Rationale for and design of the TRUE‐AHF trial: the effects of ularitide on the short‐term clinical course and long‐term mortality of patients with acute heart failure

The TRUE‐AHF is a randomized, double‐blind, parallel‐group, placebo‐controlled trial which is evaluating the effects of a 48‐h infusion of ularitide (15 ng/kg/min) on the short‐ and long‐term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long‐term follow‐up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event‐driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in‐hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE‐AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure. Trial registration: NCT01661634     

Hypertension and frailty in older adults

The association between hypertension and frailty syndrome in older adults remains unclear. There is scarce information about the prevalence of hypertension among frail elderly patients or on its relationship with frailty. Up to one quarter of frail elderly patients present without comorbidity or disability, yet frailty is a leading cause of death. The knowledge and better control of frailty risk factors could influence prognosis. The present study evaluated: (1) the prevalence of hypertension in robust, prefrail, and frail elderly; and (2) factors that might be associated with frailty including hypertension. A cross‐sectional study was conducted in 619 older adults at a university‐based outpatient center. Study protocol included sociodemographic data, measures of blood pressure and body mass index, frailty screening according to the internationally validated FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale, number of comorbidities, drug use assessment, physical activity, cognitive status, and activities of daily living. Ordinal logistic regression was used to evaluate factors associated with frailty. Prevalence of hypertension and frailty was 67.3% and 14.8%, respectively, in the total sample. Hypertension was more prevalent in the prefrail (72.5%) and frail (83%) groups than among controls (51.7%). Hypertension, physical activity, number of prescribed drugs, and cognitive performance were significantly associated with frailty status. Hypertension presented an odds ratio of 1.77 towards frailty (95% confidence interval, 1.21–2.60; P = .002). Hypertension was more prevalent in frail elderly patients and was significantly associated with frailty. Intensive control of hypertension could influence the trajectory of frailty, and this hypothesis should be explored in future prospective clinical trials.     

Invasive Versus Conservative Strategy in Frail Patients With NSTEMI: The MOSCA-FRAIL Clinical Trial Study Design

Introduction and objectives

Although clinical guidelines recommend invasive management in non–ST-segment elevation myocardial infarction (NSTEMI), this strategy is underused in frail elderly patients in the real world. Furthermore, these patients are underrepresented in clinical trials and therefore the evidence is scarce. Our hypothesis is that an invasive strategy will improve prognosis in elderly frail patients with NSTEMI.

Therapeutic Interventions for Frail Elderly Patients: Part II. Ongoing and Unpublished Randomized Trials

There is increasing momentum to measure frailty in clinical practice given its proven value as a predictor of outcomes, particularly in elderly patients with cardiovascular disease. The number of randomized clinical trials targeting frail older adults has been modest to date. Therefore, we systematically searched the ClinicalTrials.gov registry in order to review the frailty intervention trials that had been actively initiated or completed but not yet published. The interventions studied were exercise training in 2 trials, nutritional supplementation in 3 trials, combined exercise plus nutritional supplementation in 5 trials, pharmaceutical agents in 5 trials, multi-dimensional programs in 2 trials, and home-based services in 3 trials. Their respective study designs, populations, interventions, and planned outcomes are presented in this article.     

Rationale and design of The National Emphysema Treatment Trial: a prospective randomized trial of lung volume reduction surgery. The National Emphysema Treatment Trial Research Group

The National Emphysema Treatment Trial is a multicenter, randomized clinical trial of medical therapy vs medical therapy plus lung volume reduction surgery (LVRS) for the treatment of patients with severe bilateral emphysema. LVRS will be accomplished by bilateral stapled excision via median sternotomy or video-assisted thoracoscopic surgery. Every patient will complete 6 to 10 weeks of pulmonary rehabilitation prior to randomization and will participate in a maintenance program of pulmonary rehabilitation after randomization. The primary outcome to be assessed by the trial is survival. Additional outcomes to be assessed are maximum exercise capacity, pulmonary function, oxygen requirement, distance walked in 6 min, quality of life, respiratory symptoms, and health-care utilization and costs. In addition, selected clinics will evaluate lung mechanics and respiratory muscle function, partial and maximal flow-volume curves, gas exchange during maximal exercise, and right heart function. The trial is targeted to enroll patients with severe emphysema who have no significant comorbid conditions; each patient will be randomized to one of the two treatment groups. The study duration is 4.5 years with a close-out period of 6 months.     

Rationale and design of the national emphysema treatment trial. A prospective randomized trial of lung volume reduction surgery. The national emphysema treatment trial research group

The National Emphysema Treatment Trial is a multicenter, randomized clinical trial of medical therapy vs medical therapy plus lung volume reduction surgery (LVRS) for the treatment of patients with severe bilateral emphysema. LVRS will be accomplished by bilateral stapled excision via median sternotomy or video-assisted thoracoscopic surgery. Every patient will complete 6 to 10 weeks of pulmonary rehabilitation prior to randomization and will participate in a maintenance program of pulmonary rehabilitation after randomization. The primary outcome to be assessed by the trial is survival. Additional outcomes to be assessed are maximum exercise capacity, pulmonary function, oxygen requirement, distance walked in 6 min, quality of life, respiratory symptoms, and health-care utilization and costs. In addition, selected clinics will evaluate lung mechanics and respiratory muscle function, partial and maximal flow-volume curves, gas exchange during maximal exercise, and right heart function. The trial is targeted to enroll patients with severe emphysema who have no significant comorbid conditions; each patient will be randomized to one of the two treatment groups. The study duration is 4.5 years with a close-out period of 6 months.     

Evaluating the Efficacy,Safety, and Tolerability of Serelaxin When Added to Standard Therapy in Asian Patients With Acute Heart Failure: Design and Rationale of RELAX-AHF-ASIA Trial

Background

Acute heart failure (AHF), a common and growing health concern worldwide, is associated with high risk of post-discharge rehospitalization and mortality. Existing evidence indicates potential therapeutic benefits of serelaxin in Caucasian AHF patients, but corresponding data in Asians remain scarce. RELAX-AHF-ASIA, a multinational, randomized, double-blind, placebo-controlled, phase III trial, will evaluate the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients, with the use of novel assessments.

Anticoagulant Therapy for Frail Patients with Atrial Fibrillation

The prevalence of atrial fibrillation (AF) increases with age, as does the proportion of patients with frailty. AF patients with frailty have a higher risk of stroke than those without frailty, and progressive frailty caused by stroke is also associated with a worse prognosis. Despite this, anticoagulant therapy tends to not be used in frail patients because of the risk of falls and bleeding complications. However, some studies have shown that anticoagulant therapy improves the prognosis in patients with frailty. An accurate assessment of the “net-clinical-benefits” is needed in patients with frailty, with the aim of improving the prognoses of patients with frailty by selecting those who will benefit from anticoagulant therapy and actively reducing the risk of bleeding. A comprehensive intervention that includes a team of doctors and social resources is required. We herein review the effectiveness and bleeding risk associated with anticoagulant therapy in frail patients investigated in clinical studies.     

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ～6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.     

Acute heart failure: lessons learned so far

Acute heart failure (AHF) affects nearly every Canadian with heart failure (HF) at least once. Despite several attempts, no medical therapies have been shown to improve the natural history of AHF. In addition, the place of diagnosis of AHF is increasingly made in the outpatient setting. In this view, AHF is a moving target, and from recent registry data and from clinical trials, 5 critical lessons regarding the syndrome of AHF emerge: (1) The period of clinical instability preceding AHF may be much longer than previously thought. (2) Refinement of tools used to aid the early and accurate diagnosis of AHF will impact patient outcomes. (3) Standard supportive care of patients with AHF includes early use of diuretics with frequent reassessment in nearly all patients and supplemental vasodilators and oxygen therapy in selected cases. (4) Patients who survive presentation of AHF continue to suffer high rates of re-presentation, death, and rehospitalization following discharge from either hospital or emergency department. (5) Interventions shown to improve patient outcomes for AHF to date are related to process of care rather than new medications or devices.This report reviews the recent literature regarding the presentation, diagnosis, management, and prognosis of AHF. Areas of future research priority are indicated and guidelines for improving treatment are provided. AHF is an important clinical area that has not been as intensively studied as chronic HF; it presents both important needs and exciting opportunities for research and innovation.     

The need for long-term personalized management of frail CVD patients by rehabilitation and telemonitoring: A framework

Due to advances in cardiovascular medicine and preventive cardiology, patients benefit from a better prognosis, even in case of significant disease burden such as acute and chronic coronary syndromes, advanced valvular heart disease and chronic heart failure. These advances have allowed CVD patients to increase their life expectancy, but on the other hand also experience aging-related syndromes such as frailty. Despite being underrecognized, frailty is a critical, common, and co-existent condition among older CVD patients, leading to exercise intolerance and compromised adherence to cardiovascular rehabilitation (CR). Moreover, frail patients need a different approach for CR and are at very high risk for adverse events, but yet are underrepresented in conventional CR. Fortunately, recent advances have been made in technology, allowing remote monitoring, coaching and supervision of CVD patients in secondary prevention programs with promising benefits. Similarly, we hypothesized that such programs should also be implemented to treat frailty in CVD patients. However, considering frail patients’ particular needs and challenges, telerehabilitation interventions should thus be appropriately adapted. Our purpose is to provide, for the first time and based on expert opinions, a framework of how such a cardiac telerehabilitation program could be developed and implemented to manage a prevention and rehabilitation program for CVD patients with frailty.     

Underutilization of IV Nitrates in the Treatment of Acute Heart Failure

Acute heart failure (AHF) is a growing public health concern with high inhospital mortality and costs. Clinical practice guidelines, underpinned by positive randomized controlled trials, recommend the early use of intravenous (IV) nitrates in the treatment of AHF. However, the “real‐world” usage of IV nitrates has not been clearly defined. The objective of this study was to examine the use of IV nitrates in the treatment of AHF as recommended by clinical practice guidelines. A case‐record analysis was conducted of all admissions with AHF at a large teaching hospital. Of the 81 AHF patients (mean age 77 ± 11, mean SBP 130 ± 27 mmHg) enrolled for this analysis, only 5 (6%) received IV nitrates at the time of AHF admission. Forty (49%, mean age 77 ± 11, mean SBP 131 ± 27 mmHg) of these 81 patients met the guideline criteria for suitability for IV nitrates and only 5 (12%) of these received them during this admission. Patients who received IV nitrates were more likely to have higher blood pressure and all had myocardial ischemia as a precipitant. Seventy‐five (93%) of the total population received loop diuretics on admission. Overall, this study shows that loop diuretics remain the first‐line therapy in AHF with little use of IV nitrates, despite recommendations from clinical practice guidelines.     

衰弱状态对老年患者围术期不良事件影响的研究进展

在社会老龄化趋势不断加速的背景下,老年人口的外科手术比例也持续上升。尽管手术、麻醉技术和围术期医学在不断进步,老年手术患者仍在遭受不良术后结局的困扰。衰弱指老年人多系统生理储备下降,外界轻微的伤害性刺激便可引起生理机能快速而剧烈的变化,是术后不良事件发生的一个重要的风险因素。本文回顾了近年来衰弱与围术期不良事件联系的相关文献,拟就衰弱的概念、衰弱的评估工具、衰弱对围术期结局的影响以及衰弱患者围术期优化策略进行综述,以期为临床优化衰弱老年患者的身体机能,避免围术期不良结局提供理论支持。     

Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients

Aims/Introduction

Previously, a study using a narrowly defined (physical base) frailty scale reported that both good and bad (U‐shaped curve) glycated hemoglobin (HbA1c) levels were frailty risk factors in patients with type 2 diabetes mellitus. However, no such studies in Japan have shown this. We aimed to evaluate the frailty risk factors including HbA1c in elderly Japanese patients with type 2 diabetes mellitus using a broadly defined (both physical and psychosocial base) frailty scale, the Clinical Frailty Scale (CFS).

Materials and Methods

We randomly enrolled 132 elderly patients with type 2 diabetes mellitus (aged ≥65 years) and categorized the patients into nine stages of frailty using CFS. Because no patient had CFS 9, patients with a CFS score of 1–4 and 5–8 were defined as non‐frail and frail, respectively. We attempted to identify the risk factors of frailty by investigating the association between CFS stage and various patient factors.

Results

Multiple regression analysis showed that an increase in age, low levels of albumin, high‐density lipoprotein cholesterol, systolic blood pressure, HbA1c, total cholesterol, and bodyweight were statistically significant and strong independent risk factors for frailty, suggesting that reverse metabolism owing to malnutrition in elderly type 2 diabetes mellitus patients might be involved.

Conclusions

HbA1c level was not a U‐shaped risk for frailty, suggesting that relatively good glycemic control might be more important for frailty than poor control in elderly type 2 diabetes mellitus patients.     

衰弱评估在老年冠心病患者心脏康复治疗中的应用

随着医疗技术水平的进步,人类预期寿命大大增加,然而随着年龄的增加衰弱与心血管疾病的患病率也不断上升,老年人尤其如此。目前,国内关于衰弱与心血管疾病相关性的研究报道尚不多。本文重点关注衰弱评估中的肌力评估与步速评估在老年冠心病患者心脏康复治疗中的应用,以期说明衰弱评估对于预测老年冠心病患者心脏康复预后的重要性,希望能够引起临床各相关学科的重视,旨在为老年冠心病患者心脏康复的诊疗及预防提供新思路。     

Treatment of protein-energy malnutrition in chronic disorders in the elderly

Protein-energy malnutrition (PEM) is a complication to chronic disease and is associated with increased morbidity and mortality. The causal connections between malnutrition and a poorer prognosis are complex. It cannot automatically be inferred that nutritional support will improve the clinical course of elderly patients with wasting disorders, such as chronic obstructive pulmonary disease, chronic heart failure, stroke, dementia and multiple disorders or after hip fracture. The execution of nutrition treatment studies in chronically ill patients is linked to several methodological problems, including no generally accepted definition of PEM, uncertain patient compliance with supplementation, and a wide range of outcome variables. However, treatment studies indicate that dietary supplements, either alone or in combination with hormonal treatment, may have positive effects. Nutritional therapy given to patients at nutritional risk in conjunction with chronic obstructive pulmonary disease may improve respiratory function. When administered to elderly patients with multiple disorders, diet therapy may improve their functional capacity and given to elderly women after hip fractures nutritional therapy may speed up the rehabilitation process. Nevertheless, there is still a great need for randomised, controlled long-term studies of the effects of nutritional intervention programs for the chronically ill and frail elderly with a focus on determining clinically relevant outcomes.     

The benefits and limitations of a physical training program in patients with inflammatory myositis

The clinical features of inflammatory myositis are determined by the severity and extent of muscle weakness and systemic manifestations. The benefits and limitations of physical training programs and rehabilitation strategies depend on the clinical phase of the disease and analysis of underlying impairments responsible for functional limitations in the patient. Patients with early stage disease and severe weakness will be treated differently than patients who have responded to medication and are improving. Not all patients will respond to medications; their therapy programs will have different requirements. This article reviews available data on the physiologic responses to exercise in patients with inflammatory muscle diseases. New data support more aggressive approaches to progressive strengthening exercises for patients with inflammatory myositis.     

老年糖尿病患者伴衰弱的营养管理

随着我国人口老龄化,老年糖尿病患病率逐年升高。老年糖尿病患者营养不良发生风险增高,更易导致衰弱的发生。糖尿病和衰弱的发生发展相互作用,从而对患者的临床结局产生不利影响。对老年糖尿病患者的衰弱早期识别并进行合理的营养支持,可以减缓或逆转衰弱进程,提高老年患者生活质量并减少医疗负担。本文就目前国内外对于老年糖尿病患者伴衰弱的营养管理研究进展予以综述。     

Frailty in nonagenarians: A bridge too far?

• There is no clear consensus about the definition of frailty and how to accurately measure it.
• There is accumulating evidence that frail old patients have worse outcomes after TAVR compared to non‐frail patients.
• Further randomized research is needed to confirm those concerns and to standardize the role of frailty assessment in patient selection for TAVR.

     

衰弱对老年急性冠脉综合征患者预后及治疗策略的影响

衰弱是常见老年综合征之一,衰弱增加老年急性冠脉综合征(ACS)患者的死亡率、心血管事件、住院时间及出血风险,衰弱患者接受冠状动脉造影及冠状动脉介入治疗的可能性较非衰弱者低,衰弱也会增加接受冠状动脉介入治疗的患者死亡 率。老年衰弱患者是否可以从经皮冠状动脉介入治疗(PCI)中获益,以及如何进行临床决策尚缺乏足够的循证医学证据指导。