Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial
Koren M.J.,Jacksonville University |
Giugliano R.P.,Harvard University |
Raal F.J.,University of Witwatersrand |
Sullivan D.,Royal Prince Alfred Hospital |
And 9 more authors.
Circulation | Year: 2014
BACKGROUND-: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS-: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION-: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION-: URL: http://clinicaltrials.gov. Unique identifier: NCT01439880. © 2013 American Heart Association, Inc.
Colquhoun D.,Wesley Medical Center |
Sullivan D.,Royal Prince Alfred Hospital |
Civeira F.,Hospital Universitario Miguel Servet |
Rosenson R.S.,Mount Sinai School of Medicine |
And 9 more authors.
Journal of the American College of Cardiology | Year: 2014
Objectives This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. Background Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. Methods The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. Results Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. Conclusions Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905). © 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.
Gomez Sanz C.A.,Hospital Universitario Miguel Servet
Enfermeria Intensiva | Year: 2013
Introduction: Trouble sleeping is common in the elderly population and is attributed to changes that aging brings in the sleep architecture and circadian rhythm. The prevalence of insomnia shows a marked increase with advancing age, in a proportion of 14 to 32% among those over 65 years. If we add these physiological changes of sleep with those found in patients admitted to the Intensive Care Unit (ICU), the problem worsens. The prevalence of these disorders in these units is from 22 - 61%. Sleep deprivation may contribute to worsening of the patients.The main objective is to describe the quality of sleep of patients admitted to the Coronary ICU of the Hospital Miguel Servet and the environmental factors that contribute to these disorders. Material and methods: A total of 75 conscious and oriented patients in the Coronary ICU Hospital Miguel Servet were included. Data was collected between February 17 and April 30, 2011. The subjects were asked to state if they had slept well by means of a survey and to score the environmental factors that may have bothered them. Results and discussion: Most patients said they had slept well (66.7%). Noise was the environmental factor that bothered them most. In analyzing the different noises, patients identified hearing people talking as being the most annoying. Conclusion: Changes must be implemented in the unit that would favor restful sleep. © 2012 Elsevier España, S.L. y SEEIUC.
San Miguel R.,Complejo Hospitalario Of Navarra |
Gimeno-Ballester V.,Hospital Universitario Miguel Servet |
Mar J.,Hospital Alto Deba
Expert Review of Pharmacoeconomics and Outcomes Research | Year: 2014
The treatment of chronic hepatitis C has experienced a substantial progress with the arrival of Boceprevir and Telaprevir due to the significant increase in sustained viral response. Given the high cost, their approval has been followed by great deal of pharmacoeconomic literature analysing their efficiency. A systematic review of this literature was carried out, evaluating both its results and the methodology employed. 54 references were revised including 11 studies, 6 on naive populations, 3 on pre-treated patients and 2 in both of them. As the clinical heterogeneity of patients influenced sustained viral response, therapy regimens were assessed conditioned to the interleukin 28B polymorphism, the early response to treatment and the level of fibrosis, among other variables. Most of the options evaluated on a naive population presented ICERs below the acceptability threshold. The same occurred in the pre-treated population, where the subgroups analysis is perceived as a methodological limitation. © 2014 Informa UK, Ltd.
McNicholas W.T.,University College Dublin |
Verbraecken J.,University of Antwerp |
Marin J.M.,Hospital Universitario Miguel Servet
European Respiratory Review | Year: 2013
Sleep in chronic obstructive pulmonary disease (COPD) is commonly associated with oxygen desaturation, which may exceed the degree of desaturation during maximum exercise, both subjectively and objectively impairing sleep quality. The mechanisms of desaturation include hypoventilation and ventilation to perfusion mismatching. The consequences of this desaturation include cardiac arrhythmias, pulmonary hypertension and nocturnal death, especially during acute exacerbations. Coexistence of COPD and obstructive sleep apnoea (OSA), referred to as overlap syndrome, has been estimated to occur in 1% of the general adult population. Overlap patients have worse sleep-related hypoxaemia and hypercapnia than patients with COPD or OSA alone. OSA has a similar prevalence in COPD as in a general population of similar age, but oxygen desaturation during sleep is more pronounced when the two conditions coexist. Management of sleep-related problems in COPD should particularly focus on minimising sleep disturbance via measures to limit cough and dyspnoea; nocturnal oxygen therapy is not generally indicated for isolated nocturnal hypoxaemia. Treatment with continuous positive airway pressure alleviates hypoxaemia, reduces hospitalisation and pulmonary hypertension, and improves survival. © ERS 2013.
Anton A.,Hospital Universitario Miguel Servet
European journal of pain (London, England) | Year: 2012
Despite effective analgesic therapy, inadequate pain control is frequently perceived by patients and caregivers. To assess satisfaction with management of pain in cancer patients. Between January and May 2007, a cross-sectional multicentre study was conducted in 64 Medical Oncology Departments throughout Spain. A total of 525 outpatients with oncological diseases completed a questionnaire with demographic data, characteristics and intensity of pain, and perceptions and attitudes towards pain management at the time of a routine clinical visit. Physicians also completed a questionnaire with tumour-related and treatment-related data. Cluster analysis was used to classify patients into three groups (satisfied, neither satisfied nor dissatisfied or neutral, dissatisfied) according to pain intensity and satisfaction with treatment. Patients satisfied with their analgesic treatment (33%) had lower pain intensities and, when regularly asked about their pain, considered their physicians to be more involved in their treatment. Neither satisfied nor dissatisfied patients (neutral) (44%) had higher mean pain intensities. Two-thirds of them achieved marked relief of their pain and also thought that physicians were aware of their situation. Dissatisfied patients (23%) had moderate to severe pain intensities, and said that they were asked less frequently about their pain, and thought that their physicians were less involved in their analgesic treatment. Physician-patient communication and information provided to patients are essential aspects of patient perceptions and attitudes towards control of cancer-related pain. Pain is seen as a condition that may be controlled but affects the capacity to lead a normal life. © 2011 European Federation of International Association for the Study of Pain Chapters.
Divo M.,Harvard University |
Cote C.,University of South Florida |
De Torres J.P.,University of Navarra |
Casanova C.,University of La Laguna |
And 7 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012
Rationale: Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk. Objectives: To prospectively evaluate COPD comorbidities and mortality risk. Methods: We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a "comorbidome." A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index. Measurements and Main Results: Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08-1.18; P < 0.001) and non-COPD-related causes (HR, 1.18; 95% confidence interval, 1.15-1.21; P < 0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26-2.68; P < 0.001) in all BODE quartile. Conclusions: Comorbidities are frequent in COPD and 12 of them negatively influence survival.Asimple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD. Copyright © 2012 by the American Thoracic Society.
Miguel R.S.,Complejo Hospitalario Of Navarra |
Gimeno-Ballester V.,Hospital Universitario Miguel Servet |
Blazquez A.,Agencia Espanola de Medicamentos y Productos Sanitarios |
Mar J.,Hospital Alto Deba
Gut | Year: 2015
Background A new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF). Objective To estimate the cost-effectiveness of SOF-based regimens approved in the Summary of Product Characteristics (SmPC) versus the standard of care for different genotypes and patient populations (naive or pretreated). Methods A Markov model simulating CHC progression was used to estimate disease treatment costs and effects over patients' lifetimes, from the Spanish National Public Healthcare System perspective. Different therapeutic options were analysed for genotypes 1, 2 and 3 in naive population and for genotype 2 and 3 pretreated patients, according to data obtained from clinical trials. A one-way sensitivity analysis was performed to evaluate the uncertainty of certain parameters: treatment starting age, transition probabilities, drug costs and discount rate. A probabilistic sensitivity analysis was also carried out. Results For the naive population, the option SOF+pegylated-interferon-α (pIFN)+ribavirin (RBV) for 12 weeks recorded in SmPC for genotype 1 and 3 versus pIFN+RBV for 24 weeks estimated an incremental cost-effectiveness ratio (ICER) below the □40 000/quality-adjusted life-year (QALY) benchmark. For the pretreated population, SOF triple therapy reached an ICER on the threshold limit for genotype 3. Other options included in SmPC for different genotypes exceeded the accepted efficiency limit in our setting. Conclusions The options that included SOF+RBV+pIFN in a 12-week course regimen fell below the efficiency threshold considered in our setting. IFN-free regimens administered for 24 weeks reached figures over the benchmark of □40 000/QALY.
Cortes A.A.,Hospital Universitario Miguel Servet |
Urquizu L.C.,Hospital Universitario Miguel Servet |
Cubero J.H.,Hospital Universitario Miguel Servet
Translational Lung Cancer Research | Year: 2015
Adjuvant chemotherapy (AC) plays now a significant role in the treatment of resected nonsmall cell lung cancer (NSCLC) patients and has become standard in clinical practice. It took more than two decades of clinical research to show its value, but it is has been well established that its benefit translates into a 4-5% absolute increase in 5-year survival according to published meta-analysis. This improvement is obtained with two-drug, Cisplatin-based regimens (multiples choices are acceptable but vinorelbine is the drug with more reported evidence) and usually four courses are recommended. Survival increase is restricted to cases in which there is involvement of lymph nodes (both N1 and N2 levels). For N0 cases AC might be considered, with a lower level of evidence, for tumors larger than 4 cm in diameter. At the present time, molecular predictive factors and gene signatures are investigational. Patient selection is of paramount importance. Proper recovery from surgery and the absence of major comorbidities are essential features. Toxicity is significant, but manageable and transient. Neutropenia is the most relevant side effect due to the risk of febrile neutropenia. The role of timing of administration, adjuvant radiotherapy (RT) and of newer drugs under evaluation is also reviewed. © Translational lung cancer research. All rights reserved.
Modrego P.J.,Hospital Universitario Miguel Servet
Journal of Alzheimer's Disease | Year: 2010
Depression is a comorbid condition in Alzheimer's disease (AD) with negative consequences in patients and caregivers. Pathophysiology and optimal treatment are matters to be elucidated. A search of articles dealing with depression in AD was conducted in MEDLINE with special attention to epidemiology, pathophysiology, and treatment. Depression may predate dementia and tends to occur in up to 50% of AD patients with a decrease of noradrenalin and serotonin in the brain being the most plausible cause. Only 7 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression were found: 4 with sertraline, 1 with fluoxetine, 1 with imipramine, and another one with clomipramine. The total number of treated patients was 318. The weighted odds ratio (OR) was calculated with the method of Mantel-Haenszel. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are better than placebo in treating depression in AD (weighted OR: 1.82, 95% CI: 1.13-2.96), with sertraline being one of the most used drugs. The differences were significant in 2 trials and not significant in four. The magnitude of effect is globally modest. Moreover, it is noteworthy mentioning the high rates of response to placebo in most studies. Depression is one of the most frequent behavioral symptoms in AD. Although antidepressants may work in AD, given the small number of patients treated, the effect is unclear. Further large randomized controlled clinical trials are warranted in order to know the best drug to begin with and the actual degree of efficacy. © 2010 IOS Press and the authors. All rights reserved.