Clinical Trials and Evaluation Unit

London, United Kingdom

Clinical Trials and Evaluation Unit

London, United Kingdom
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Mulder B.A.,University of Groningen | Van Veldhuisen D.J.,University of Groningen | Crijns H.J.G.M.,Maastricht University | Bohm M.,Universitatsklinikum des Saarlandes | And 7 more authors.
European Journal of Heart Failure | Year: 2012

AimsBeneficial effects of beta-blockade remain unclear in heart failure patients who have atrial fibrillation (AF), especially in the elderly. We evaluated the effect of nebivolol on cardiovascular outcomes in elderly patients with heart failure and AF.Methods and resultsThe SENIORS trial showed an overall benefit of nebivolol compared with placebo in 2128 heart failure patients >70 years of age. At baseline, AF was present in 738 (34.7%) patients. The primary outcome was all-cause mortality or cardiovascular hospitalizations. After 21 months, the cumulative incidence of the primary outcome was significantly more common in patients with AF compared with those with sinus rhythm (38.5% vs. 30.4%, respectively, P < 0.001). In patients with AF, nebivolol had no beneficial effect on the primary outcome [nebivolol vs. placebo, 37.1% vs. 39.8%, hazard ratio (HR) 0.92, 95% confidence interval (CI), 0.73-1.17, P = 0.46], in contrast to patients with sinus rhythm (28.15 vs. 32.9%, in the nebivolol vs. placebo group, respectively, HR 0.82, 95% CI 0.67-0.99, P=0.049). In patients with AF, the primary outcome was similar in the impaired and preserved left ventricular ejection fraction (LVEF) groups (39.0% with LVEF ≤35% vs. 37.3% in patients with LVEF > 35%). There was also no evidence of benefit of nebivolol in AF patients stratified by LVEF.ConclusionNebivolol failed to improve outcomes in elderly patients with stable heart failure and co-existing AF, irrespective of LVEF. Furthermore, in patients with AF, outcome was comparable between patients with preserved and impaired LVEF. © 2012 The Author.


Kotecha D.,University of Birmingham | Kotecha D.,Clinical Trials and Evaluation Unit | Kotecha D.,Monash University | Holmes J.,University of Oxford | And 20 more authors.
The Lancet | Year: 2014

Background Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. Methods We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012. Findings 18 254 patients were assessed, and of these 13 946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13 945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. Interpretation Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. Funding Menarini Farmaceutica Internazionale (administrative support grant). © 2014 Elsevier Ltd. All rights reserved.


Von Haehling S.,Applied Cachexia Research | Von Haehling S.,Center for Cardiovascular Research | Van Veldhuisen D.J.,University of Groningen | Roughton M.,Clinical Trials and Evaluation Unit | And 8 more authors.
European Journal of Heart Failure | Year: 2011

AimsAnaemia is a co-morbidity frequently seen in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Its presence carries adverse prognostic effects. The effects of anaemia have not been extensively investigated in patients with preserved or only mildly reduced LVEF. We sought to investigate prevalence and incidence of anaemia in patients with HF irrespective of whether reduced or preserved ejection fraction are present. In addition, we sought to study the effects of nebivolol on the development of anaemia.Methods and resultsWe analysed data from 2069 patients randomized to nebivolol or placebo in the SENIORS study, 391 (10.0) of whom were anaemic. Anaemia was similarly common in patients with LVEF≤35 and those with LVEF>35 (19.0 vs. 18.7, P 0.89). Anaemic patients were older, had lower diastolic blood pressure, and worse kidney function (all P< 0.05). No difference was found between patients on nebivolol or placebo with regard to the presence of anaemia. A total of 348 (16.8) patients died during follow-up. The combined primary endpoint of all-cause mortality and cardiovascular hospital admission was reached by 687 (33.2) patients during follow-up, 164 (23.4) of whom were anaemic. Anaemic patients had a higher risk of reaching a primary endpoint than non-anaemics [LVEF≤35: hazard ratio (HR) 1.47, 95 confidence interval (CI) 1.181.82, P< 0.001; LVEF>35: HR 1.47, 95 CI 1.092.00, P 0.012]. After multivariable adjustment, haemoglobin remained an independent predictor of the primary outcome in this cohort of patients (HR 0.94 per 1 g/dL increase, 95 CI 0.890.99, P 0.017).ConclusionsAnaemia is an independent predictor of death or hospitalization for cardiovascular reasons among elderly patients with chronic HF and reduced or preserved/mildly reduced LVEF. Nebivolol does not affect haemoglobin values during follow-up. © 2011 The Author.


Chan K.M.J.,Imperial College London | Chan K.M.J.,Clinical Trials and Evaluation Unit | Chan K.M.J.,Royal Brompton and Harefield National Health Service Foundation Trust | Punjabi P.P.,Imperial College London | And 16 more authors.
Circulation | Year: 2012

BACKGROUND: The role of mitral valve repair (MVR) during coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MR) is uncertain. We conducted a randomized, controlled trial to determine whether repairing the mitral valve during CABG may improve functional capacity and left ventricular reverse remodeling compared with CABG alone. METHODS AND RESULTS: Seventy-three patients referred for CABG with moderate ischemic MR and an ejection fraction >30% were randomized to receive CABG plus MVR (34 patients) or CABG only (39 patients). The study was stopped early after review of interim data. At 1 year, there was a greater improvement in the primary end point of peak oxygen consumption in the CABG plus MVR group compared with the CABG group (3.3 mL/kg/min versus 0.8 mL/kg/min; P<0.001). There was also a greater improvement in the secondary end points in the CABG plus MVR group compared with the CABG group: left ventricular end-systolic volume index, MR volume, and plasma B-type natriuretic peptide reduction of 22.2 mL/m, 28.2 mL/beat, and 557.4 pg/mL, respectively versus 4.4 mL/m (P=0.002), 9.2 mL/beat (P=0.001), and 394.7 pg/mL (P=0.003), respectively. Operation duration, blood transfusion, intubation duration, and hospital stay duration were greater in the CABG plus MVR group. Deaths at 30 days and 1 year were similar in both groups: 3% and 9%, respectively in the CABG plus MVR group, versus 3% (P=1.00) and 5% (P=0.66), respectively in the CABG group. CONCLUSIONS: Adding mitral annuloplasty to CABG in patients with moderate ischemic MR may improve functional capacity, left ventricular reverse remodeling, MR severity, and B-type natriuretic peptide levels, compared with CABG alone. The impact of these benefits on longer term clinical outcomes remains to be defined. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00413998. © 2012 American Heart Association, Inc.


Manzano L.,University of Alcalá | Manzano L.,Hospital Universitario Ramn y Cajal | Manzano L.,Clinical Trials and Evaluation Unit | Babalis D.,Clinical Trials and Evaluation Unit | And 13 more authors.
European Journal of Heart Failure | Year: 2011

Aims Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged <70 years in order to develop a risk model for this population. Methods and resultsThe SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients <70 years with HF (ejection fraction ≤35, or recent HF admission). We randomly selected 1400 patients from the full dataset to produce a derivation cohort and the remaining 728 patients were used as a validation cohort. Baseline variables were entered into a bootstrap model with 200 iterations to determine their association with two outcomes, the composite of all-cause mortality or cardiovascular hospitalization, or all-cause mortality alone. Variables retaining a significant association with these outcomes in a multivariate model were used to develop a risk prediction score tested in the validation cohort. Five factors were associated with increased risk of both outcomes in the multivariate model: higher New York Heart Association class, higher uric acid level, lower body mass index, prior myocardial infarction, and larger left atrial (LA) dimension. For the composite outcome, peripheral arterial disease, years with heart failure, right bundle branch block, diabetes mellitus, and orthopnoea were also retained. For all-cause mortality, creatinine, 6 min walk test distance, coronary artery disease, and age were retained. Conclusion In addition to conventional prognostic markers, uric acid and LA dimension appear to be important novel risk prediction markers in elderly patients with heart failure, and could be useful in guiding management. © 2011 The Author.


Fleet J.E.,Royal Brompton and Harefield NHS Foundation Trust | Guha K.,Royal Brompton and Harefield NHS Foundation Trust | Piper S.,Royal Brompton and Harefield NHS Foundation Trust | Banya W.,Clinical Trials and Evaluation Unit | And 3 more authors.
Journal of Cystic Fibrosis | Year: 2013

Background: Azithromycin is widely used as an immunomodulatory agent in the treatment of cystic fibrosis with previous literature documenting improvements in lung function and a reduction in infective exacerbations. The maximal study period in adults has been six months. Methods: 81 adult patients taking continuous azithromycin were retrospectively identified. Percentage predicted FEV1 and courses of intravenous antibiotics were examined at yearly intervals two years prior to and two years after azithromycin initiation. Results: FEV1 deteriorated in the two years before starting azithromycin by a mean of 2.02% per year. In the year following initiation, FEV1 increased by 1.15% (P=0.01). However, a mean 2.58% reduction was observed in year two. There was no statistically significant effect on courses of intravenous antibiotics. Conclusions: Azithromycin resulted in an improved FEV1 at year one. This effect was not sustained beyond the first year of treatment. © 2012 European Cystic Fibrosis Society.


Geisler T.,Clinical Trials and Evaluation Unit | Geisler T.,University Hospital of Tuebingen | Gawaz M.,University Hospital of Tuebingen | Steinhubl S.R.,The Medicines Company | And 3 more authors.
Pharmacology and Therapeutics | Year: 2010

There is a wide consensus that intensified antiplatelet therapy contributes to the reduction of major atherothrombotic complications in cardiovascular (CV) disease. In the setting of PCI (percutaneous coronary intervention) and acute coronary syndromes, dual antiplatelet therapy at optimal dosing and timing has significantly lowered the risk of thrombotic complications. There is a growing body of evidence that there is variability in response to antiplatelet treatments and this represents a potentially important clinical problem. Understanding the mechanisms underlying this phenomenon is important in improving patient care, but due to the diversity of factors involved, a clear predictive model for responsiveness to antiplatelet therapy is still missing. Attempts have been made to characterize the efficacy of antiplatelet therapy using platelet function testing but based on current information, its routine use is not recommended particularly as costs and cost effectiveness have not been established and agreement between laboratory methods is lacking. Hence, it is necessary to identify risk factors for decreased efficacy of standard antiplatelet drug treatment. It may be useful to adjust antiplatelet therapy based on individual risk assessment, especially as new platelet inhibitors are being introduced or are in development including prasugrel as well as the non-thienopyridines, ticagrelor, elinogrel, the ATP analog cangrelor, and thrombin receptor antagonists. This article focuses on antiplatelet therapy in patients at high risk for cardiovascular events and discusses the options for individual risk assessment and strategies to personalize therapy in the light of the large number of recent developments. © 2010 Elsevier Inc.


Migliore M.,University of Catania | Milosevic M.,University of Novi Sad | Lees B.,Clinical Trials and Evaluation Unit | Treasure T.,University College London | Maria G.D.,University of Catania
Future Oncology | Year: 2015

The PulMiCC trial is a randomized controlled trial testing the effect on survival of pulmonary metastasectomy in patients with colorectal cancer. In stage 1 of the trial patients with treated primary colorectal cancer metastatic to the lungs are invited to consent for protocol-based evaluation of their suitability for metastasectomy. The evaluation is as in current practice and includes PET/CT. A decision for or against metastasectomy may be based on the opinion of the clinicians and the preference of the patient. If there is uncertainty the patient is invited to consent to have the treatment arm assigned by randomization in stage 2 of PulMiCC. More than 300 patients have entered stage 1 and more than 70 are in stage 2. © 2015 Future Medicine Ltd.


Stock C.J.,Imperial College London | Sato H.,Imperial College London | Fonseca C.,University College London | Banya W.A.S.,Clinical Trials and Evaluation Unit | And 11 more authors.
Thorax | Year: 2013

Background: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. Methods: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. Results: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04×10-17; OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. Conclusions We confirm the MUC5B variant association: with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.


Taggart D.P.,University of Oxford | Altman D.G.,University of Oxford | Gray A.M.,University of Oxford | Lees B.,Clinical Trials and Evaluation Unit | And 6 more authors.
European Heart Journal | Year: 2010

Aims Observational data suggest that the use of bilateral internal mammary arteries (BIMA) during coronary artery bypass graft surgery provides superior revascularization to a single internal mammary artery (SIMA), but concerns about safety have prevented the widespread use of BIMA. The Arterial Revascularisation Trial (ART) is a randomized trial of BIMA vs. SIMA, with a primary outcome of survival at 10 years. This paper reports mortality, morbidity, and resource use data at 1 year. Methods and resultsCoronary artery bypass graft patients were enrolled in 28 hospitals in seven countries. Three thousand one hundred and two patients were randomly assigned to SIMA (n = 1554) or BIMA (n = 1548). The mean number of grafts was 3 for both groups. Forty per cent of the SIMA procedures and 42 of the BIMA were performed off-pump. Mortality at 30 days was 18 of 1548 (1.2) for SIMA and 19 of 1537 (1.2) for BIMA, and at 1 year was 36 of 1540 (2.3) and 38 of 1529 (2.5), respectively. The rates of stroke, myocardial infarction, and repeat revascularization were all ≤2 at 1 year and similar between the two groups. Sternal wound reconstruction was required in 0.6 and 1.9 of the SIMA and BIMA groups, respectively. Conclusion Data from ART demonstrate similar clinical outcomes for SIMA and BIMA at 1 year but BIMA grafts are associated with a small absolute increase (1.3) in the need for sternal wound reconstruction. The results suggest that the use of BIMA grafts is feasible on a routine basis. The 10-year results of the ART will confirm whether BIMA grafting results in lower mortality and the need for repeat intervention.Trial registration: Controlled-trials.com (ISRCTN46552265). © 2010 The European Society of Cardiology. All rights reserved.

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