Annual Review of Medicine - Volume 65, 2014

The term translational research is typically used to refer both to “bench to bedside” research, in which preclinical research findings inform the development of novel therapeutics, and to the dissemination of new treatments to the community to encourage the use of the new health practices and treatments. Both definitions are germane to understanding the evidence base for treatment of post-traumatic stress disorder (PTSD) today. This article offers (a) an overview of evidence-based treatments for PTSD, (b) a description of a translational model of PTSD, and (c) a discussion of common barriers to dissemination and implementation of the empirically validated treatments. Recent studies in the field are discussed with a focus on pharmacotherapies, psychotherapies, and combined treatments.

Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor–based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer.

Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions.

Transcatheter aortic valve replacement (TAVR) is an emerging technology for the management of patients with severe aortic stenosis (AS). First reported in 2002, TAVR has made remarkable progress in the past decade with completion of major randomized clinical trials, multiple observational registries, and evolution of several new devices. This article is a brief introductory overview of the TAVR procedure, devices, trials and registries, and newer developments in the field.

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.

In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.

Published phase I and II trials with two fully human monoclonal antibodies to PCSK9 have provided comprehensive evidence that inhibiting PCSK9 is a very effective method to reduce low-density lipoprotein cholesterol (LDL-C). In all populations studied so far, whether on statins or LDL-C-reducing diet alone, with or without a genetic defect in the LDL receptor, and in subjects intolerant to statins, the LDL-C reductions have been large and consistent. Even the most efficacious statin, rosuvastatin, at its highest dose has not achieved such reductions. The clinical trials have established that monoclonal antibody therapy targeted to PCSK9 may be administered subcutaneously every two or four weeks. Current data suggest these drugs will provide an effective therapeutic option for LDL-C reduction and that, if proven safe in phase III trials, they will be as important to LDL-C control, and likely to cardiovascular disease risk reduction, as statins have been over the past three decades.

Hypercholesterolemia is considered the primary risk factor for cardiovascular disease. An estimated 200 million prescriptions are issued per year for statins to treat hypercholesterolemia. Importantly, statins have additional beneficial effects independent of their effects on lipids. Recent studies have shown that statins reduce thrombosis via multiple pathways, including inhibiting platelet activation and reducing the pathologic expression of the procoagulant protein tissue factor. Many of the antithrombotic effects of statins are attributed to inhibiting prenylation of RhoA and effects on other intracellular signaling molecules such as NF-κB and KLF2. These antithrombotic activities of statins likely contribute to the ability of statins to reduce the incidence of cardiovascular death.

Growing concern regarding costs of care and health outcomes in the United States has led to widespread calls to address the issue of health care spending. Today, providers across the country are working both to improve the quality and to reduce the cost of health care. These activities span multiple care delivery settings and include care standardization and redesign, shared decision making, palliative care, care coordination, readmission reduction, patient engagement, predictive modeling, and direct cost reduction. These efforts differ from those undertaken in the past because of the availability of information technology tools to collect and analyze data, and because of the emphasis on cost reduction in conjunction with quality improvement. Although the available literature reflects only a small fraction of the provider activities currently in progress, there is cause for hope for achieving a sustainable, innovative, and value-driven health care system.

In an era of ever-increasing healthcare costs, new treatments must not only improve outcomes and quality of care but also be cost-effective. This is most challenging for emergency and critical care. Bigger and better has been the mantra of Western medical care for decades, leading to costlier but not necessarily better care. Recent advances focused on new implementation processes for evidence-based best practices such as checklists and bundles have transformed medical care. We outline recent advances in medical practice that have positively affected both the quality of care and its cost-effectiveness. Future medical care must be smarter and more effective if we are to meet the increasing demands of an aging patient population in the context of ever more limited resources.

New financial penalties for institutions with high readmission rates have intensified efforts to reduce rehospitalization. Several interventions that involve multiple components (e.g., patient needs assessment, medication reconciliation, patient education, arranging timely outpatient appointments, and providing telephone follow-up) have successfully reduced readmission rates for patients discharged to home. The effect of interventions on readmission rates is related to the number of components implemented; single-component interventions are unlikely to reduce readmissions significantly. For patients discharged to postacute care facilities, multicomponent interventions have reduced readmissions through enhanced communication, medication safety, advanced care planning, and enhanced training to manage medical conditions that commonly precipitate readmission. To help hospitals direct resources and services to patients with greater likelihood of readmission, risk-stratification methods are available. Future work should better define the roles of home-based services, information technology, mental health care, caregiver support, community partnerships, and new transitional care personnel.