsStatins do not reduce sudden cardiac death, all-cause mortality, but may slightly decrease hospitalization for worsening heart failure in HF patients. The evaluation of the risk of biases suggested moderate quality of the published results. Until new evidence is available, this study supports the 2013 ACCF/AHA guidelines to not systematically prescribe statins in "only" HF patients, which should help avoid unnecessary polypharmacy.

Aims: Guidelines for the management of chronic heart failure (CHF) cite the results of randomized controlled trials (RCTs) to support treatment recommendations. The significance of an observed treatment-effect relies on the use of a boundary p-value, most commonly p

Background Chronic diseases, like diabetes mellitus, heart disease and cancer are leading causes of death and disability. These conditions are at least partially preventable or modifiable, e.g. by enhancing patients’ self-management. We aimed to examine the effectiveness of telephone-based health coaching (TBHC) in chronically ill patients. Methods and Findings This prospective, pragmatic randomized controlled trial compares an intervention group (IG) of participants in TBHC to a control group (CG) without TBHC. Endpoints were assessed two years after enrolment. Three different groups of insurees with 1) multiple conditions (chronic campaign), 2) heart failure (heart failure campaign), or 3) chronic mental illness conditions (mental health campaign) were targeted. The telephone coaching included evidence-based information and was based on the concepts of motivational interviewing, shared decision-making, and collaborative goal setting. Patients received an average of 12.9 calls. Primary outcome was time from enrolment until hospital readmission within a two-year follow-up period. Secondary outcomes comprised the probability of hospital readmission, number of daily defined medication doses (DDD), frequency and duration of inability to work, and mortality within two years. All outcomes were collected from routine data provided by the statutory health insurance. As informed consent was obtained after randomization, propensity score matching (PSM) was used to minimize selection bias introduced by decliners. For the analysis of hospital readmission and mortality, we calculated Kaplan-Meier curves and estimated hazard ratios (HR). Probability of hospital readmission and probability of death were analysed by calculating odds ratios (OR). Quantity of health service use and inability to work were analysed by linear random effects regression models. PSM resulted in patient samples of 5,309 (IG: 2,713; CG: 2,596) in the chronic campaign, of 660 (IG: 338; CG: 322) in the heart failure campaign, and of 239 (IG: 101; KG: 138) in the mental health campaign. In none of the three campaigns, there were significant differences between IG and CG in time until hospital readmission. In the chronic campaign, the probability of hospital readmission was higher in the IG than in the CG (OR = 1.13; p = 0.045); no significant differences could be found for the other two campaigns. In the heart failure campaign, the IG showed a significantly reduced number of hospital admissions (-0.41; p = 0.012), although the corresponding reduction in the number of hospital days was not significant. In the chronic campaign, the IG showed significantly increased number of DDDs. Most striking, there were significant differences in mortality between IG and CG in the chronic campaign (OR = 0.64; p = 0.005) as well as in the heart failure campaign (OR = 0.44; p = 0.001). Conclusions While TBHC seems to reduce hospitalization only in specific patient groups, it may reduce mortality in patients with chronic somatic conditions. Further research should examine intervention effects in various subgroups of patients, for example for different diagnostic groups within the chronic campaign, or duration of coaching. Trial Registration German Clinical Trials Register DRKS00000584

BACKGROUND AND OBJECTIVES: Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects. METHODS: We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia). RESULTS: Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p

Background Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews. Methods and Findings We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07–1.24) to 1.06 (95% CI 0.99–1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 (95% CI 0.97–1.18) to 1.14 (95% CI 1.03–1.26). The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies; we cannot assume our findings extend to a broader range of interventions and settings. Conclusions The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited reviews and had the potential to change the conclusions of the reviews. Systematic reviews that incorporate non-randomized studies of medical interventions should include a detailed assessment of RoB for each included study., David Henry and colleagues re-evaluate findings from two systematic reviews using the new ACROBAT-NRSI bias assessment tool for non-randomized studies., Editors' Summary Background In the past, clinicians used their own experience to help them make decisions about the best treatments (interventions) for their patients. Nowadays, “evidence-based medicine”—largely based on findings from randomized controlled trials (RCTs)—guides most clinical decisions. RCTs—studies that compare outcomes in groups of patients chosen at random to receive different interventions—are the best way to assess the efficacy of an intervention (the performance of a treatment under ideal conditions), but individual trials often fail to show a statistically significant difference (a difference unlikely to have arisen by chance) between two interventions. Significant differences between interventions can be detected, however, by undertaking a systematic review (a study that identifies all the RCTs on a given intervention using predefined criteria) and a meta-analysis (a statistical technique for combining, or “synthesizing,” the findings from several independent RCTs). Why Was This Study Done? Systematic reviews of healthcare interventions can also include non-randomized studies, which use administrative databases to identify people receiving different interventions and electronic health records to determine clinical outcomes. However, non-randomized studies of interventions are prone to many “biases” that affect the accuracy of their findings. For example, a potential bias in non-randomized studies is “confounding,” the possibility that an unmeasured characteristic shared by the people receiving a specific intervention, rather than the intervention itself, is responsible for the observed outcome. When undertaking systematic reviews and meta-analyses, it is essential to measure the risk of bias (RoB) in each individual study included in the review and meta-analysis. But, although a widely used tool is available for measuring RoB in RCTs, bias is seldom considered in detail when synthesizing the results of non-randomized studies of interventions. Here, the researchers assess the reliability and usability of ACROBAT-NRSI, a tool developed by Cochrane (an organization that promotes evidence-informed health decision-making) for the assessment of RoB in non-randomized intervention studies. ACROBAT-NRSI assists authors in identifying potential concerns across seven bias domains and assesses the overall RoB of individual non-randomized intervention studies. What Did the Researchers Do and Find? Two of the researchers independently applied the ACROBAT-NRSI process to 37 papers included in two widely cited systematic reviews of non-randomized studies of the relationship between the use of thiazolidinediones (drugs used to treat diabetes, such as rosiglitazone and pioglitazone) and cyclooxygenase-2 (COX-2) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs] such as ibuprofen) and major cardiovascular events (heart attack [myocardial infarction] and heart failure). The two researchers largely agreed on their RoB assessments (good inter-rater agreement), which, after training and early experience, took roughly 2.5 hours to complete for each study. In the thiazolidinedione review, six studies had low overall RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. In the COX-2 inhibitor review, two studies low overall RoB, fourteen had moderate RoB, and five had serious RoB. When the researchers restricted meta-analysis to studies with low or moderate RoB, estimates of the pooled relative risks of cardiovascular events with COX-2 inhibitors (compared with no NSAID) changed little, except for a rise in the relative risk associated with ibuprofen. Finally, although the risk estimates for myocardial infarction, heart failure, and death for rosiglitazone compared with pioglitazone remained significantly raised when analyses were confined to studies with low or moderate RoB, there was no significantly increased risk of myocardial infarction when the analysis was confined to studies with low RoB. What Do These Findings Mean? These findings show that there was considerable variability in RoB among the studies included in two systematic reviews of non-randomized intervention studies. Although all 37 studies included in these reviews were originally considered to be of sufficiently high quality for inclusion using less comprehensive—or less RoB-focused—critical appraisal tools, only eight were judged to have low RoB using ACROBAT-NRSI. Notably, exclusion of studies with moderate, serious, or critical RoB resulted in clinically important changes to some of the conclusions of the original reviews. Because the researchers considered only two systematic reviews, their findings may not be generalizable—ACROBAT-NRSI needs further testing across a range of study types. Moreover, because the tool is designed to be used within a team setting, studies are needed to investigate whether the performance of the tool depends on the team’s skill mix. Importantly, however, these findings highlight the importance of including a detailed RoB assessment for each study included in systematic reviews of non-randomized studies of medical interventions. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001987. More information about ACROBAT-NRSI (A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions) is available; the main Cochrane website provides information about Cochrane and its work; the Cochrane Handbook for Systematic Reviews of Interventions has a chapter on including non-randomized studies in systematic reviews Wikipedia has pages on evidence-based medicine, clinical trials, systematic review, and meta-analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) ClinicalTrials.gov, the US National Institutes of Health clinical trials registry, provides additional background information about clinical trials

AIMS: Iron deficiency (ID) and anaemia are common in patients with chronic heart failure (CHF). The presence of anaemia is associated with increased morbidity and mortality in CHF, and ID is a major reason for the development of anaemia. Preliminary studies using intravenous (i.v.) iron supplementation alone in patients with CHF and ID have shown improvements in symptom status. FAIR-HF (Clinical Trials.gov NCT00520780) was designed to determine the effect of i.v. iron repletion therapy using ferric carboxymaltose on self-reported patient global assessment (PGA) and New York Heart Association (NYHA) in patients with CHF and ID. METHODS AND RESULTS: This is a multi-centre, randomized, double-blind, placebo-controlled study recruiting ambulatory patients with symptomatic CHF with LVEF < or = 40% (NYHA II) or < or =45% (NYHA III), ID [ferritin

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Background There are concerns about the potential for unintentional harms when clinical practice guidelines are applied to patients with multimorbidity. The objective was to summarize the evidence regarding the effect(s) of comorbidity on the outcomes of medication for an index chronic condition. Methods A systematic review was conducted of studies published in MEDLINE and Cochrane Trials before May 2012. The search strategy was constructed to identify articles indexed with “comorbidity” or a related term or by a given condition and one or more additional specified comorbid conditions. The search yielded 3252 articles, of which 37 passed the title/abstract screening process, and 22 were included after full-text review. An additional 23 articles were identified by screening the reference lists for included articles. Information was extracted on study design; population; therapy; comparison groups; outcome(s); main findings. Findings Indexing of articles was inconsistent, with no term for “multimorbidity,” and rare use of “comorbidity”. Only one article examined the effects of comorbidity per se, finding no benefit of tight control of DM among persons with high comorbidity, defined using a comorbidity index. The remainder examined pairs of conditions, the majority of which were post-hoc analyses of randomized controlled trials and which found no difference in outcomes according to whether a comorbid condition was present. Several demonstrated no difference or an increased risk of adverse outcome among persons with DM and tight control of HTN as compared to usual control. Several demonstrated lack of benefit of statins among persons with end-stage renal disease. Conclusions There is limited evidence regarding the effects of multiple comorbidities on treatment outcomes. The majority of studies demonstrated no effect of a single comorbid condition on outcomes. Additional studies examining a broad range of comorbidity are required, along with clear and consistent indexing to allow for improved synthesis of the evidence.

BACKGROUND: Physicians' shortage in many countries and demands of high-quality and affordable care make physician-nurse substitution an appealing workforce strategy. The objective of this study is to conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the impact of physician-nurse substitution in primary care on clinical parameters. METHODS: We systematically searched OVID Medline and Embase, The Cochrane Library and CINAHL, up to August 2012; selected peer-reviewed RCTs comparing physician-led care with nurse-led care on changes in clinical parameters. Study selection and data extraction were performed in duplicate by independent reviewers. We assessed the individual study risk of bias; calculated the study-specific and pooled relative risks (RR) or weighted mean differences (WMD); and performed fixed-effects meta-analyses. RESULTS: 11 RCTs (N = 30,247) were included; most were from Europe, generally small with higher risk of bias. In all studies, nurses provided care for complex conditions including HIV, hypertension, heart failure, cerebrovascular diseases, diabetes, asthma, Parkinson's disease and incontinence. Meta-analyses showed greater reductions in systolic blood pressure (SBP) in favour of nurse-led care (WMD -4.27 mmHg, 95% CI -6.31 to -2.23) but no statistically significant differences between groups in the reduction of diastolic blood pressure (DBP) (WMD -1.48 mmHg, 95%CI -3.05 to -0.09), total cholesterol (TC) (WMD -0.08 mmol/l, 95%CI -0.22 to 0.07) or glycosylated haemoglobin (WMD 0.12%HbAc1, 95%CI -0.13 to 0.37). Of other 32 clinical parameters identified, less than a fifth favoured nurse-led care while 25 showed no significant differences between groups. LIMITATIONS: disease-specific interventions from a small selection of healthcare systems, insufficient quantity and quality of studies, many different parameters. CONCLUSIONS: trained nurses appeared to be better than physicians at lowering SBP but similar at lowering DBP, TC or HbA1c. There is insufficient evidence that nurse-led care leads to better outcomes of other clinical parameters than physician-led care.

AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity. Fil: McMurray, John J. V.. University of Glasgow; Reino Unido Fil: Anand, Inder S.. University of Minnesota; Estados Unidos Fil: Diaz, Rafael. Estudios Clínicos Latinoamérica; Argentina Fil: Maggioni, Aldo P.. Associazione Nazionale Medici Cardiologi Ospedalieri; Italia Fil: O'Connor, Christopher. University of Duke; Estados Unidos Fil: Pfeffer, Marc A.. Brigham and Women’s Hospita; Estados Unidos Fil: Solomon, Scott D.. Brigham and Women’s Hospital; Estados Unidos Fil: Tendera, Micha. Medical University of Silesia; Polonia Fil: van Veldhuisen, Dirk J.. University of Groningen; Países Bajos Fil: Moetaz, Albizem. Amgen Inc.; Estados Unidos Fil: Cheng, Sunfa. Amgen Inc.; Estados Unidos Fil: Scarlata, Debra. Amgen Inc.; Estados Unidos Fil: Swedberg, Karl. University of Gothenburg; Suecia Fil: Young, James B.. Cleveland Clinic. Endocrinology and Metabolism Institute; Estados Unidos Fil: Toblli, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: RED-HF Committees Investigators. No especifíca

BackgroundThe role of cardiac natriuretic peptides in the management of patients with chronic heart failure (HF) remains uncertain. The purpose of this study was to evaluate whether natriuretic peptide-guided therapy, compared to clinically-guided therapy, improves mortality and hospitalization rate in patients with chronic HF.Methodology/principal findingsMEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched for articles reporting natriuretic peptide-guided therapy in HF until August 2012. All randomized trials reporting clinical end-points (all-cause mortality and/or HF-related hospitalization and/or all-cause hospitalization) were included. Meta-analysis was performed to assess the influence of treatment on outcomes. Sensitivity analysis was performed to test the influence of potential effect modifiers and of each trial included in meta-analysis on results. Twelve trials enrolling 2,686 participants were included. Natriuretic peptide-guided therapy (either B-type natriuretic peptide [BNP]- or N-terminal pro-B-type natriuretic peptide [NT-proBNP]-guided therapy) significantly reduced all-cause mortality (Odds Ratio [OR]:0.738; 95% Confidence Interval [CI]:0.596 to 0.913; p = 0.005) and HF-related hospitalization (OR:0.554; CI:0.399 to 0.769; p = 0.000), but not all-cause hospitalization (OR:0.803; CI:0.629 to 1.024; p = 0.077). When separately assessed, NT-proBNP-guided therapy significantly reduced all-cause mortality (OR:0.717; CI:0.563 to 0.914; p = 0.007) and HF-related hospitalization (OR:0.531; CI:0.347 to 0.811; p = 0.003), but not all-cause hospitalization (OR:0.779; CI:0.414 to 1.465; p = 0.438), whereas BNP-guided therapy did not significantly reduce all-cause mortality (OR:0.814; CI:0.518 to 1.279; p = 0.371), HF-related hospitalization (OR:0.599; CI:0.303 to 1.187; p = 0.142) or all-cause hospitalization (OR:0.726; CI:0.509 to 1.035; p = 0.077). [corrected].Conclusions/significanceUse of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalization in patients with chronic HF. In particular, NT-proBNP-guided therapy reduced all-cause mortality and HF-related hospitalization but not all-cause hospitalization, whereas BNP-guided therapy did not significantly reduce both mortality and morbidity.

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and meta-analyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union.

Background: The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported.\ud \ud Hypothesis: That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival.\ud \ud Animals: Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America.\ud \ud Methods: The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo.\ud \ud The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint.\ud \ud Results: The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034).\ud \ud Conclusion and Clinical Importance: The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.