Research Spotlight

Vemulapalli, S., J. D. Carroll and M. J. Mack (2019). “Volume and Outcomes for Transcatheter Aortic-Valve Replacement. Reply.” New England Journal of Medicine 381(14): 1394-1395.

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We agree with Noble and Frei that 30-day mortality should not be the sole indicator of site quality. We are currently deriving and validating metrics that emphasize a composite of 30-day morbidity and mortality as well as “alive and well” status at 1 year on the basis of survival and improved quality of life. Yet, the measurement of 30-day mortality remains vital for patient safety. Our analyses of volume suggest that it is a surrogate for quality and that adequate volume is necessary to accurately estimate expected risk-adjusted outcomes. Goldberg et al. raise the complex issue of geographic access to TAVR, for which there are few data. In the United States, we have a “spoke and hub” medical system with centralization of some services because of cost, infrastructure, and quality considerations. As a result, TAVR is not unique in being restricted to certain centers. Despite this, the United States has more hospitals, and more hospitals per capita, performing TAVR than any other country. Although geography is relatively easily measured, access to care is a complex construct of geographic location, socioeconomic status, ethnic group, race, insurance status, patients’ preferences, and physician-related factors, among others. More research is needed to clarify the extent to which each of these factors contributes to access to care issues for TAVR. Our analysis did not fully address access to TAVR, and the analysis that Goldberg and Gray suggested may lead to interesting results. We agree with Sharma that the results of our study were relevant to the CMS National Coverage Determination. However, we differ with Sharma’s interpretation of our results and their relationship to the findings of Russo et al. Russo and colleagues examined only one commercially approved device, defined the beginning of the learning curve on the basis of the first use of the latest generation of the SAPIEN system rather than on the basis of all previous experience, and probably underestimated the site volume by not including CoreValve use. We constructed hierarchical models that accounted for operator case number and then modeled the marginal effect of annual volume on mortality beyond the contribution of operator case number. Since the “learning curve” is essentially defined by mortality as a function of case number, modeling the association between volume and mortality after taking into account case number effectively isolates the annual volume–mortality relationship from the learning curve. With this technique, we found that there was a volume–mortality relationship beyond the learning curve and that it was independent of procedure year and patient risk. (Authors’ reply to correspondence about their article, Vemulapalli S, Carroll JD, Mack MJ, et al. Procedural volume and outcomes for transcatheter aortic-valve replacement. N Engl J Med 2019;380:2541-2550.)

Butler, J., S. D. Anker and M. Packer (2019). “Redefining Heart Failure With a Reduced Ejection Fraction.” JAMA Sep 13. [Epub ahead of print].

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The current approach to classifying patients with heart failure based on the measurement of left ventricular ejection fraction (LVEF) lacks a strong clinical, pathophysiological, or evidentiary basis. In particular, the concept that there exists a unique group of patients with an LVEF of 40% to 50% that differs from those with an LVEF lower than 40% is based on an arbitrary historical distinction. Patients who have “heart failure with a mid-range ejection fraction” do not have a unique pattern of symptoms or pathophysiology; the range of values for those with a mid-range LVEF is so narrow that delineation of the subgroup is inconsistent with the accuracy and reproducibility of the methods routinely used to assess systolic function in clinical practice. Furthermore, consistent evidence across several classes of drugs now indicates that treatments that are effective in reducing the risk of major adverse clinical outcomes in patients with an LVEF of 40% or lower are also beneficial in those with an LVEF of 41% to 50%. The precise number of patients with heart failure and LVEF of 41% to 50% is not known. Yet it is important to emphasize that this proposal applies only to patients with LVEF of 41% to 50% who have established symptoms of chronic heart failure. Any role of neurohormonal antagonists in asymptomatic patients with such mild impairment of systolic function has not been evaluated or established. The current approach of distinguishing patients with heart failure and a reduced ejection fraction (HFrEF) from those with heart failure with a preserved ejection fraction (HFpEF) based on a threshold of 40% reflects the consequences of a nonphysiological distinction made by clinical trialists 30 years ago. Reliance on such a threshold may deprive patients who truly have impaired systolic function and a subnormal LVEF from treatments that are likely to reduce morbidity and mortality. It appears reasonable for physicians to consider patients with an abnormally low LVEF and established symptoms of heart failure to belong to the same group, ie, heart failure with a reduced LVEF, and to provide such patients the benefits of treatment known to be effective in HFrEF. Based on the findings of clinical trials and the need to reduce the adverse consequences of heart failure on public health, serious consideration should be given to increasing the LVEF threshold for the use of evidence-based treatments from its current value of 40% to a value of 50%. (Excerpt from text, p. E2; no abstract available.)

Haugen, C. E., M. McAdams-DeMarco, E. C. Verna, R. Rahimi, M. R. Kappus, M. A. Dunn, M. L. Volk, A. Gurakar, A. Duarte-Rojo, D. R. Ganger, J. G. O’Leary, D. Ladner, J. Garonzik-Wang, D. L. Segev and J. C. Lai (2019). “Association Between Liver Transplant Wait-list Mortality and Frailty Based on Body Mass Index.” JAMA Surgery 2019 Sep 11. [Epub ahead of print].

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Importance: Among liver transplant candidates, obesity and frailty are associated with increased risk of death while they are on the wait-list. However, use of body mass index (BMI) may not detect candidates at a higher risk of death owing to the fact that ascites and muscle wasting are seen across transplant candidates of all BMI measurements. Objective: To evaluate whether the association between wait-list mortality and frailty varied by BMI of liver transplant candidates. Design, Setting, and Participants: A prospective cohort study was conducted at 9 liver transplant centers in the United States from March 1, 2012, to May 1, 2018, among 1108 adult liver transplant candidates without hepatocellular carcinoma. Exposures: At outpatient evaluation, the Liver Frailty Index score was calculated (grip strength, chair stands, and balance), with frailty defined as a Liver Frailty Index score of 4.5 or more. Candidates’ BMI was categorized as nonobese (18.5-29.9), class 1 obesity (30.0-34.9), and class 2 or greater obesity (>/=35.0). Main Outcomes and Measures: The risk of wait-list mortality was quantified using competing risks regression by candidate frailty, adjusting for age, sex, race/ethnicity, Model for End-stage Liver Disease Sodium score, cause of liver disease, and ascites, including an interaction with candidate BMI. Results: Of 1108 liver transplant candidates (474 women and 634 men; mean [SD] age, 55 [10] years), 290 (26.2%) were frail; 170 of 670 nonobese candidates (25.4%), 64 of 246 candidates with class 1 obesity (26.0%), and 56 of 192 candidates with class 2 or greater obesity (29.2%) were frail (P = .57). Frail nonobese candidates and frail candidates with class 1 obesity had a higher risk of wait-list mortality compared with their nonfrail counterparts (nonobese candidates: adjusted subhazard ratio, 1.54; 95% CI, 1.02-2.33; P = .04; and candidates with class 1 obesity: adjusted subhazard ratio, 1.72; 95% CI, 0.99-2.99; P = .06; P = .75 for interaction). However, frail candidates with class 2 or greater obesity had a 3.19-fold higher adjusted risk of wait-list mortality compared with nonfrail candidates with class 2 or greater obesity (95% CI, 1.75-5.82; P < .001; P = .047 for interaction). Conclusions and Relevance: This study's finding suggest that among nonobese liver transplant candidates and candidates with class 1 obesity, frailty was associated with a 2-fold higher risk of wait-list mortality. However, the mortality risk associated with frailty differed for candidates with class 2 or greater obesity, with frail candidates having a more than 3-fold higher risk of wait-list mortality compared with nonfrail patients. Frailty assessments may help to identify vulnerable patients, particularly those with a BMI of 35.0 or more, in whom a clinician's visual evaluation may be less reliable to assess muscle mass and nutritional status.

Tan, A. R., G. S. Wright, A. R. Thummala, M. A. Danso, L. Popovic, T. J. Pluard, H. S. Han, Z. Vojnovic, N. Vasev, L. Ma, D. A. Richards, S. T. Wilks, D. Milenkovic, Z. Yang, J. M. Antal, S. R. Morris and J. O’Shaughnessy (2019). “Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.” Lancet Oncology Sep 27. [Epub ahead of print].

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BACKGROUND: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged >/=18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m(2) and intravenous carboplatin (area under the concentration-time curve 2 mug x h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m(2) on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual. FINDINGS: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8.4 months (IQR 3.8-13.6) for group 1, 12.7 months (5.5-17.4) for group 2, and 12.9 months (6.7-16.8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0.8 day (SD 2.4) in group 1, 1.5 days (3.5) in group 2, and 1.0 day (2.6) in group 3 (group 3 vs group 1 one-sided adjusted p=0.70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0.70). Overall survival was 12.6 months (IQR 5.8-15.6) in group 1, 20.1 months (9.4-not reached) in group 2, and 17.8 months (8.8-not reached) in group 3 (group 3 vs group 1 two-sided p=0.0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths. INTERPRETATION: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted. FUNDING: G1 Therapeutics.

van der Knaap, M. S., R. Schiffmann, F. Mochel and N. I. Wolf (2019). “Diagnosis, prognosis, and treatment of leukodystrophies.” Lancet Neurology 18(10): 962-972.

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Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.