Research Spotlight

Schiffmann, R. and B. Banwell (2016). “Brain mri and motor function in leukodystrophies.” Neurology 87(8): 748-749.

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There is a need to develop clinical outcome measures for future treatment trials, particularly for pediatric studies and for studies of rare disorders for which such outcome metrics are neither currently well-defined nor validated.1 Patient-reported outcome measures should reflect outcomes that are meaningful to patient-perceived quality of life and sensitive to patient-identified change over time. Physician-reported outcome measures are typically quantifiable and consistently applied across multiple study sites by different investigators, which requires that the metrics be well-defined and that investigator training be rigorous. While clinically relevant outcomes are considered the “gold standard,” and are often the mandated primary outcome of federally funded research, many slowly progressive disorders do not demonstrate clinically apparent change over the time course of a clinical trial. Thus, there is a need for biomarkers, such as neuroimaging measures, that may be more sensitive to change over the typical 2- to 5-year period of a trial. Key to the applicability of such surrogate measures, however, is that they ultimately correlate with changes in neurologic function.

Packer, M. (2016). “The room where it happens: A skeptic’s analysis of the new heart failure guidelines.” J Card Fail 22(9): 726-730.

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New heart failure guidelines have been issued during the past several months, both in the United States and in Europe, in response to recent advances in and the approval of new drugs for the treatment of heart failure. Although guidelines documents are often viewed as authoritative and purely evidence-based, there are replete with meaningful (and inexplicable) inconsistencies, which derive from a review of the same body of scientific data by different groups. This satirical review highlights several examples of the entertaining foolishness of recent guideline documents in the good-natured hope that physicians will understand what the guidelines are, and more importantly, what they are not. Specifically, this paper describes the emergence of a new nonexistent disease; the strange battle between 2 bradycardic drugs (digoxin and ivabradine); the confusion that reigns over the positioning and dosing of inhibitors of the renin-angiotensin system; and the special recommendations that have been issued for certain special populations. As Otto von Bismarck remarked, guideline deliberations are like sausages; it is better not to see them being made. Yet, even after they are ready for public view, we should be cautious. Practitioners who rely on them for clinical decision-making engage in an unnecessary form of self-deception; those who read them literally and adhere to them strictly do not practice evidence-based medicine; and those who delve into them in a search for the truth are destined to be disappointed.

Messe, S. R. and M. J. Mack (2016). “Improving outcomes from transcatheter aortic valve implantation: Protecting the brain from the heart.” Jama 316(6): 587-588.

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In this issue of JAMA, Haussig and colleagues6 report the results of the CLEAN-TAVI study. This randomized clinical trial assessed the utility of an embolic protection device (the CLARET Montage Dual Filter System) designed for use in transcatheter aortic valve implantation (TAVI). Once deployed through the right brachial artery, this device uses 2 filters to cover 3 of the 4 cervicocephalic vessels, including both carotid arteries and the right vertebral artery, while the left vertebral artery remains unprotected. A total of 100 patients with severe aortic stenosis were randomized to undergo TAVI with (n = 50) or without (n = 50) the cerebral embolic protection device; the device was successfully placed in 92% of patients in the intervention group, with no device-related complications reported. The primary end point was the numerical difference in new postprocedure lesions in potentially protected brain territories detected on MRI at 2 days following TAVI.

Hundemer, G. L., A. Z. Fenves, K. M. Phillips and M. Emmett (2016). “Sodium thiosulfate and the anion gap in patients treated by hemodialysis.” Am J Kidney Dis 68(3): 499-500.

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Calciphylaxis is a syndrome of microvascular calcification and thrombosis leading to painful purpuric skin lesions that progress to necrotic ulcers. Calciphylaxis occurs primarily in patients with ESRD, for which its prevalence has been estimated at 1% annually, and carries a high mortality rate.1 and 2 Increasingly, sodium thiosulfate (STS) is used off-label for treating calciphylaxis. The STS mechanism of action in this condition is unknown. One postulated mechanism is by binding to calcium phosphate salts to form soluble calcium thiosulfate, though additional antioxidant, vasodilatory, and direct inhibitory actions on vascular calcification have been proposed.3, 4 and 5 Dosing of STS, which contains 12.7 mEq/g of sodium and thiosulfate, is empirical and typically 12.5 or 25 g is given during the final 30 to 60 minutes of a hemodialysis (HD) session. A retrospective study showed that 73% of patients treated for calciphylaxis with STS had clinical improvement, with 26% having complete resolution of skin lesions.6

Menter, A., J. C. Cather, M. Jarratt, X. Meng, A. Guana and J. Nyirady (2016). “Efficacy of secukinumab on moderate-to-severe plaque psoriasis affecting different body regions: A pooled analysis of four phase 3 studies.” Dermatol Ther (Heidelb): 2016 Aug [Epub ahead of print].

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The impact of psoriasis varies with the body region affected. In addition, patients have different perceptions of disease improvement and treatment satisfaction based on the location of skin clearance with treatment. The monoclonal antibody secukinumab selectively targets interleukin-17A-a central cytokine of psoriasis-and provides rapid and sustained clearance for moderate-to-severe psoriasis affecting all body regions. The objective of this study was to evaluate the efficacy of secukinumab on moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. METHODS: Data were pooled from four phase 3 studies. To be included in the analysis for each body region, patients were required to have a Psoriasis Area and Severity Index (PASI) score >/=12 for that body region and psoriasis covering >/=10% of the surface area of that region. Secukinumab was administered at Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48. RESULTS: Across the trunk, upper limbs, and lower limbs, initial PASI subscore responses were sustained to Week 52. At Week 52, trunk (T) PASI 90/100 responses were achieved by 78.4%/71.1% of patients receiving secukinumab 300 mg, respectively, and by 66.3%/56.9% of patients receiving secukinumab 150 mg, respectively. At Week 52, upper limb (UL) PASI 90/100 responses were achieved by 67.3%/59.1% of patients receiving secukinumab 300 mg, respectively, and by 50.3%/43.3% of patients receiving secukinumab 150 mg, respectively. At Week 52, lower limb (LL) PASI 90/100 responses were achieved by 63.9%/55.3% of patients receiving secukinumab 300 mg, respectively, and by 45.1%/36.4% of patients receiving secukinumab 150 mg, respectively. A 50% reduction in mean PASI subscore occurred after 2.8, 2.9, and 3.4 weeks with secukinumab 300 mg on the trunk, upper limbs, and lower limbs, respectively. CONCLUSION: Secukinumab provided robust and sustained efficacy for moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs.