Pharmacotherapy
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The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
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The key issues clinicians are facing regarding drotrecogin alfa (activated) include questions concerning the pathophysiology and appropriate patient selection for administration of this drug. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the efficacy of drotrecogin alfa (activated) was demonstrated in patients with severe sepsis. Because of this trial's strict inclusion and exclusion criteria, however, the applicability of the study criteria to different types of patients raises important issues. Coupling the data from the PROWESS trial with additional information being gained from expanding clinical experience, as well as additional studies, clinicians will be able to better understand and refine the use of activated protein C within their respective practices.
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Review
Strategies to optimize drotrecogin alfa (activated) use: guidelines and therapeutic controversies.
Drotrecogin alfa (activated) is a new agent that may substantially affect the treatment of patients with severe sepsis. Despite its therapeutic promise, treatment with drotrecogin alfa (activated) represents a new challenge for many clinicians and health care centers. ⋯ We outline factors that should be considered when developing drotrecogin alfa (activated) therapy guidelines and address realistic questions that routinely arise in clinical practice regarding the implementation of such guidelines and the administration of this product. In general, the guidelines must facilitate optimization of drug therapy and not be viewed as hurdles to drug therapy Developing clear guidelines that are based on evidence, outlining a specific process to facilitate optimal therapy, and educating all parties involved are paramount to ensuring that the benefits of therapy are maximized.
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Review
Pharmacokinetics and clinical use of drotrecogin alfa (activated) in patients with severe sepsis.
Drotrecogin alfa (activated) pharmacokinetics have been reported in healthy volunteers and in patients with severe sepsis. Clearance is rapid and appears to increase with weight; consequently, drotrecogin alfa (activated) is dosed on a weight basis. Drotrecogin alfa (activated) promotes fibrinolysis and inhibits thrombin production to produce an anticoagulant effect. ⋯ Monitoring parameters correspond with bleeding and should include international normalized ratio, platelet count, hematocrit, and overt signs of bleeding. Because of the protein nature of drotrecogin alfa (activated), pharmacists should be aware of the proper preparation and stability issues in order to afford efficient, cost-effective administration. As further data on drotrecogin alfa (activated) therapy become available, dosing and monitoring strategies may be altered to optimize the clinical benefits.
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Selecting therapies in health care requires rigorous review of clinical and economic data. The financial implications of new clinical treatment options are an important component. The preferred method for evaluating the costs and effects of therapies is cost-effectiveness analysis along with an estimation of utility associated with the life-years gained. ⋯ Furthermore, the reported cost/quality-adjusted life-year of $48,800 is consistent with many other common life-saving measures. Recently approved new technology payments for hospitals treating patients with drotrecogin alfa (activated) minimize financial impact. Clinicians and administrators should work collaboratively to optimize the therapy of patients with severe sepsis, minimize the financial impact on the health care system, and maximize the utility of drotrecogin alfa (activated).