Lee Joseph

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy

Low-density lipoprotein cholesterol (LDL-C) reduction with statins is the cornerstone of atherosclerotic cardiovascular disease (CVD) prevention. The LDL-C lowering non-statin therapy ezetimibe also modestly reduces CVD risk when added to statin therapy. There remains a clinical need for additional LDL-C lowering agents to reduce CVD risk in patients with genetic hypercholesterolemia, statin intolerance, or who are at high risk due to clinical CVD or diabetes. In clinical trials, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition using monoclonal antibodies has demonstrated robust LDL-C lowering efficacy of 50-65% and a favorable safety profile. These agents are a promising therapeutic strategy for addressing the unmet needs for additional CVD risk reduction. Regulatory approval for PCSK9 monoclonal antibodies may occur in the near future, and additional agents for PCSK9 inhibition are under development. This review focuses on the mechanism of LDL-C reduction using PCSK9 inhibition, as well as the phase I to III clinical trials of PCSK9 inhibitors. Results of the ongoing phase III CVD outcome trials are eagerly awaited.

Managing Extended Oral Anticoagulation After Unprovoked Venous Thromboembolism.

Venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, is a major public health problem associated with increased morbidity and mortality. Despite the high recurrence risk associated with unprovoked VTE, extended anticoagulation remains controversial. Oral antithrombotic agents for extended VTE treatment comprise the vitamin K antagonists, aspirin, and the direct oral anticoagulants (also known as target-specific oral anticoagulants and formerly known as the new or novel oral anticoagulants) including rivaroxaban, dabigatran, apixaban, and edoxaban. The efficacy of these anticoagulants in reducing the risk of VTE recurrence (>80%-90% relative risk reduction) is offset by the risk of major bleeding that approaches 3% per year. Stratifying risks of recurrence and bleeding to identify patients at low, intermediate, or high risk and carefully considering the pharmacologic profile of the antithrombotic agents will help clinicians in choosing the optimal anticoagulant and duration and/or surveillance strategy. This review will discuss the current guidelines for extended VTE treatment, review the clinical trials involving the direct oral anticoagulants, and present the clinical considerations and concerns involving extended therapy.

Temporal Changes in the Racial Gap in Survival After In-Hospital Cardiac Arrest

Importance Previous studies have found marked differences in survival after in-hospital cardiac arrest by race. Whether racial differences in survival have narrowed as overall survival has improved remains unknown. Objectives To examine whether racial differences in survival after in-hospital cardiac arrest have narrowed over time and if such differences could be explained by acute resuscitation survival, postresuscitation survival, and/or greater temporal improvement in survival at hospitals with higher proportions of black patients. Design, Setting, and Participants In this cohort study from Get With the Guidelines–Resuscitation, performed from January 1, 2000, through December 31, 2014, a total of 112 139 patients with in-hospital cardiac arrest who were hospitalized in intensive care units or general inpatient units were studied. Data analysis was performed from April 7, 2015, to May 24, 2017. Exposure Race (black or white). Main Outcomes and Measures The primary outcome was survival to discharge. Secondary outcomes were acute resuscitation survival and postresuscitation survival. Multivariable hierarchical (2-level) regression models were used to calculate calendar-year rates of survival for black and white patients after adjusting for baseline characteristics. Results Among 112 139 patients with in-hospital cardiac arrest, 30 241 (27.0%) were black (mean [SD] age, 61.6 [16.4] years) and 81 898 (73.0%) were white (mean [SD] age, 67.5 [15.2] years). Risk-adjusted survival improved over time in black (11.3% in 2000 and 21.4% in 2014) and white patients (15.8% in 2000 and 23.2% in 2014; P for trend <.001 for both), with greater survival improvement among black patients on an absolute (P for trend = .02) and relative scale (P for interaction = .01). A reduction in survival differences between black and white patients was attributable to elimination of racial differences in acute resuscitation survival (black individuals: 44.7% in 2000 and 64.1% in 2014; white individuals: 47.1% in 2000 and 64.0% in 2014; P for interaction <.001). Compared with hospitals with fewer black patients, hospitals with a higher proportion of black patients with in-hospital cardiac arrest achieved larger survival gains over time. Conclusions and Relevance A substantial reduction in racial differences in survival after in-hospital cardiac arrest has occurred that has been largely mediated by elimination of racial differences in acute resuscitation survival and greater survival improvement at hospitals with a higher proportion of black patients. Further understanding of the mechanisms of this improvement could provide novel insights for the elimination of racial differences in survival for other conditions.

Non-Atherosclerotic Vascular Disease in Women

Opinion statementTakayasu arteritis, fibromuscular dysplasia (FMD), spontaneous arterial dissection, Raynaud’s phenomenon, and chilblains are vascular conditions that are associated with an increased predisposition in women and are often underdiagnosed. Takayasu arteritis has an incidence rate of 2.6 cases per million individuals per year in the USA and predominantly affects women of childbearing age. HLA-B5 genetic locus is linked with Takayasu arteritis susceptibility. Methods to determine active disease are limiting; currently utilized clinical and imaging findings and laboratory tests are of limited value for this purpose. Pregnancy poses risks for maternal and fetal complications, and these patients need additional monitoring and care before and after conception. Controlling hypertension and immunosuppression using steroids, biological and non-biological immunosuppressants, are key components of managing patients with this arteritis. FMD commonly affects middle-aged, white females. Its true prevalence is unknown. Renal and cerebrovascular beds are the most frequently involved vascular beds. Its clinical presentation varies from no symptoms to catastrophic events. Controlling vascular risk factors, periodic surveillance, and revascularization when indicated are important factors in FMD management. Spontaneous arterial dissections are less common, but are an important cause of morbidity and mortality in specific populations. Cervicocephalic dissection causes 10–20% of the strokes in young adults, and coronary artery dissection is the culprit in almost one fourth of young women presenting with acute myocardial infarction. Early diagnosis is key to improving prognosis in these patients, as the majority of patients have spontaneous resolution of the dissection with conservative management alone. Increased clinician awareness of the presentation features and angiographic findings are imperative for early diagnosis. Raynaud’s phenomenon and chilblains are cold- or stress-induced cutaneous lesions, commonly involving distal extremities. Secondary causes such as connective tissue diseases and malignancies must be thoroughly excluded during evaluation of these conditions. Cold avoidance, systemic and local warming, and oral vasodilator therapy are the mainstays of therapy.

ATRIAL SEPTAL ANEURYSM AND CHIARI NETWORK ARE NOT INNOCENT BYSTANDERS: ASSOCIATION WITH CARDIOMYOPATHY, CARDIAC CONDUCTION ABNORMALITIES, AND ARRHYTHMIAS EXIST

Chiari network and atrial septal aneurysm (ASA) are considered “normal” anatomic variants though ASA has been associated with embolic events. The relationship of these variants with cardiomyopathy, cardiac conduction abnormalities and arrhythmias has not been described. From all adult patients

Clotting Around Catheters and Devices

Catheter- and device-related upper extremity deep vein thrombosis is a commonly encountered entity in clinical practice and may be associated with such complications as pulmonary embolism and catheter-related infection. It is seen often in patients with malignancy who have indwelling catheters for chemotherapy administration, and it may develop when catheters are improperly positioned. The diagnosis is made using ultrasonography, although venography may be used when ultrasound is nondiagnostic. Pharmacologic prophylaxis with heparins or vitamin K antagonists is not recommended. Treatment of symptomatic thrombosis usually consists of a short course of therapeutic anticoagulation, with removal of the catheter only if it is no longer needed.