Research Spotlight

Packer, M., C. O’Connor, J. J. V. McMurray, J. Wittes, W. T. Abraham, S. D. Anker, K. Dickstein, G. Filippatos, R. Holcomb, H. Krum, A. P. Maggioni, A. Mebazaa, W. F. Peacock, M. C. Petrie, P. Ponikowski, F. Ruschitzka, D. J. van Veldhuisen, L. S. Kowarski, M. Schactman and J. Holzmeister (2017). “Effect of ularitide on cardiovascular mortality in acute heart failure.” N Engl J Med 376(20): 1956-1964.

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BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients’ long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality.

Yahagi, K., E. Ladich, R. Kutys, H. Mori, L. G. Svensson, M. J. Mack, H. C. Herrmann, C. R. Smith, M. B. Leon, R. Virmani and A. V. Finn (2017). “Pathology of balloon-expandable transcatheter aortic valves.” Catheter Cardiovasc Interv: 2017 Jun [Epub ahead of print].

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BACKGROUND: The Placement of AoRtic TraNscathetER Valves trials (PARTNER) showed favorable safety and efficacy versus medical or surgical therapy in inoperable, high, and intermediate surgical risk patients with severe aortic stenosis. However, the biological responses to transcatheter aortic valves have not been well characterized. OBJECTIVES: The aim of this study was to perform pathologic assessment of Edwards SAPIEN transcatheter aortic valves removed either at autopsy or surgically during the PARTNER I and II clinical trials. METHODS: Explanted valves and frame were evaluated for pathologic responses including extent of thrombus, inflammation, neointima, and leaflet degeneration/calcification according to semiquantitative grading by implant duration (90 days). RESULTS: A total of 22 cases (median age 82.0 years, 45% men) were included, with a duration of implantation that ranged from 0 to 1739 days (median duration 16.5 days [interquartile range, 2.8-68.3]). Valve thrombosis resulting in severe aortic stenosis was observed in one case. Moderate leaflet thrombus was seen in 14% of cases (n = 3) and all were asymptomatic. Calcification was seen in two valves: one with severe leaflet calcification had severe aortic stenosis requiring surgical replacement, while the other showed early calcification. Mild structural leaflet changes were exclusively seen in valve implants >90 days. Valve inflammation and thrombus formation was mild in majority of the cases. CONCLUSIONS: Overall, our study demonstrates moderate thrombus formation in 14% and calcification in only 2 valves, >/=4 years duration. In this short-duration study, acceptable durability and biocompatibility of the Edwards SAPIEN transcatheter valve system was demonstrated; however, further studies are required to confirm the significance and application of our findings.

Dickler, M. N., S. Tolaney, H. S. Rugo, J. Cortes, V. Dieras, D. A. Patt, H. Wildiers, C. A. Hudis, J. A. O’Shaughnessy, E. Zamora, D. Yardley, M. Frenzel, A. G. Koustenis and J. Baselga (2017). “Monarch 1, a phase 2 study of abemaciclib, a cdk4 and cdk6 inhibitor, as a single agent, in patients with refractory hr+/her2- metastatic breast cancer.” Clin Cancer Res: 2017 May [Epub ahead of print].

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PURPOSE:
The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC).

Experimental Design:
MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS) and overall survival (OS).

Results:
Patients (n=132) had a median of 3 (range 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had >/=3 metastatic sites. At the 12 month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI: 13.3, 27.5; 15% not excluded); clinical benefit rate (CR+PR+SD>/=6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).

Conclusions:

In this poor-prognosis, heavily pre-treated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single agent abemaciciclib was well tolerated and exhibited promising clinical activity.

Downey, L. C., C. M. Cotten, C. P. Hornik, M. M. Laughon, V. N. Tolia, R. H. Clark and P. B. Smith (2017). “Association of in utero magnesium exposure and spontaneous intestinal perforations in extremely low birth weight infants.” J Perinatol 37(6): 641-644.

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OBJECTIVE: The objective of this study is to determine whether antenatal exposure to magnesium is associated with spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants (1000 g). STUDY DESIGN: We identified all ELBW infants admitted to 1 of 323 neonatal intensive care units from 2007 to 2013. We used multivariable conditional logistic regression to compare outcomes in the first 21 days after birth between infants exposed and unexposed to magnesium in utero. RESULTS: Of the 28 035 infants, 11 789 (42%) were exposed to antenatal magnesium (AM). There was no difference in the risk of SIP, odds ratio=1.08 (95% confidence interval; 0.91 to 1.29), between infants exposed and unexposed to AM. Mortality in the first 21 days after birth was lower in the magnesium-exposed infants, odds ratio=0.76 (0.70 to 0.83). CONCLUSION: AM exposure in ELBW infants was not associated with increased risk of SIP.

Driver, S., M. Reynolds, M. Douglas and M. Bennett (2017). “Describing weight loss attempts and physical activity among individuals with tbi prior to participation in a weight-loss program.” J Head Trauma Rehabil: 2017 May [Epub ahead of print].

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OBJECTIVE: Describe (1) weight loss history, (2) perceptions about lifestyle changes, and (3) physical activity among a sample of individuals with traumatic brain injury prior to a 12-month lifestyle change program. SETTING: Community-based. PARTICIPANTS: Individuals enrolled in a lifestyle change program, 6 months or more post-traumatic brain injury, body mass index of 25 or greater, 18 to 64 years of age, with physician’s clearance to participate. DESIGN: Convenience sample. MAIN MEASURES: Self-report data were collected before beginning the lifestyle change program including descriptive, weight loss history and physical activity behavior using the Modifiable Activity Questionnaire. RESULTS: The final sample included 22 participants (M age = 46 years) injured a median of 8 years ago. Mean weight was 208.5 lb (SD = 40.2), with average body mass index of 31.84 (SD = 4.4). Since injury, 72.7% reported prior weight loss attempts, with 50% gaining 10 lb or more. All participants indicated high motivation for lifestyle changes. Perceived benefits included feeling better, improving overall health, and increased energy. Barriers included physical health complications. Types of physical activity completed included walking (68%, 180 min/mo) and swimming (32%, 79 min/mo). CONCLUSION: Results indicate that many individuals gained weight since injury and attempted weight loss, demonstrating a need for evidence-based lifestyle interventions. Future research is needed to determine whether individuals with traumatic brain injury are able to achieve and maintain weigh loss through intervention.