Research Spotlight

Anker, S.D., Butler, J., Filippatos, G., Khan, M.S., Marx, N., Lam, C.S.P., Schnaidt, S., Ofstad, A.P., Brueckmann, M., Jamal, W., Bocchi, E.A., Ponikowski, P., Perrone, S.V., Januzzi, J.L., Verma, S., Böhm, M., Ferreira, J.P., Pocock, S.J., Zannad, F. and Packer, M. (2021). “Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.” Circulation 143(4): 337-349.

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BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.

Bardia, A., Kaklamani, V., Wilks, S., Weise, A., Richards, D., Harb, W., Osborne, C., Wesolowski, R., Karuturi, M., Conkling, P., Bagley, R.G., Wang, Y., Conlan, M.G. and Kabos, P. (2021). “Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.” J Clin Oncol Jan 29;JCO2002272. [Epub ahead of print].

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PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

Desai, C.S., Szempruch, K.R., Vonderau, J.S., Chetboun, M., Pattou, F., Coates, T., De Paep, D.L., Hawthorne, W.J., Khan, K.M., de Koning, E.J.P., Naziruddin, B., Posselt, A., Schrope, B.A., Wijkstrom, M., Witkowski, P. and Shapiro, A.M.J. (2021). “Anticoagulation practices in total pancreatectomy with autologous islet cell transplant patients: an international survey of clinical programs.” Transpl Int Jan 16. [Epub ahead of print].

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The results point toward high variability of practice but some generalizations regarding the concern for hypercoagulable status, use of unfractionated heparin intraoperatively, and use of anticoagulation with LMWH in the postoperative period. The comparisons of complications from different centers would be more meaningful if a uniform protocol was established. If robust data could be collected in a prospective manner, it would assist in informing patients regarding surgical risks and postoperative expectations. Urgent efforts are required to create a consensus guideline on appropriate management either by forming a group that could use corroborative evidence to generate one or by conducting a prospective multicenter randomized trial comparing efficacy and risk. [No abstract available. Excerpt from article].

Wu, T.C., Ankrom, C., Joseph, M., Trevino, A., Zhu, L., Warach, S., Novakovic, R.R., Goldberg, M.P., Birnbaum, L.A., Mir, O., Rodriguez, G.J., Alderazi, Y.J., Hassan, A.E. and Savitz, S.I. (2021). “IAT-TiMeS: Intra-Arterial Thrombectomy Transfer Metric Study in Texas.” J Stroke Cerebrovasc Dis 30(3): 105602.

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OBJECTIVE: We aim to report intra-arterial thrombectomy transfer metrics for ischemic stroke patients that were transferred to hub hospitals for possible intra-arterial thrombectomy in multiple geographic regions throughout the state of Texas and to identify potential barriers and delays in the intra-arterial thrombectomy transfer process. METHOD: We prospectively collected data from 8 participating Texas comprehensive stroke/thrombectomy capable centers from 7 major regions in the State of Texas. We collected baseline clinical and imaging data related to the pre-transfer evaluation, transfer metrics, and post-transfer clinical and imaging data. RESULTS: A total of 103 acute ischemic stroke patients suspected/confirmed to have large vessel occlusions between December 2016 to May 2019 that were transferred to hubs as possible intra-arterial thrombectomy candidates were enrolled. A total of 56 (54%) patients were sent from the spoke to the hub via ground ambulance with 47 (46%) patients traveling via air ambulance. The median spoke arrival to hub arrival time was 174 min, median spoke arrival to departure from spoke was 131 min, and median travel time was 39 min. The spoke arrival time to transfer initiation was 68 min. CT-perfusion obtained at the spoke and earlier initiation of transfer were statistically associated with shorter transfer times. CONCLUSION: Transfer of intra-arterial thrombectomy patients in Texas may take over 4 h from spoke arrival to hub arrival. This time may be shortened by earlier transfer initiation and acceptance.

Menter, A., Krueger, G.G., Paek, S.Y., Kivelevitch, D., Adamopoulos, I.E. and Langley, R.G. (2021). “Interleukin-17 and Interleukin-23: A Narrative Review of Mechanisms of Action in Psoriasis and Associated Comorbidities.” Dermatol Ther (Heidelb) Jan 29. [Epub ahead of print].

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Psoriasis is an immune-mediated inflammatory skin disease associated with numerous inflammatory comorbidities, including increased cardiovascular risk. The interleukin (IL)-23/IL-17 axis plays a central role in the immunopathogenesis of psoriasis and related comorbidities by acting to stimulate keratinocyte hyperproliferation and feed-forwarding circuits of perpetual T cell-mediated inflammation. IL-17 plays an important role in the downstream portion of the psoriatic inflammatory cascade. This review discusses the distinct mechanisms of action of IL-17 and IL-23 in the immunopathogenesis of psoriasis and related comorbidities plus the significant therapeutic benefits of selectively inhibiting these cytokines in patients with moderate to severe plaque psoriasis.