Research Spotlight

Schadendorf, D., J. D. Wolchok, F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Chesney, C. Robert, K. Grossmann, D. McDermott, D. Walker, R. Bhore, J. Larkin and M. A. Postow (2017). “Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase ii and iii trials.” J Clin Oncol 35(34): 3807-3814.

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Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Schiffmann, R., M. E. Wallace, D. Rinaldi, I. Ledoux, M. P. Luton, S. Coleman, H. O. Akman, K. Martin, J. Y. Hogrel, D. Blankenship, J. Turner and F. Mochel (2017). “A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.” J Inherit Metab Dis: 2017 Nov [Epub ahead of print].

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BACKGROUND: Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. METHODS AND RESULTS: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 +/- 164 m (range 95-672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) -11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. CONCLUSIONS: We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity.

Shutze, W., B. Richardson, R. Shutze, K. Tran, A. Dao, G. O. Ogola, A. Young and G. Pearl (2017). “Midterm and long-term follow-up in competitive athletes undergoing thoracic outlet decompression for neurogenic thoracic outlet syndrome.” J Vasc Surg 66(6): 1798-1805.

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BACKGROUND: Neurogenic thoracic outlet syndrome (NTOS) results from compression of the brachial plexus by the clavicle, first rib, and scalene muscles and may develop secondary to repetitive motion of the upper extremity. Athletes routinely perform repetitive motions, and sports requiring significant arm and shoulder use may put the participant at increased risk for NTOS. Competitive athletes who develop NTOS may require first rib resection and scalenectomy (FRRS) for symptomatic relief. However, the effectiveness of FRRS has not previously been studied in this vulnerable population. METHODS: This is a cross-sectional study of competitive athletes with NTOS who received FRRS by the senior author between 2009 and 2014. Eligible patients were contacted by phone and invited to complete a nine-item survey assessing the long-term effects of FRRS on pain medication use, postoperative physical therapy duration, patient satisfaction, symptom relief, activities of daily living, athletic performance, time to return of athletic performance, and need for other operations. Multivariate analyses of the following risk factors were performed: age, pectoralis minor release, preoperative narcotic use, athletic shutdown, and involvement in a throwing sport. RESULTS: There were 232 competitive athletes who met the inclusion criteria, and 67 of these (age, 14-48 years; 35 male; 99% white) responded to the survey. The average time between surgery and survey completion was 3.9 years (range, 2.2-7.0 years). The most frequent sports conducted by this group were baseball and softball (n = 44 [66%]), volleyball (n = 7 [10%]), and cheerleading and gymnastics (n = 5 [7%]), ranging from high-school to professional levels. The survey results revealed that 96% were improved in pain medication use, 75% would undergo FRRS on the contralateral side if needed, 82% had resolution of symptoms, and 94% were able to perform activities of daily living without limitation; 70% returned to the same or better level of athletic activity after FRRS, and this occurred within 1 year in 50%. Multivariate regression analysis identified younger age as a predictor of the length of physical therapy and preoperative narcotics use as a predictor of symptom resolution. CONCLUSIONS: At our center, >40% of patients requiring FRRS for NTOS are competitive athletes. The results of this study show that the majority of them are able to return to their precompetitive state after FRRS, and few experience limitations in their daily living activities. Half can return to competition at or exceeding their premorbid ability level within 6 months of surgery. The majority are pleased with their decision to undergo FRRS. Further investigation is needed to identify predictive factors for successful return to competitive athletics.

Yoon, S. H., T. Schmidt, S. Bleiziffer, N. Schofer, C. Fiorina, A. J. Munoz-Garcia, E. Yzeiraj, I. J. Amat-Santos, D. Tchetche, C. Jung, B. Fujita, A. Mangieri, M. A. Deutsch, T. Ubben, F. Deuschl, S. Kuwata, C. De Biase, T. Williams, A. Dhoble, W. K. Kim, E. Ferrari, M. Barbanti, E. M. Vollema, A. Miceli, C. Giannini, G. F. Attizzani, W. K. F. Kong, E. Gutierrez-Ibanes, V. A. Jimenez Diaz, H. C. Wijeysundera, H. Kaneko, T. Chakravarty, M. Makar, H. Sievert, C. Hengstenberg, B. D. Prendergast, F. Vincent, M. Abdel-Wahab, L. Nombela-Franco, M. Silaschi, G. Tarantini, C. Butter, S. M. Ensminger, D. Hildick-Smith, A. S. Petronio, W. H. Yin, F. De Marco, L. Testa, N. M. Van Mieghem, B. K. Whisenant, K. H. Kuck, A. Colombo, S. Kar, C. Moris, V. Delgado, F. Maisano, F. Nietlispach, M. J. Mack, J. Schofer, U. Schaefer, J. J. Bax, C. Frerker, A. Latib and R. R. Makkar (2017). “Transcatheter aortic valve replacement in pure native aortic valve regurgitation.” J Am Coll Cardiol 70(22): 2752-2763.

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BACKGROUND: Limited data exist about safety and efficacy of transcatheter aortic valve replacement (TAVR) in patients with pure native aortic regurgitation (AR). OBJECTIVES: This study sought to compare the outcomes of TAVR with early- and new-generation devices in symptomatic patients with pure native AR. METHODS: From the pure native AR TAVR multicenter registry, procedural and clinical outcomes were assessed according to VARC-2 criteria and compared between early- and new-generation devices. RESULTS: A total of 331 patients with a mean STS score of 6.7 +/- 6.7 underwent TAVR. The early- and new-generation devices were used in 119 patients (36.0%) and 212 patients (64.0%), respectively. STS score tended to be lower in the new-generation device group (6.2 +/- 6.7 vs. 7.6 +/- 6.7; p = 0.08), but transfemoral access was more frequently used in the early-generation device group (87.4% vs. 60.8%; p < 0.001). Compared with the early-generation devices, the new-generation devices were associated with a significantly higher device success rate (81.1% vs. 61.3%; p < 0.001) due to lower rates of second valve implantation (12.7% vs. 24.4%; p = 0.007) and post-procedural AR >/= moderate (4.2% vs. 18.8%; p < 0.001). There were no significant differences in major 30-day endpoints between the 2 groups. The cumulative rates of all-cause and cardiovascular death at 1-year follow-up were 24.1% and 15.6%, respectively. The 1-year all-cause mortality rate was significantly higher in the patients with post-procedural AR >/= moderate compared with those with post-procedural AR /= moderate was independently associated with 1-year all-cause mortality (hazard ratio: 2.85; 95% confidence interval: 1.52 to 5.35; p = 0.001). CONCLUSIONS: Compared with the early-generation devices, TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR. In patients with pure native AR, significant post-procedural AR was independently associated with increased mortality.

Zannad, F., M. L. A. Alonso Garcia, J. S. Borer, W. G. Stough, T. Clutton-Brock, Y. Rosenberg and M. Packer (2017). “Role of payers in the development of cardiovascular therapeutics: Misalignment between approval and reimbursement.” J Am Coll Cardiol 70(22): 2822-2830.

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Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers’ decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.