Oral anticoagulation therapy for elderly patients with atrial fibrillation: utility of bleeding risk covariates to better understand and moderate risks.

Elderly individuals are prone to nonvalvular atrial fibrillation (AF) with associated risks of arterial thromboembolic disease. Despite definitive guidelines, oral anticoagulant therapy (OAC) is notoriously underutilized in patients with AF. Physicians cite excessive bleeding risk as one reason they omit OAC for their older patients with AF. Improved understanding of the pathophysiology of age-related bleeding may improve risk-benefit assessments for warfarin and newer antithrombotic agents. We reviewed the literature to identify age-related pathophysiological elements that can exacerbate the likelihood of bleeding. In the context of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly (HAS-BLED) bleeding risk framework, we highlight age-related physiological dynamics that predispose to hemorrhage. The combination of increased age (>65 years) with the other elements of the risk factor stratification model identifies patients with AF who are especially susceptible to OAC-related bleeding, irrespective of the agent used. Empirically adjusting OAC dose relative to these common bleeding risks may help to achieve an improved risk-benefit therapeutic ratio.

Management of atrial fibrillation: direct factor IIa and Xa inhibitors or "warfarin shotgun"?

Nonvalvular atrial fibrillation increases in prevalence with age and often requires long-term oral anticoagulation to prevent ischemic stroke. Vitamin K antagonists are highly effective for stroke prevention. However, suboptimal risk assessment, variability in response, drug and food interactions, and monitoring requirements result in underprescription of warfarin by physicians and poor adherence to therapy by patients. In addition, the vitamin K antagonists modulate coagulation by inhibiting multiple coagulation factors (factors II, VII, IX, and X). New oral direct factor IIa and Xa inhibitors offer improved risk-benefit profiles, simplifying thromboprophylaxis and overcoming some practical barriers to long-term therapy. Their potential benefit is a function of targeting specific activated factors produced at key junctions of the coagulation system. However, important questions about patient management with these new agents have not been fully answered by studies completed to date and clinical inertia must yet be overcome.

The science of megestrol acetate delivery: potential to improve outcomes in cachexia.

Cachexia, usually defined as the loss of >5% of an individual's baseline bodyweight over 2-6 months, occurs with a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia is considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrol acetate, are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve stimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of the principal catabolic cytokines. Because the bioavailability of megestrol acetate directly affects its efficacy and safety, the formulation was refined to enhance its pharmacokinetics. Such efforts yielded megestrol acetate in a tablet form, followed by a concentrated oral suspension form, and an oral suspension form developed using nanocrystal technology. Nanocrystal technology was designed specifically to optimize drug delivery and enhance the bioavailability of drugs that have poor solubility in water. Megestrol acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment of cachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new megestrol acetate formulation has the potential to significantly shorten the time to clinical response and thus may improve outcomes in patients with anorexia-cachexia.

Hematologic changes in sepsis and their therapeutic implications.

The blood and bone marrow constitute the hematologic organ system. Unlike other organ systems, hematologic organs are distributed in space and provide for a variety of seemingly unrelated functions. The hematologic system has both cellular and fluid-phase elements. Cellular elements include erythrocytes, leukocytes, and platelets; fluid phase elements include coagulation factors, natural antithrombotics, and proteins of the fibrinolytic system. The most common abnormalities of the hematologic system in patients with sepsis are anemia, leukocytosis, thrombocytopenia, and activation of the hemostatic system. Dysfunction of the hematologic organ system is an early manifestation of severe sepsis and is seen in virtually all patients with this disease. In concert with alterations in the endothelium, hematologic changes reflect both the body's reaction to an infectious insult as well as attempts to restore homeostasis. Dysfunction of the hematologic organ system can contribute to multiple organ dysfunctions and death. Recognizing these sepsis-associated changes and understanding the underlying pathophysiology are key to improving outcomes in patients with this deadly disease.

Advances in the understanding of clinical manifestations and therapy of severe sepsis: an update for critical care nurses.

Severe sepsis is a major public health concern and a burden on the healthcare system. Despite improvements in efforts to control the source of infection and increased recognition by healthcare providers of patients with the disease, the mortality rate remains unacceptably high, from 30% to 50%. The systemic inflammatory response syndrome criteria are used as diagnostic indicators of sepsis when they occur in patients with known or suspected infection. The outcome of a patient with severe sepsis is often related to the occurrence of sepsis-induced multiple organ dysfunction syndrome. Multiple organ dysfunction syndrome appears to result from a cascade of organism-related factors, inflammatory mediators, endothelial injury, disturbed hemostasis, and microcirculatory abnormalities. In patients with severe sepsis, derangements of inflammation and coagulation are tightly linked. Although numerous clinical trials focused on interventions in one or the other of the inflammatory and coagulation systems failed to show reduced mortality due to sepsis, a member of a new class of drugs called "cogins" was effective. In its active form, protein C has anti-inflammatory, antithrombotic, and profibrinolytic properties that can reduce organ injury associated with severe sepsis. A recombinant form of activated protein C, drotrecogin alfa (activated), significantly reduces 28-day mortality due to all causes in patients with severe sepsis and has an acceptable safety profile. This review provides an overview of severe sepsis, highlighting recent advances in treatment of the disease and the role of critical care nurses.