Olmesartan,Other Antihypertensives,and Chronic Diarrhea Among Patients Undergoing Endoscopic Procedures: A Case-Control Study

ObjectiveTo investigate a recent association between the use of the angiotensin receptor-blocker (ARB) olmesartan and a severe enteropathy resembling celiac disease.Patients and MethodsWe searched our endoscopy database for all outpatient esophagogastroduodenoscopy (EGD) or colonoscopy examinations in patients aged at least 50 years during the period January 1, 2007, to March 31, 2013. Cases were those whose examination indication was diarrhea, and controls were those whose examination indication was esophageal reflux (EGD) or colorectal cancer screening (colonoscopy). We compared cases with controls with regard to the proportion of those listing olmesartan among their medications. Secondary exposures were the proportion of those taking nonolmesartan ARBs or other antihypertensive medications. We also examined biopsy results to determine whether there were histologic changes associated with the use of olmesartan.ResultsWe identified 2088 patients undergoing EGD and 12,428 patients undergoing colonoscopy meeting inclusion criteria. On multivariate analysis, there was no statistically significant association between olmesartan and diarrhea among those undergoing EGD (odds ratio, 1.99; 95% CI, 0.79-5.00) or colonoscopy (odds ratio, 0.63; 95% CI, 0.23-1.74). Review of pathology reports of the EGD and colonoscopy groups showed no association between the use of olmesartan and the histologic diagnosis of celiac disease (P=.61) or microscopic colitis (P=1.0), respectively.ConclusionOur findings suggest that neither olmesartan nor other ARBs were associated with diarrhea among patients undergoing endoscopy. The spruelike enteropathy recently associated with olmesartan is likely a rare adverse effect and milder presentations are unlikely.     

Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology

The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.     

Diagnosis and Management of Benign,Atypical, and Indeterminate Breast Lesions Detected on Core Needle Biopsy

Imaging abnormalities detected by mammographic screening often lead to diagnostic evaluations, with suspicious abnormalities subjected to image-guided core needle biopsy (CNB) to exclude malignancy. Most CNBs reveal benign pathological alterations, termed benign breast disease (BBD). Adoption of CNB presents challenges with pathologic classification of breast abnormalities and management of patients with benign or atypical histological findings. Patient management and counseling after CNB diagnosis of BBD depends on postbiopsy determination of radiologic-pathologic concordancy. Communication between radiologists and pathologists is crucial in patient management. Management is dependent on the histological type of BBD. Patients with concordant pathologic imaging results can be reassured of benign biopsy findings and advised about the future risk of developing breast cancer. Surgical consultation is advised for patients with discordant findings, symptomatic patients, and high-risk lesions. This review highlights benign breast lesions that are encountered on CNB and summarizes management strategies. For this review, we conducted a search of PubMed, with no date limitations, and used the following search terms (or a combination of terms): atypical ductal hyperplasia, atypical hyperplasia, atypical lobular hyperplasia, benign breast disease, cellular fibroepithelial lesions, columnar cell lesions, complex sclerosing lesion, core needle biopsy, fibroadenomas, flat epithelial atypia, lobular carcinoma in situ, lobular neoplasia, mucocele-like lesions, phyllodes tumor, pseudoangiomatous stromal hyperplasia, radial scar, and vascular lesions. The selection of references included in this review was based on study relevance and quality. We used additional articles culled from the bibliographies of retrieved articles to examine the published evidence for risk factors of BBD.     

Bedside to Bench: Role of Muscarinic Receptor Activation in Ultrarapid Growth of Colorectal Cancer in a Patient With Pheochromocytoma

An elderly man with long-standing, nonresectable pheochromocytoma had rapid development of rectal adenocarcinoma despite close endoscopic surveillance. We determined that the patient’s colorectal cancer overexpressed muscarinic receptor subtype 3, whereas his pheochromocytoma expressed choline acetyltransferase, an enzyme required to produce acetylcholine, which is a muscarinic receptor agonist. These findings suggested that acetylcholine release from the pheochromocytoma stimulated rapid growth of the rectal neoplasm. As proof of principle, we found that culture media conditioned by pheochromocytoma cells stimulates proliferation of a human colon cancer cell line, an effect attenuated by atropine, a muscarinic receptor inhibitor. Our observations provide both clinical and laboratory evidence that muscarinic receptor agonists promote the growth of colorectal neoplasia.     

The Increasing Incidence of Young-Onset Colorectal Cancer: A Call to Action

In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.     

Barrett Esophagus

Barrett esophagus is a metaplastic change in the lining of the distal esophageal epithelium, characterized by replacement of the normal squamous epithelium by specialized intestinal metaplasia. The presence of Barrett esophagus increases the risk of esophageal adenocarcinoma several-fold. Esophageal adenocarcinoma is a malignancy with rapidly rising incidence and persistently poor outcomes when diagnosed after the onset of symptoms. Risk factors for Barrett esophagus include chronic gastroesophageal reflux, central obesity, white race, male gender, older age, smoking, and a family history of Barrett esophagus or esophageal adenocarcinoma. Screening for Barrett esophagus in those with several risk factors followed by endoscopic surveillance to detect dysplasia or adenocarcinoma is currently recommended by society guidelines. Minimally invasive nonendoscopic tools for the early detection of Barrett esophagus are currently being developed. Multimodality endoscopic therapy—using a combination of endoscopic resection and ablation techniques—for the treatment of dysplasia and early adenocarcinoma is successful in eliminating intestinal metaplasia and preventing progression to adenocarcinoma, with outcomes comparable to those after esophagectomy. Risk stratification of those diagnosed with Barrett esophagus is a challenge at present, with active research focused on identifying clinical and biomarker panels to identify those with low and high risk of progression. This narrative review highlights some of the challenges and recent progress in this field.     

Prostate Cancer Ki-67 (MIB-1) Expression,Perineural Invasion,and Gleason Score as Biopsy-Based Predictors of Prostate Cancer Mortality: The Mayo Model

ObjectiveTo determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality.Patients and MethodsBetween 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index.ResultsWith a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms.ConclusionThis study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice.     

Chronic Cough: An Update

Cough persisting beyond 8 weeks (ie, chronic cough) is one of the most common reasons for an outpatient visit. A protracted cough can negatively affect one’s quality of life by causing anxiety, physical discomfort, social isolation, and personal embarrassment. Herein, the anatomy and physiology of the cough reflex are reviewed. Upper airway cough syndrome, asthma, eosinophilic bronchitis, and gastroesophageal reflux disease account for most chronic cough after excluding smoking, angiotensin-converting enzyme inhibitor use, and chronic bronchitis. Many patients have more than one reason for chronic cough. Treating the underlying cause(s) resolves cough in most instances. There are some coughs that seem refractory despite an extensive work-up. The possibility of a hypersensitive cough reflex response has been proposed to explain these cases. Several clinical algorithms to evaluate chronic cough are presented.     

Immediate Open Repair vs Surveillance in Patients with Small Abdominal Aortic Aneurysms: Survival Differences by Aneurysm Size

ObjectiveTo assess whether survival differences exist between patients undergoing immediate open repair vs surveillance with selective repair for 4.0- to 5.4-cm abdominal aortic aneurysms (AAAs) and whether these differences vary by diameter, within sexes, or overall.Patients and MethodsThe study cohort included 2226 patients randomized to immediate repair or surveillance for the UK Small Aneurysm Trial (September 1, 1991, through July 31, 1998; follow-up, 2.6-6.9 years) or the Aneurysm Detection and Management trial (August 1, 1992, through July 31, 2000; follow-up, 3.5-8.0 years). Survival differences were assessed with proportional hazard models, adjusted for a comprehensive array of clinical and nonclinical risk factors. Interaction between treatment and AAA size was added to the model to assess whether the effect of immediate open repair vs surveillance varied by AAA size.ResultsThe adjusted analysis revealed no statistically significant survival difference between immediate open repair and surveillance patients (hazard ratio [HR], 0.99; 95% CI, 0.83-1.18; mean follow-up time, 1921 days for both study groups). This lack of treatment effect persisted when men (HR, 1.01; 95% CI, 0.84-1.21) and women (HR, 0.96; 95% CI, 0.49-1.86) were examined separately and did not vary by AAA size (P=.39 for the entire cohort and P=.24 for women).ConclusionImmediate open repair offered no significant survival benefit, even in patients with the largest AAAs and highest risk of rupture. Because recent trials failed to find a survival benefit of immediate endovascular repair over surveillance for small asymptomatic AAAs, our findings suggest that the gray area of first-line management for these patients should be resolved in favor of surveillance.     

Breast Density and Breast Cancer Risk: A Practical Review

New legislation in several states requiring breast density notification in all mammogram reports has increased awareness of breast density. Estimates indicate that up to 50% of women undergoing mammography will have high breast density; thus, with increased attention and high prevalence of increased breast density, it is crucial that primary care clinicians understand the implications of dense breasts and are able to provide appropriate counseling. This review provides an overview of breast density, specifically by defining breast density, exploring the association between breast density and breast cancer risk, both from masking and as an independent risk factor, and reviewing supplemental screening options as part of a larger framework for counseling patients with dense breasts.     

Safety and Efficacy of Extracorporeal Shock Wave Myocardial Revascularization Therapy for Refractory Angina Pectoris

ObjectiveTo assess the safety and efficacy of extracorporeal shockwave myocardial revascularization (ESMR) therapy in treating patients with refractory angina pectoris.Patients and MethodsA single-arm multicenter prospective trial to assess safety and efficacy of the ESMR therapy in patients with refractory angina (class III/IV angina) was performed. Screening exercise treadmill tests and pharmacological single-photon emission computed tomography (SPECT) were performed for all patients to assess exercise capacity and ischemic burden. Patients were treated with 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy end points were exercise capacity by using treadmill test as well as ischemic burden on pharmacological SPECT at 4 months after the last ESMR treatment. Safety measures included electrocardiography, echocardiography, troponin, creatine kinase, and brain natriuretic peptide testing, and pain questionnaires.ResultsFifteen patients with medically refractory angina and no revascularization options were enrolled. There was a statistically significant mean increase of 122.3±156.9 seconds (38% increase compared with baseline; P=.01) in exercise treadmill time from baseline (319.8±157.2 seconds) to last follow-up after the ESMR treatment (422.1±183.3 seconds). There was no improvement in the summed stress perfusion scores after pharmacologically induced stress SPECT at 4 months after the last ESMR treatment in comparison to that at screening; however, SPECT summed stress score revealed that untreated areas had greater progression in ischemic burden vs treated areas (3.69±6.2 vs 0.31±4.5; P=.03). There was no significant change in the mean summed echo score from baseline to posttreatment (0.4±5.1; P=.70). The ESMR therapy was performed safely without any adverse events in electrocardiography, echocardiography, troponins, creatine kinase, or brain natriuretic peptide. Pain during the ESMR treatment was minimal (a score of 0.5±1.2 to 1.1±1.2 out of 10).ConclusionIn this multicenter feasibility study, ESMR seems to be a safe and efficacious treatment for patients with refractory angina pectoris. However, larger sham-controlled trials will be required to confirm these findings.     

Preprocedural Considerations in Gastrointestinal Endoscopy

The current practice of open-access endoscopy allows primary care and other non-gastroenterology physicians to directly refer patients for routine gastrointestinal endoscopic procedures. Open-access endoscopy is considered to be more cost-effective and time efficient than the traditional practice of referring patients for preprocedural consultation with a gastrointestinal endoscopist. Several studies have evaluated the performance of endoscopic procedures in an open-access environment and the utility of structured referral mechanisms to ensure safe and appropriately indicated procedures. This review focuses on 4 common preprocedural issues in gastrointestinal endoscopy encountered by primary care physicians: management of anticoagulation and antiplatelet therapy, indication for prophylactic antibiotic drug therapy, need for anesthesia-assisted sedation, and management of poor bowel preparation. We summarize the current guidelines that address these 4 common preprocedural issues to facilitate safe and clinically appropriate procedures in open-access endoscopy.     

The Mayo Clinic Biobank: A Building Block for Individualized Medicine

ObjectiveTo report the design and implementation of the first 3 years of enrollment of the Mayo Clinic Biobank.Patients and MethodsPreparations for this biobank began with a 4-day Deliberative Community Engagement with local residents to obtain community input into the design and governance of the biobank. Recruitment, which began in April 2009, is ongoing, with a target goal of 50,000. Any Mayo Clinic patient who is 18 years or older, able to consent, and a US resident is eligible to participate. Each participant completes a health history questionnaire, provides a blood sample, and allows access to existing tissue specimens and all data from their Mayo Clinic electronic medical record. A community advisory board provides ongoing advice and guidance on complex decisions.ResultsAfter 3 years of recruitment, 21,736 individuals have enrolled. Fifty-eight percent (12,498) of participants are female and 95% (20,541) of European ancestry. Median participant age is 62 years. Seventy-four percent (16,171) live in Minnesota, with 42% (9157) from Olmsted County, where the Mayo Clinic in Rochester, Minnesota, is located. The 5 most commonly self-reported conditions are hyperlipidemia (8979, 41%), hypertension (8174, 38%), osteoarthritis (6448, 30%), any cancer (6224, 29%), and gastroesophageal reflux disease (5669, 26%). Among patients with self-reported cancer, the 5 most common types are nonmelanoma skin cancer (2950, 14%), prostate cancer (1107, 12% in men), breast cancer (941, 4%), melanoma (692, 3%), and cervical cancer (240, 2% in women). Fifty-six percent (12,115) of participants have at least 15 years of electronic medical record history. To date, more than 60 projects and more than 69,000 samples have been approved for use.ConclusionThe Mayo Clinic Biobank has quickly been established as a valuable resource for researchers.     

Latest Advances in Chemotherapeutic,Targeted, and Immune Approaches in the Treatment of Metastatic Melanoma

Melanoma is the most dangerous form of skin cancer owing to its metastatic potential and is an important public health concern. The melanoma incidence has been increasing worldwide. Although potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti–cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blocking antibodies, as well as combination strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review was to summarize the evolution of and recent advances in the treatment of metastatic melanoma. Therefore, we conducted a comprehensive PubMed search between January 1, 1960, and February 1, 2014, using the search term melanoma or metastatic melanoma combined with terms such as chemotherapy, immunotherapy, CTLA-4, PD-1, PD-L1, adoptive T cell, targeted therapy, MAPK, molecular biology, and survival.     

Frequency and Implication of Autoimmune Serologies in Idiopathic Pulmonary Fibrosis

ObjectiveTo assess the frequency and clinical implications of positive autoimmune serologies in patients with biopsy-confirmed idiopathic pulmonary fibrosis (IPF).Patients and MethodsWe reviewed the records of patients at our institution with biopsy-confirmed usual interstitial pneumonia (UIP) from January 1, 1995, through December 31, 2010, for frequency and distribution of autoimmune serologies. Patients with IPF with and without positive serologies were compared.ResultsThree hundred eighty-nine consecutive patients with biopsy-confirmed IPF underwent serologic testing, with positive serologic test results being found in 112 (29%). Of 2051 individual screening serologic tests performed, results of 163 tests were positive (8%), with antinuclear antibody being the most frequent (47%). There was no difference in age at biopsy (P=.21), gender (P=.21), or presenting radiologic features between those with or without positive serology. More frequent use of immunosuppressive treatment (P=.02) was noted in those with positive serology. No survival difference was observed (log-rank; P=.43). Median follow-up for the whole cohort was 43.5 months.ConclusionPositive autoimmune serology may occur in as much as one-third of the patients with biopsy-confirmed IPF with no associated clinical implication or survival advantage. Systematic use of autoimmune laboratory panels in patients without clinical features of connective tissue disease should be reconsidered in patients with suspected UIP on chest computed tomography scan or confirmed UIP on biopsy.     

Racial Disparities in Survival for Patients With Clinically Localized Prostate Cancer Adjusted for Treatment Effects

ObjectiveTo examine whether racial disparities in survival exist among black, Hispanic, and Asian patients compared with white patients with clinically localized prostate cancer (CLPC) after adjustment for the effects of treatment.Patients and MethodsWe performed a retrospective cohort study of patients with CLPC diagnosed from January 1, 1995, through December 31, 2003, as documented in the Surveillance, Epidemiology, and End Results registry. Treatment-stratified, risk-adjusted Cox proportional hazards models were constructed.ResultsDuring the study period, CLPC was diagnosed in 294,160 patients. Of these patients, 123,850 (42.1%) underwent surgery and 101,627 (34.5%) underwent radiotherapy, whereas 68,683 (23.3%) received no treatment. Overall 5-year and 10-year survival rates for Asians (85.6% and 67.6%, respectively), Hispanics (85.9% and 69.0%, respectively), and whites (83.9% and 65.7%, respectively) were higher than for blacks (81.5% and 61.7%, respectively) (P<.001). Prostate cancer–specific survival also varied significantly by race (P<.001). A risk-adjusted model stratified by primary treatment modality revealed that blacks had worse overall survival than whites (hazard ratio, 1.37; 95% CI, 1.33-1.41; P<.001), whereas Asians had better survival compared with whites (hazard ratio, 0.79; 95% CI, 0.76-0.83; P<.001). After the effects of treatment were accounted for, Hispanics had similar overall survival compared with whites (hazard ratio, 0.97; 95% CI, 0.94-1.01; P=.10).ConclusionBlacks with CLPC have poorer survival than whites, whereas Asians have better survival, even after risk adjustment and stratification by treatment. These data may be relevant to US regions with large underserved populations that have limited access to health care.     

Influence of Early Surgical Treatment on the Prognosis of Left-Sided Infective Endocarditis: A Multicenter Cohort Study

ObjectiveTo analyze the influence of early valve operation on mortality in patients with left-sided infective endocarditis (IE).Patients and MethodsA multicenter cohort study was carried out between 1990 and 2010. Data from consecutive patients with definite IE and possible left-sided IE were collected. Propensity score matching and adjustment for survivor bias were used to control for confounders. The primary outcome was in-hospital mortality.ResultsA total of 1019 patients with a mean age of 61 years (interquartile range, 47-71 years) were included. Early surgical treatment was performed in 417 episodes (40.9%). By propensity score, we matched 316 episodes: 158 who underwent early surgical treatment and 158 who did not (medical treatment group). In-hospital mortality and late mortality were lower in the surgically treated group (26.6% vs 41.8%; absolute risk reduction [ARR], −15.2%; P=.004 and 29.7% vs 46.2%; ARR, −16.5%; P=.002, respectively). Operation was independently associated with a lower risk of in-hospital mortality (odds ratio, 0.42; 95% CI, 0.22-0.79; P=.007). Operation was associated with reduced mortality in patients with paravalvular complications (ARR, −40.5%), severe heart failure (ARR, −32%), and native valve endocarditis (ARR, −17.8%).ConclusionThis study supports the benefit of surgical treatment in patients with left-sided IE carried out during the initial phase of hospitalization, especially in patients with moderate or severe heart failure and paravalvular extension of infection.     

Sudden Cardiac Death From the Perspective of Coronary Artery Disease

Sudden cardiac death accounts for approximately 50% of all deaths attributed to cardiovascular disease in the United States. It is most commonly associated with coronary artery disease and can be its initial manifestation or may occur in the period after an acute myocardial infarction. Decreasing the rate of sudden cardiac death requires the identification and treatment of at-risk patients through evidence-based pharmacotherapy and interventional strategies aimed at primary and secondary prevention. For this review, we searched PubMed for potentially relevant articles published from January 1, 1970, through March 1, 2014, using the following key search terms: sudden cardiac death, ischemic heart disease, coronary artery disease, myocardial infarction, and cardiac arrest. Searches were enhanced by scanning bibliographies of identified articles, and those deemed relevant were selected for full-text review. This review outlines various mechanisms for sudden cardiac death in the setting of coronary artery disease, describes risk factors for sudden cardiac death, explores the management of cardiac arrest, and outlines optimal practice for the monitoring and treatment of patients after an acute ST-segment elevation myocardial infarction to decrease the risk of sudden death.     

Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies

Multiple sclerosis (MS) is a chronic inflammatory demyelinating central nervous system disease that typically strikes young adults, especially women. The pathobiology of MS includes inflammatory and neurodegenerative mechanisms that affect both white and gray matter. These mechanisms underlie the relapsing, and often eventually progressive, course of MS, which is heterogeneous; confident prediction of long-term individual prognosis is not yet possible. However, because revised MS diagnostic criteria that incorporate neuroimaging data facilitate early diagnosis, most patients are faced with making important long-term treatment decisions, most notably the use and selection of disease-modifying therapy (DMT). Currently, there are 10 approved MS DMTs with varying degrees of efficacy for reducing relapse risk and preserving neurological function, but their long-term benefits remain unclear. Moreover, available DMTs differ with respect to the route and frequency of administration, tolerability and likelihood of treatment adherence, common adverse effects, risk of major toxicity, and pregnancy-related risks. Thorough understanding of the benefit-risk profiles of these therapies is necessary to establish logical and safe treatment plans for individuals with MS. We review the available evidence supporting risk-benefit profiles for available and emerging DMTs. We also assess the place of individual DMTs within the context of several different MS management strategies, including those currently in use (sequential monotherapy, escalation therapy, and induction and maintenance therapy) and others that may soon become feasible (combination approaches and “personalized medicine”). We conducted this review using a comprehensive search of MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, from January 1, 1990, to August 31, 2013. The following search terms were used: multiple sclerosis, randomized controlled trials, interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, BG-12, alemtuzumab, rituximab, ocrelizumab, daclizumab, neutralizing antibodies, progressive multifocal leukoencephalopathy.     

Treatment Discontinuations With New Oral Agents for Long-term Anticoagulation: Insights From a Meta-analysis of 18 Randomized Trials Including 101,801 Patients

ObjectiveTo systematically examine discontinuation rates with new US Food and Drug Administration–approved oral anticoagulants (NOACs) in patients with various indications for long-term anticoagulation.Patients and MethodsPoor adherence to medications is considered a potential and frequent cause of treatment failure. We searched the PubMed, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases for articles published from January 1, 2001, through September 15, 2013. The following Medical Subject Heading terms and/or keywords were used for our database searches: rivaroxaban, dabigatran, apixaban, new oral anticoagulants, oral thrombin inhibitors, and oral factor Xa inhibitors. Articles in English that focused on randomized controlled trials (RCTs) comparing NOACs (apixaban, dabigatran, and rivaroxaban) with conventional therapy or placebo were abstracted. Independent extraction of relevant data was performed by 2 authors. The primary end point of interest was discontinuation due to all causes. Other end points of interest were discontinuation due to adverse events, consent withdrawal, and nonadherence.ResultsEighteen RCTs including a total of 101,801 patients were included for analysis. Total study drug discontinuation rates were not statistically different with NOACs in comparison to pharmacologically active comparators for treatment of venous thromboembolism/pulmonary embolism (risk ratio [RR], 0.91; 95% CI, 0.74-1.13; P=.40) and for NOACs in comparison to warfarin and aspirin for prevention of stroke in patients with atrial fibrillation (RR, 1.01; 95% CI, 0.87-1.17; P=.92). In contrast, in acute coronary syndromes, total study drug discontinuation with NOACs was significantly higher than with placebo (RR, 1.40; 95% CI, 1.07-1.83; P=.01). Overall discontinuations were comparable to those with active comparators.ConclusionStudy drug discontinuations with NOACs were not significantly different from those with conventional drugs in treatment of venous thromboembolism/pulmonary embolism and prevention of stroke in patients with atrial fibrillation but were worse in acute coronary syndromes as noted in evidence from contemporary RCTs.