Research Spotlight

Ahmad, K. A., S. J. Desai, M. M. Bennett, S. F. Ahmad, Y. T. Ng, R. H. Clark and V. N. Tolia (2016). “Changing antiepileptic drug use for seizures in us neonatal intensive care units from 2005 to 2014.” J Perinatol: 2016 Nov [Epub ahead of print].

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OBJECTIVE: Neonatal seizures are a common problem in the neonatal intensive care unit and are frequently treated with antiepileptic drugs. Limited data exist on current or changing antiepileptic drug use for seizures in the neonatal intensive care unit.We sought to describe trends of antiepileptic drug exposure in a large volume of US neonatal intensive care unit from 2005 to 2014 and we hypothesized increasing levetiracetam exposure over the 10-year study period. STUDY DESIGN: Retrospective cohort study of infants from the Pediatrix Medical Group Clinical Data Warehouse, a large, multicenter, deidentified data set. Data were analyzed for trends in 2-year time periods. Our cohort included infants with a diagnosis of seizures who received an antiepileptic drug that were discharged from the neonatal intensive care unit from 1 January 2005 to 31 December 2014. RESULTS: Among 778 395 infants from 341 facilities, we identified 9134 infants with a seizure diagnosis who received an antiepileptic drug. Phenobarbital was used in 98% of the cohort. From 2005-2006 to 2013-2014 phenobarbital exposure declined from 99 to 96% (P<0.001), phenytoin exposure decreased from 15 to 11% (P<0.001) and levetiracetam exposure increased 10-fold from 1.4 to 14% (P<0.001). Overall, <1% of infants were exposed to carbamazepine, lidocaine or topiramate. CONCLUSIONS: Infants with seizures were overwhelmingly exposed to phenobarbital, despite a significant increase in levetiracetam exposure. The use of phenytoin declined and has been surpassed by levetiracetam as the second most widely used antiepileptic in the neonatal intensive care unit. These changes in antiepileptic drug usage patterns have occurred in the absence of novel efficacy data in neonates.

Hortobagyi, G. N., S. M. Stemmer, H. A. Burris, Y. S. Yap, G. S. Sonke, S. Paluch-Shimon, M. Campone, K. L. Blackwell, F. Andre, E. P. Winer, W. Janni, S. Verma, P. Conte, C. L. Arteaga, D. A. Cameron, K. Petrakova, L. L. Hart, C. Villanueva, A. Chan, E. Jakobsen, A. Nusch, O. Burdaeva, E. M. Grischke, E. Alba, E. Wist, N. Marschner, A. M. Favret, D. Yardley, T. Bachelot, L. M. Tseng, S. Blau, F. Xuan, F. Souami, M. Miller, C. Germa, S. Hirawat and J. O’Shaughnessy (2016). “Ribociclib as first-line therapy for hr-positive, advanced breast cancer.” N Engl J Med 375(18): 1738-1748.

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Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29x10-5. Results The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29x10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. Conclusions Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.

Klintmalm, G. B., F. Vincenti and A. Kirk (2016). “Steroid-responsive acute rejection should not be the end point for immunosuppressive trials.” Am J Transplant 16(11): 3077-3078.

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Today, early, steroid-unresponsive acute cellular rejec-tions are uncommon, and when they occur, they aretypically responsive to depletional antibody therapy. His-torically, an aggressive acute cellular rejection (ACR)could manifest itself acutely as a septic shock. Graftswere frequently lost to acute rejection and patient deathswere commonly seen in all organ recipients. Today thatis extremely rare. As an example, at Baylor UniversityMedical Center in our prospective protocolized, locked-down, research database, of 1268 consecutive patientswho received a primary liver transplant alone during thepast 10 years, 273 patients experienced at least oneACR in the first 3 postoperative months, of which 37were steroid resistant. There were only three grafts lostfrom ACR, and none have occurred since 2007. In 344isolated kidney transplantations in the past 2 years, nografts were lost to ACR. The lack of effect of T cell–mediated rejection on long-term outcome has been welldocumented (2). Consequently, although ACR is undesir-able, it no longer dictates patient survival, rehabilitation,or quality of life, while immunosuppressive toxicityclearly does.

Capoulade, R., X. Zeng, J. R. Overbey, G. Ailawadi, J. H. Alexander, D. Ascheim, M. Bowdish, A. C. Gelijns, P. Grayburn, I. L. Kron, R. A. Levine, M. J. Mack, S. Melnitchouk, R. E. Michler, J. C. Mullen, P. O’Gara, M. K. Parides, P. Smith, P. Voisine and J. Hung (2016). “Impact of left ventricular to mitral valve ring mismatch on recurrent ischemic mitral regurgitation after ring annuloplasty.” Circulation 134(17): 1247-1256.

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BACKGROUND: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. METHODS: Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size). RESULTS: At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05-4.62; P=0.038) remained significantly associated with 1-year MR recurrence. CONCLUSIONS: LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone.

Kurlansky, P., M. Herbert, S. Prince and M. Mack (2016). “Coronary artery bypass graft versus percutaneous coronary intervention: Meds matter: Impact of adherence to medical therapy on comparative outcomes.” Circulation 134(17): 1238-1246.

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BACKGROUND: Multiple studies have compared coronary artery bypass graft (CABG) with percutaneous coronary interventions (PCI) for coronary revascularization. There is considerable evidence that adherence to medical therapy can affect the outcomes of therapeutic interventions. However, the long-term influence of compliance with recommended medical therapy on the comparative outcomes of CABG versus PCI remains to be defined. METHODS: All non-ST-segment-elevation myocardial infarction patients undergoing coronary revascularization in an 8-hospital network were followed for up to 8 years to determine medication history and major adverse cardiac events: all-cause mortality, nonfatal myocardial infarction, and reintervention. All mortalities were checked against the Social Security Death Index. Survival curves were derived with Kaplan-Meier methods; hazard ratios were calculated with the Cox proportional hazard model; and propensity score matching was used to account for differences in patient selection. RESULTS: Among the 973 CABG and 2255 PCI patients, Kaplan-Meier major adverse cardiac event-free survival curves demonstrated a significant benefit for antiplatelet, lipid-lowering, and beta-blocker therapy in both the CABG and PCI groups (P=0.001 for all 3 medications). Cox regression identified compliance with optimal medical therapy as a more powerful predictor of major adverse cardiac event-free survival than choice of therapy (hazard ratio for noncompliance=2.79; 95% confidence limits, 2.19-3.54; P<0.001; hazard ratio for PCI versus CABG=1.68, 95% confidence limits, 138-2.04; P<0.001). In propensity-matched patients, CABG outcomes were superior to PCI outcomes in patients nonadherent to optimal medical therapy (P=0.001) but were not different in patients adherent to optimal medical therapy (P=0.574). CONCLUSIONS: Regardless of coronary revascularization strategy, medication adherence has a dramatic effect on long-term outcome. Among comparable patients who adhere to optimal medical therapy, outcomes of PCI and CABG may not differ; however, among nonadherent patients, CABG affords better major adverse cardiac event-free survival. Therefore, patient compliance with medical therapy may inform clinical decision making and should be incorporated into all future comparative studies of comparative coronary revascularization strategies.