Research Spotlight

Lebwohl, M., Deodhar, A., Griffiths, C.E.M., Menter, M.A., Poddubnyy, D., Bao, W., Jehl, V., Marfo, K., Primatesta, P., Shete, A., Trivedi, V. and Mease, P.J. (2021). “The risk of malignancy in secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis patients: analysis of up to five-year clinical trial and post-marketing surveillance data.” Br J Dermatol.

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BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVE: To assess the malignancy risk in secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients. METHODS: This integrated safety analysis from both the secukinumab clinical trial program and post-marketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of five years follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates (EAIR; incidence rates/100-patient treatment-years [PTY]). Standardised incidence ratios (SIR) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. The crude incidence of malignancy was also reported using post-marketing surveillance data. RESULTS: Safety data from 10,685 psoriasis, 2,523 PsA and 1,311 AS secukinumab-treated patients from 49 clinical trials were included. Across indications over a five-year period, the EAIR of malignancy was 0.85/100 PTY (95% confidence intervals [CI]: 0.74, 0.98) in secukinumab-treated patients, corresponding to 204 patients/23,908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by a SIR of 0.99 (95% CI: 0.82, 1.19) across indications. The estimated crude cumulative incidence reporting rate/100 PTY for malignancy was 0.27 in the post-marketing surveillance data across indications with a cumulative exposure of 285,811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to five years of secukinumab treatment. These data support the long-term us of secukinumab in these indications.

Hara, H., Ono, M., Kawashima, H., Kogame, N., Mack, M.J., Holmes, D.R., Morice, M.C., Davierwala, P.M., Mohr, F.W., Thuijs, D., Head, S.J., Kappetein, A.P., Onuma, Y. and Serruys, P.W. (2021). “Impact of stent length and diameter on 10-year mortality in the SYNTAXES trial.” Catheter Cardiovasc Interv.

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OBJECTIVES: We investigated the impact of total stent length (TSL) and average nominal stent diameter (ASD) on 10-year mortality after percutaneous coronary intervention (PCI) in the SYNTAXES trial. BACKGROUND: TSL and ASD in patients treated with PCI are associated with major adverse cardiovascular events. However, the treatment effect of PCI with extensive and/or small stenting as compared with coronary artery bypass grafting (CABG) for complex coronary artery disease has not been fully evaluated. METHODS: Impacts on mortality of extensive stenting defined as TSL >100 mm and small stenting as ASD <3 mm were analyzed in 893 PCI patients and were compared to 865 CABG patients. RESULTS: TSL as a continuous variable was significantly associated with 10-year mortality (adjusted hazard ratio [HR], 1.05 [1.01-1.09] per 10 mm increase). PCI patients with extensive stenting had a higher 10 year mortality than CABG patients (adjusted HR, 1.97 [1.41-2.74]) or not- extensive stenting PCI (adjusted HR, 1.94 [1.36-2.77]). Although ASD did not have a significant association with 10 year mortality (adjusted HR, 0.97 [0.85-1.11] per 0.25 mm increase), PCI with small stents was associated with a higher 10 year mortality, compared to CABG (adjusted HR, 1.66 [1.23-2.26]) and PCI performed with large stents (adjusted HR, 1.74 [1.19-2.53]). Patients treated with not-extensive and large stents had similar mortality rates (24.0 versus 23.8%) as those treated with CABG. CONCLUSIONS: Extensive and small stenting were associated with higher 10 year mortality, compared with CABG. When patients have to be treated with extensive or small stenting, revascularization with CABG should be preferred.

Généreux, P., Piazza, N., Alu, M.C., Nazif, T., Hahn, R.T., Pibarot, P., Bax, J.J., Leipsic, J.A., Blanke, P., Blackstone, E.H., Finn, M.T., Kapadia, S., Linke, A., Mack, M.J., Makkar, R., Mehran, R., Popma, J.J., Reardon, M., Rodes-Cabau, J., Van Mieghem, N.M., Webb, J.G., Cohen, D.J. and Leon, M.B. (2021). “Valve Academic Research Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical Research.” J Am Coll Cardiol.

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AIMS: The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. METHODS AND RESULTS: Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. CONCLUSIONS: Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

Chikwe, J., O’Gara, P., Fremes, S., Sundt, T., Habib, R.H., Gammie, J., Gaudino, M., Badhwar, V., Gillinov, M., Acker, M., Rowe, G., Gill, G., Goldstone, A.B., Schwann, T., Gelijns, A., Trento, A., Mack, M. and Adams, D.H. (2021). “Mitral Surgery after Transcatheter Edge-to-Edge Repair: Society of Thoracic Surgeons Database Analysis.” J Am Coll Cardiol.

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BACKGROUND: Transcatheter edge-to-edge (TEER) mitral repair may be complicated by residual or recurrent mitral regurgitation. Increasing need for surgical reintervention has been reported but operative outcomes are ill-defined. OBJECTIVES: This study evaluated national outcomes of mitral surgery after TEER. METHODS: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database was used to identify 524 adults who underwent mitral surgery after TEER between July 2014 and June 2020. Emergencies (5.0%, n=26), previous mitral surgery (5.3%, n=28) or open implantation of transcatheter prostheses (1.5%, n=8) were excluded. The primary outcome was 30-day or in-hospital mortality. RESULTS: In the study cohort of 463 patients median age was 76 years (interquartile range (IQR) 67-81 years), median left ventricular ejection fraction 57% (IQR 48-62%), and 177 (38.2%) patients had degenerative disease. Major concomitant cardiac surgery was performed in 137 (29.4%) patients: in patients undergoing isolated mitral surgery median STS predicted mortality was 6.5% (IQR 3.9-10.5%), observed mortality was 10.2% (n=23/225) and the ratio of observed to expected mortality was 1.2 (95% CI 0.8-1.9). Predictors of mortality included urgent surgery (odds ratio (OR) 2.4, 95% confidence interval (CI) 1.3-4.6), non-degenerative / unknown etiology (OR 2.2, 95% CI 1.1-4.5), creatinine >2.0mg/dl (OR 3.8, 95% CI 1.9-7.9) and age >80 (OR 2.1, 95% CI 1.1-4.4). In a volume outcomes analysis in an expanded cohort of 591 patients at 227 hospitals, operative mortality was 2.6% (n=2/76) in 4 centers that performed >10 cases versus 12.4% (n= 64/515) in centers performing fewer (p=0.01). The surgical repair rate after failed TEER was 4.8% (n=22), and 6.8% (n=12) in degenerative disease. CONCLUSION: This study indicates mitral repair is infrequently achieved after failed TEER, which may have implications for treatment choice in lower-risk and younger patients with degenerative disease. These findings should inform patient consent for TEER, clinical trial design and clinical performance measures.

Mateos, M.V., Gavriatopoulou, M., Facon, T., Auner, H.W., Leleu, X., Hájek, R., Dimopoulos, M.A., Delimpasi, S., Simonova, M., Špička, I., Pour, L., Kriachok, I., Pylypenko, H., Doronin, V., Usenko, G., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Stevens, D.A., Quach, H., Jagannath, S., Moreau, P., Levy, M., Badros, A.Z., Anderson, L.D., Jr., Bahlis, N.J., Cavo, M., Chai, Y., Jeha, J., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Richardson, P.G. and Grosicki, S. (2021). “Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma.” J Hematol Oncol 14(1): 59.

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Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m(2)) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .