Sleep Apnea Heterogeneity, Phenotypes, and Cardiovascular Risk. Implications for Trial Design and Precision Sleep Medicine.
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ABSTRACT:
SUBMITTER: Zinchuk A
PROVIDER: S-EPMC6701039 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Sleep Apnea Heterogeneity, Phenotypes, and Cardiovascular Risk. Implications for Trial Design and Precision Sleep Medicine.
Zinchuk Andrey A Yaggi H Klar HK
American journal of respiratory and critical care medicine 20190801 4
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Project description:AbstractThe Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed.Clinical trials registration numberNCT00738179.Australia new zealand clinical trials registry numberACTRN12608000409370.
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Project description:BackgroundObstructive sleep apnoea (OSA) is a heterogeneous disorder, and improved understanding of physiologic phenotypes and their clinical implications is needed. We aimed to determine whether routine polysomnographic data can be used to identify OSA phenotypes (clusters) and to assess the associations between the phenotypes and cardiovascular outcomes.MethodsCross-sectional and longitudinal analyses of a multisite, observational US Veteran (n=1247) cohort were performed. Principal components-based clustering was used to identify polysomnographic features in OSA's four pathophysiological domains (sleep architecture disturbance, autonomic dysregulation, breathing disturbance and hypoxia). Using these features, OSA phenotypes were identified by cluster analysis (K-means). Cox survival analysis was used to evaluate longitudinal relationships between clusters and the combined outcome of incident transient ischaemic attack, stroke, acute coronary syndrome or death.ResultsSeven patient clusters were identified based on distinguishing polysomnographic features: 'mild', 'periodic limb movements of sleep (PLMS)', 'NREM and arousal', 'REM and hypoxia', 'hypopnoea and hypoxia', 'arousal and poor sleep' and 'combined severe'. In adjusted analyses, the risk (compared with 'mild') of the combined outcome (HR (95% CI)) was significantly increased for 'PLMS', (2.02 (1.32 to 3.08)), 'hypopnoea and hypoxia' (1.74 (1.02 to 2.99)) and 'combined severe' (1.69 (1.09 to 2.62)). Conventional apnoea-hypopnoea index (AHI) severity categories of moderate (15≤AHI<30) and severe (AHI ≥30), compared with mild/none category (AHI <15), were not associated with increased risk.ConclusionsAmong patients referred for OSA evaluation, routine polysomnographic data can identify physiological phenotypes that capture risk of adverse cardiovascular outcomes otherwise missed by conventional OSA severity classification.
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Project description:Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
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Project description:The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design.
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Project description:Previous studies have reported the effects of obstructive sleep apnea (OSA) and cardiometabolic disorders on cardiovascular disease (CVD), but associations between cardiometabolic biomarkers and two cardinal features of OSA (chronic intermittent hypoxia and sleep fragmentation) and their interactions on CVD in OSA populations remain unclear. A total of 1727 subjects were included in this observational study. Data on overnight polysomnography parameters, biochemical biomarkers, and anthropometric measurements were collected. Metabolic syndrome (MS), including blood pressure, waist circumference (WC), fasting glucose, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), was diagnosed based on modified criteria of the Adult Treatment Panel III. WC, mean arterial pressure, TG and low-density lipoprotein cholesterol (LDL-C) were independently associated with apnea-hypopnea index (AHI) after adjustment for confounding factors (β = 0.578, P = 0.000; β = 0.157, P = 0.001; β = 1.003, P = 0.019; and β = 4.067, P = 0.0005, respectively). Furthermore, the interaction analysis revealed joint effects between hypertension, obesity, hyperglycemia, and LDL-C dyslipidemia and AHI on CVD. The relative excess risks of CVD due to the interactions with OSA were 2.06, 1.02, 0.48, and 1.42, respectively (all P < 0.05). In contrast, we found no independent effect of the microarousal index (MAI) on CVD. However, LDL-C level and some MS components (WC, TG) were associated with MAI. Our findings indicate that hypoxemia and cardiometabolic disorders in OSA may potentiate their unfavorable effects on CVD. Sleep fragmentation may indirectly predispose patients with OSA to an increased risk of CVD. Thus, cardiometabolic disorders and OSA synergistically influence cardiometabolic risk patterns.
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Project description:THE SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE) STUDY (CLINICAL TRIALS REGISTRATION NUMBER: NCT00738170) is an academic initiated and conducted, multinational, open, blinded endpoint, randomised controlled trial designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the incidence of serious cardiovascular events in patients with established cardiovascular disease. The answer to this question is of major importance to populations undergoing ageing and lifestyle changes all over the world. The SAVE study brings together respiratory, sleep and cardiovascular clinician-scientists in a unique interdisciplinary collaborative effort with industry sponsors to conduct the largest and most ambitious clinical trial yet conducted in the field of sleep apnea, with a global recruitment target of 5000 patients. Following its launch in Australia and China in late 2008, SAVE has now entered a phase of international expansion with new recruitment networks being established in New Zealand, India and Latin America. This article describes the rationale for the SAVE study, the considerations behind its design, and progress thus far in establishing the recruitment network. The report emphasises the important role that Chinese sleep and cardiovascular investigators have played in the start-up phase of this landmark international project.
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Project description:Sleep apnea is a common chronic disease that is associated with coronary heart disease, stroke, heart failure and mortality, although the ability of sleep apnea treatment to reduce cardiovascular morbidity and mortality has not been demonstrated. In contrast to patients seeking treatment in sleep disorders centers, as many as half of individuals with moderate to severe sleep apnea in the general population do not report excessive sleepiness; however, if treatment of sleep apnea were shown to reduce cardiovascular disease risk, this would provide a strong rationale for treatment of sleep apnea even in the absence of daytime sleepiness. This article summarizes the status of clinical trials evaluating the potential cardiovascular benefits of sleep apnea treatment and discusses the challenges of conducting such trials, and introduces the International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT), a clinical research collaboration formed to foster cardiovascular sleep research.Gottlieb DJ; Craig SE; Lorenzi-Filho G; Heeley E; Redline S; McEvoy RD; Durán-Cantolla J. Sleep apnea cardiovascular clinical trials- current status and steps forward: the International Collaboration of Sleep Apnea Cardiovascular Trialists. SLEEP 2013;36(7):975-980.
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Project description:Sleep apnea is highly prevalent in patients with cardiovascular disease. These disordered breathing events are associated with a profile of perturbations that include intermittent hypoxia, oxidative stress, sympathetic activation, and endothelial dysfunction, all of which are critical mediators of cardiovascular disease. Evidence supports a causal association of sleep apnea with the incidence and morbidity of hypertension, coronary heart disease, arrhythmia, heart failure, and stroke. Several discoveries in the pathogenesis, along with developments in the treatment of sleep apnea, have accumulated in recent years. In this review, we discuss the mechanisms of sleep apnea, the evidence that addresses the links between sleep apnea and cardiovascular disease, and research that has addressed the effect of sleep apnea treatment on cardiovascular disease and clinical endpoints. Finally, we review the recent development in sleep apnea treatment options, with special consideration of treating patients with heart disease. Future directions for selective areas are suggested.
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