Phase II trials in heart failure: the role of cardiovascular imaging

The development of new therapies for heart failure (HF), especially acute HF, has proven to be quite challenging; and therapies evaluated in HF have greatly outnumbered treatments that are eventually successful in obtaining regulatory approval. Thus, the development of therapies for HF remains a vexing problem for pharmaceutical and device companies, clinical trialists, and health care professionals. Nowhere is this more apparent than in the phase II HF clinical trial, in which the goal is to determine whether an investigational agent should move forward to a phase III trial. Recent advancements in noninvasive cardiovascular imaging have allowed a new era of comprehensive phenotyping of cardiac structure and function in phase II HF trials. Besides using imaging parameters to predict success of subsequent phase III outcome studies, it is essential to also use imaging in phase II HF trials in a way that increases understanding of drug or device mechanism. Determination of the patients who would benefit most from a particular drug or device could decrease heterogeneity of phase III trial participants and lead to more successful HF clinical trials. In this review, we outline advantages and disadvantages of imaging various aspects of cardiac structure and function that are potential targets for therapy in HF, compare and contrast imaging modalities, provide practical advice for the use of cardiovascular imaging in drug development, and conclude with some novel uses of cardiac imaging in phase II HF trials.     

Sarcoidosis-Related Cardiomyopathy: Current Knowledge,Challenges, and Future Perspectives State-of-the-Art Review

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.     

Disturbances in blood flow and ‘medicine's greatest imitator’

First described in 1959, intravascular lymphoma (IVL) remains one of the most clinically challenging diagnoses due to its diverse and non‐specific clinical manifestations and evasiveness in detection by standard investigations. Indeed, IVL deserves the title of ‘medicine's greatest imitator’. We highlight a case of IVL where the diagnosis came too late in the clinical course, detected by random skin biopsy. Clinicians should strongly consider this diagnosis in presentations with persistent symptomatology despite appropriate interventions.     

Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials

Aims Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug‐dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. Methods A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug‐taking behavior, as measured by self‐report and qualitative or quantitative biological markers, are evaluated. Results Drug‐taking behavior, measured ideally by a combination of self‐report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. Conclusions We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them.     

Implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis

ICD Shocks in Cardiac Sarcoidosis . Background: An implantable cardioverter defibrillator (ICD) is indicated for some patients with cardiac sarcoidosis (CS) for prevention of sudden death. However, there are little data regarding the event rates of ICD therapies in these patients. We sought to identify the incidence and characteristics of ICD therapies in this patient population. Methods: We performed a cohort study of patients with ICDs at 3 institutions. Cases were those patients with CS and an ICD implanted for primary or secondary prevention of sudden death. Additionally, we included a comparison with historical controls of ICD therapy rates reported in clinical trials evaluating the ICD for primary and secondary prevention of sudden death. Results: Of the 112 CS subjects identified, 36 (32.1%) received appropriate therapies for ventricular tachyarrhythmias (VT) over a mean follow‐up period of 29.2 months. VT storm (>3 episodes in 24 hours) occurred in 16 (14.2%) CS subjects. Inappropriate therapies occurred in 13 CS subjects (11.6%). Covariates associated with appropriate ICD therapies included left ventricular ejection fraction (LVEF) <55% (OR 6.52 [95% CI 2.43–17.5]), right ventricular dysfunction (OR 6.73 [95% CI 2.69–16.8]), and symptomatic heart failure (OR 4.33 [95% CI 1.86–10.1]). Conclusions: In our cohort of patients with CS and ICDs, almost one‐third receive appropriate therapies. This may be due to a myocardial inflammatory process leading to increased triggered activity and subsequent scarring leading to reentrant tachyarrhythmias. Adjusted predictors of ICD therapies in this population include left or right ventricular dysfunction. (J Cardiovasc Electrophysiol, Vol. 23, pp. 925‐929, September 2012)     

Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand

Encephalitis is a complex neurological syndrome caused by inflammation of the brain parenchyma. The management of encephalitis is challenging because: the differential diagnosis of encephalopathy is broad; there is often rapid disease progression; it often requires intensive supportive management; and there are many aetiologic agents for which there is no definitive treatment. Patients with possible meningoencephalitis are often encountered in the emergency care environment where clinicians must consider differential diagnoses, perform appropriate investigations and initiate empiric antimicrobials. For patients who require admission to hospital and in whom encephalitis is likely, a staged approach to investigation and management is preferred with the potential involvement of multiple medical specialties. Key considerations in the investigation and management of patients with encephalitis addressed in this guideline include: Which first‐line investigations should be performed?; Which aetiologies should be considered possible based on clinical features, risk factors and radiological features?; What tests should be arranged in order to diagnose the common causes of encephalitis?; When to consider empiric antimicrobials and immune modulatory therapies?; and What is the role of brain biopsy?     

Biomarker guided therapy for heart failure: focus on natriuretic peptides

The management of heart failure remains challenging despite many therapeutic advances. Rigorous clinical trial evidence supports administration of multiple therapies, but utilization of evidence-based treatment remains inconsistent and suboptimal. Disease management programs appear effective, but remain costly and difficult to implement in today’s care system. Another approach involves optimizing therapy based on serial monitoring of cardiac biomarkers. Emerging results suggest that guiding therapy based on serial changes in natriuretic peptides may be an effective strategy. Although pilot work has provided encouraging results, appropriately designed, large-scale, prospective randomized trials are needed to confirm these preliminary findings and definitively establish this therapeutic approach.     

Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme

Aim: Effective type 2 diabetes management requires a multifactorial approach extending beyond glycaemic control. Clinical practice guidelines suggest targets for HbA1c, blood pressure and lipids, and emphasize weight reduction and avoiding hypoglycaemia. The phase 3 clinical trial programme for liraglutide, a human glucagon‐like peptide 1 analogue, showed significant improvements in HbA1c and weight with a low risk of hypoglycaemia compared to other diabetes therapies. In this context, we performed a meta‐analysis of data from these trials evaluating the proportion of patients achieving a clinically relevant composite measure of diabetes control consisting of an HbA1c <7% without weight gain or hypoglycaemia. Methods: A prespecified meta‐analysis was performed on 26‐week patient‐level data from seven trials (N = 4625) evaluating liraglutide with commonly used therapies for type 2 diabetes: glimepiride, rosiglitazone, glargine, exenatide, sitagliptin or placebo, adjusting for baseline HbA1c and weight, for a composite outcome of HbA1c <7.0%, no weight gain and no hypoglycaemic events. Results: At 26 weeks, 40% of the liraglutide 1.8 mg group, 32% of the liraglutide 1.2 mg group and 6–25% of comparators (6% rosiglitazone, 8% glimepiride, 15% glargine, 25% exenatide, 11% sitagliptin, 8% placebo) achieved this composite outcome. Odds ratios favoured liraglutide 1.8 mg by 2.0‐ to 10.5‐fold over comparators. Conclusions: As assessed by the composite outcome of HbA1c <7%, no hypoglycaemia and no weight gain, liraglutide was clearly superior to the other commonly used therapies. However, the long‐term clinical impact of this observation remains to be shown.     

Pharmacological treatment for Type 2 diabetes integrating findings from cardiovascular outcome trials: an expert consensus in the UK

In people with Type 2 diabetes, cardiovascular disease is a leading cause of morbidity and mortality. Thus, as well as controlling glucose, reducing the risk of cardiovascular events is a key goal. The results of cardiovascular outcome trials have led to updates for many national and international guidelines. England, Wales and Northern Ireland remain exceptions, with the most recent update to the National Institute for Health and Care Excellence (NICE) guidelines published in 2015. We reviewed current national and international guidelines and recommendations on the management of people with Type 2 diabetes. This article shares our consensus on clinical recommendations for the use of sodium‐glucose co‐transporter 2 inhibitors (SGLT‐2is) and glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) in people with Type 2 diabetes and established or at very high risk of cardiovascular disease in the UK. We also consider cost‐effectiveness for these therapies. We recommend considering each person's cardiovascular risk and using diabetes therapies with proven cardiovascular benefits when appropriate to improve long‐term outcomes and cost‐effectiveness.     

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND: Hepatocellular carcinoma (HCC) is a com-plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con-founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal-ity globally with a rising trend of incidence in some of the de-veloped countries, which indicates the need for better surgical and nonsurgical management strategies.
DATA SOURCES: PubMed database was searched for relevant articles in English on the issue of HCC management.
RESULTS: Surgical resection represents a potentially cura-tive option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and micro-wave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The signiifcant survival beneift with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treat-ment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential beneift is sug-gested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immuno-therapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches.
CONCLUSION: Treatment decisions have become increasing-ly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a compre-hensive, multidisciplinary approach.     

Treatment of Pericardial Disease

The pericardium is composed of visceral and parietal components. In view of the pericardium's simple structure, pathologic processes involving it are understandably few. However, despite a limited number of clinical syndromes, the pericardium is affected by virtually every category of disease, including infectious, neoplastic, immune—inflammatory, metabolic, iatrogenic, and traumatic. Thus, the recognition of pericardial heart disease remains challenging. Treatment of pericardial disease is also problematic in that there is a paucity of randomized, placebo‐controlled trials from which appropriate therapy may be selected and important clinical decisions assisted. This article reviews pericarditis and its sequelae, pericardial effusions, cardiac tamponade and constrictive pericarditis,     

The bone marrow--cardiac axis of myocardial regeneration

Congestive heart failure remains the leading cause of morbidity and mortality in the developed world. Current therapies do not address the underlying pathophysiology of this disease, namely, the progressive loss of functional cardiomyocytes. The notion of repairing or regenerating lost myocardium via cell-based therapies remains highly appealing. The recent identification of adult stem cells, including both cardiac stem/progenitor cells and bone marrow stem cells, has triggered an explosive interest in using these cells for physiologically relevant cardiomyogenesis. Enthusiasm for cardiac regeneration via cell therapy has further been fueled by the many encouraging reports in both animals and human studies. Further intensive research in basic science and clinical arenas are needed to make this next great frontier in cardiovascular regenerative medicine a reality. In this review, we focus on the role of bone marrow-derived stem cells and cardiac stem/progenitor cells in cardiomyocyte homeostasis and myocardial repair and regeneration, as well as provide a brief overview of current clinical trials using cell-based therapeutic approaches in patients with heart disease.     

Small vessel vasculitis of the lung

The diagnosis and management of SVV remains one of the most challenging clinical scenarios encountered by a clinician. Careful attention to detail and a thorough knowledge of the specific disorders, their therapies, and complications thereof is required to optimally care for these patients. The recent completion of a number of randomized, controlled, multicenter clinical trials has greatly improved our knowledge base and ability to care for vasculitis patient. The next decade holds even more promise.     

Interventional therapies for malignant pleural effusions: The present and the future

The approach to management of malignant pleural effusions (MPE) has changed over the past few decades. The key goals of MPE management are to relieve patient symptoms using the least invasive means and in the most cost‐effective manner. There is now a realization that patient‐reported outcome measures should be the primary goal of MPE treatment, and this now is the focus in most clinical trials. Efforts to minimize patient morbidity are complemented by development of less invasive treatments that have mostly replaced the more aggressive surgical approaches of the past. Therapeutic thoracentesis is simple, effective and generally safe, although its benefits may only be temporary. Pleurodesis is the conventional and for a long time the only definitive therapy available. However, the efficacy and safety of talc pleurodesis has been challenged. Indwelling pleural catheter (IPC) drainage is increasingly accepted worldwide and represents a new concept to improve symptoms without necessarily generating pleural symphysis. Recent studies support the effectiveness of IPC treatment and provide reassurance regarding its safety. An unprecedented number of clinical trials are now underway to improve various aspects of MPE care. However, choosing an optimal intervention for MPE in an individual patient remains a challenge due to our limited understanding of the underlying pathophysiology of breathlessness in MPE and a lack of predictors of survival and pleurodesis outcome. This review provides an overview of common pleural interventional procedures used for MPE management, controversies and limitations of current practice, and areas of research most needed to improve practice in future.     

Advances in the understanding and management of angioimmunoblastic T‐cell lymphoma

Angioimmunoblastic T‐cell lymphoma (AITL) is a distinct peripheral T‐cell lymphoma (PTCL) entity with peculiar clinical and pathological features. The recent identification of follicular helper T (T_FH) cell as the cell of origin of this neoplasm represents a major step in our understanding of the pathobiological characteristics of the disease and should, in the future, clarify the diagnostic criteria for AITL and help to delineate its spectrum, especially from PTCL, not otherwise specified (PTCL, NOS). Deciphering the pathogenesis of the disease is needed to identify targets for new therapies that are expected to improve the poor outcome of AITL patients, when treated with conventional chemotherapy regimens. In this respect, efforts will be needed to evaluate promising innovative therapies in prospective clinical trials.     

Impact of Remote Monitoring on Clinical Outcomes

Follow‐up of patients with cardiac implantable electronic devices is challenging due to both their increasing volume and technical complexity coupled to increasing clinical complexity of recipient patients. Remote monitoring (RM) offers an opportunity to resolve some of these difficulties by improving clinic efficiencies and providing a mechanism for device monitoring and patient management. Several recent randomized clinical trials and registries have demonstrated that RM may reduce in‐hospital visit numbers, time required for patient follow‐up, physician and nurse time, and hospital and social costs. Furthermore, patient retention and adherence to follow‐up schedule are significantly improved by RM. Continuous wireless monitoring of data stored in the device memory with automatic alerts allows early detection of device malfunctions and of events, such as atrial fibrillation, ventricular arrhythmias, and heart failure suitable for clinical intervention. Early reaction may improve patient outcome. RM is easy to use and patients showed a high level of acceptance and satisfaction. Implementing RM in daily practice may require changes in clinic workflow. New organizational models promote significant efficiencies regarding physician and nursing time. Data management techniques are under development. Despite these demonstrable advantages of RM, adoption still remains modest, even in health care systems incentivized to use this follow‐up method.     

Mechanical Circulatory Support in Cardiogenic Shock: Shock Team or Bust?

Cardiogenic shock (CS) accounts for 15% of all admissions to cardiac intensive care units, with acute myocardial infarction cardiogenic shock (AMICS) accounting for 30% of these. In contrast to other areas in cardiac care in which survival has continued to improve over the last two decades, CS still carries a mortality of around 40%. Temporary mechanical circulatory support (tMCS) therapies have shown inconsistent results in improving outcomes in CS, with the overall evidence not supporting its use, at least in unselected patients. Some of the main stumbling blocks leading to disappointing results of tMCS in CS are challenging patient identification and selection; delayed timing; lack of a systematic approach; inappropriate use of adjunct therapies and tools; lack of escalation/de-escalation and long-term planning; and disparities in regional/centre access to MCS. Among the most promising solutions to this challenge is the cardiogenic shock team (CST), which takes a standardized multidisciplinary approach to the acute management of CS. This paradigm brings expertise from advanced heart failure, interventional cardiology, cardiac surgery, cardiac intensive care, nursing, and others to address all of the aforementioned issues effectively. Unsurprisingly, hurdles to implementation exist, such as establishing effective team dynamics, maintenance of competence, and securing and maintaining adequate resources. However, although the shock-team approach is still in the early stages of clinical evolution, preliminary studies have been encouraging and suggest the value of broader application and evaluation.     

Current Status of Cell-Based Therapy for Heart Failure

In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow–derived mononuclear cells, bone marrow–derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell–based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future.     

Epidemiology,Pathogenesis, and Diagnosis of Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is a widely underdiagnosed yet clinically significant form of granulomatous myocarditis associated with significant morbidity and mortality. Clinical presentation ranges from silent cardiac involvement detected on imaging to cardiomyopathy or sudden cardiac death. Diagnosis of CS remains challenging due to the lack of sensitivity and specificity of any single diagnostic method, underscoring the importance of elevated clinical suspicion and the use of multimodality imaging to guide diagnosis and treatment. In this review, we discuss the epidemiology, pathogenesis, clinical features, and diagnosis of this clinically evading and enigmatic disease.