Weekly Evidence Update 7.23.18

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection (NEJM 7/2018)

Procalcitonin is typically expressed only in the C-cells of the thyroid gland for the generation calcitonin in healthy individuals. However, its expression is greatly upregulated in non-neuroendocrine tissues in the setting of infection via the CALC-1 gene. Thus, procalcitonin has served as an attractive marker with numerous studies demonstrating its specificity for the presence of an underlying bacterial infection compared to viral infections. This has led to the integration of measurement of procalcitonin levels into the workup for patients with suspected sepsis. The ideal clinical use of procalcitonin remains somewhat unclear. More evidence is emerging that it has a strong role in de-escalation of antibiotic therapy. However, major societal guidelines (IDSA, ATS) do not endorse its routine use in their most recent iteration for the diagnosis of HAP/VAP. A 2016 Cochrane review found here, and this 2017 meta-analysis published in the Lancet demonstrated a reduction in mortality and antibiotic exposure in the procalcitonin guided therapy group in patients with acute respiratory infections. The authors of the above study performed a multicenter, randomized controlled trial at 14 U.S. hospitals. Patients were randomized to either a pro-calcitonin guided therapy group-where the provider was given guidance in interpreting procalcitonin levels but maintained autonomy regarding whether or not to initiate antibiotic therapy- or a standard of care group, where providers made decisions based on available clinical information. The procalcitonin group adhered to guideline recommendations for 72.9% of patients in the ED, and 64.8% of patients overall. There was no significant difference in antibiotic exposure during the first month between groups (p=0.87). There was no significant difference in percentage of patients receiving antibiotics, ED antibiotic prescribing, or hospital antibiotic days. There were fewer antibiotics prescribed for acute bronchitis amongst the procalcitonin guided group.

Take Home: Procalcitonin directed therapy guidelines did not reduce antibiotic exposure compared to usual care when applied to a “real life” scenario, highlighting the gap between clinical trials and day-to-day clinical care. Procalcitonin use for initiation and de-escalation of antibiotic therapy helps reduce antibiotic exposure in trial settings, and has been associated with decreased 30-day mortality.

Find the article here

Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans (Blood 7/2018)

Bleeding risks in patients on antiplatelet therapy have been reported to be increased as much as 59% for aspirin compared to non-users. The incidence of bleeding in patients on dual anti-platelet (DAPT) therapy following an acute coronary syndrome with PCI has been demonstrated to be as high as 24% in the 6 months following the initial event, as highlighted in this 2016 JACC meta-analysis. Thus, being able to selectively inhibit platelet thrombus formation while maintaining overall hemostasis is an elusive goal. Bruton tyrosine kinase is important for B-lymphocyte development (hence its role in Bruton’s X-linked agammaglobulinemia), and has emerged as an effective target for the initial treatment of chronic lymphocytic leukemia. The authors of this plenary paper from Blood report an exciting finding with the use of BTK inhibitors ibrutinib and acalabrutinib. The authors noted that platelet aggregation occurs via 2 distinct mechanisms depending on the collagen substrate. In atherosclerotic collagen, platelet aggregation occurs via von Willebrand factor (VWF) and platelet glycoprotein GP1b. Additionally this collagen expresses GPVI which interacts with platelet receptors. In healthy collagen, platelet activation occurs primarily through integrin α2β1- platelet interactions, in addition to VWF and GP1b. The researchers found that BTK inhibitors would block platelet aggregation signaling in atherosclerotic plaque, while leaving signaling intact (and thereby thrombosis intact), in healthy collagen tissue. This hypothesis was tested in vitro and in vivo in patients already receiving BTK therapy due to malignancy, and 2 healthy controls (physicians). Both in vitro and in vivo, BTK inhibition lead to inhibition of platelet activation on atherosclerotic plaque, but intact platelet function on healthy collagen. Ibrutinib therapy is associated with many adverse side effects including rash, atrial fibrillation, and not surprisingly: bleeding. Many of these events were in patients taking full dose ibrutinib. A lower dose and intermittent dosing scheme may lead to fewer adverse events. Additionally, Acalabrutinib therapy (NEJM 1/2016). has been shown to mitigate many of these adverse events with lower rates of bleeding and atrial fibrillation.

Take Home: Bruton Tyrosine Kinase appears to be an attractive target to block platelet aggregation on atherosclerotic plaques, while leaving physiologic hemostasis intact on healthy collagen. This paper highlights the important role of translational research with significant clinical implications. Further controlled trials will be needed to determine the clinical efficacy and safety of these agents for use as anti-thrombotic therapy.

Find the article here