Research Spotlight

Ghouadni, A., S. Delaloge, P. Lardelli, C. Kahatt, T. Byrski, J. L. Blum, A. Goncalves, M. Campone, A. Nieto, V. Alfaro, M. Cullell-Young and J. Lubinski (2017). “Higher antitumor activity of trabectedin in germline brca2 carriers with advanced breast cancer as compared to brca1 carriers: A subset analysis of a dedicated phase ii trial.” Breast 34: 18-23.

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Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m2 as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations. The primary efficacy endpoint was the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST) by independent expert review. Duration of response (DR) and progression-free survival (PFS) were secondary efficacy endpoints. Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Data from 26 BRCA1-mutated and 13 BRCA2-mutated patients were analyzed. 69% of BRCA1-mutated cancers were triple-negative vs. 31% of BRCA2-mutated ones. 77% of BRCA1 and 31% of BRCA2 carriers were platinum-pretreated. The ORR in BRCA2-mutated patients was higher than in BRCA1-mutated patients (33.3% vs. 9.1%). DR ranged for 1.4-6.8 months in BRCA2-mutated patients and for 1.5-1.7 months in BRCA1-mutated patients. More BRCA2-mutated patients had disease stabilization for >/=4 months (25.0% vs. 9.1%) and their median PFS was longer (4.7 vs. 2.5 months). Trabectedin was well tolerated in both patient subtypes. In conclusion, trabectedin showed higher antitumor activity in relapsed MBC patients with germline BRCA2 mutations than in those with BRCA1 mutations.

Goldberg, R. J. and H. L. Nguyen (2017). “Unlocking the keys to site activation and recruitment success in a randomized controlled trial.” Stroke: 2017 Aug [Epub ahead of print].

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Two of the most crucial requirements for successfully carrying out and completing an RCT are the initial construction of different hypothetical scenarios to determine how many healthy individuals or patients with a specific disease or condition are needed to be enrolled in the trial and eventually followed on either a short- or long-term basis to find clinically meaningful differences in one’s principal study outcomes and, subsequently, to go out into the field, find, and recruit a sufficient number of patients to the proposed trial to satisfy one’s predetermined sample size requirements. Moreover, the logistical operations of an RCT need to be performed within the confines of a manageable budget and typically tight timeline for patient enrollment and follow-up in which all too often projected estimates of the number of patients to be enrolled and successfully retained in the trial greatly exceed reality.

McCullough, P. A. (2017). “How trialists and pharmaceutical sponsors have failed us by thinking that acute heart failure is a 48-hour illness.” Am J Cardiol 120(3): 505-508.

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Trials of novel therapies for acute heart failure (HF) have followed a convention of short term, most commonly a 48-hour infusion of parenteral therapy compared with placebo or an active drug in a randomized, double-blind study design. Such trials include OPTIME-CHF, SURVIVE, VERITAS, PROTECT, ASCEND-HF, TRUE-HF, and RELAX-AHF-2. This article reviews how this practice in trials began and summarizes the reasons why such a brief exposure of any novel therapy has failed to reduce the end points of rehospitalization or death. Future trials should consider acute and extended use of novel agents to better match the pathophysiology of decompensation and recovery from acute HF.

Mooney, J., S. L. Sellers, P. Blanke, P. Pibarot, R. T. Hahn, D. Dvir, P. S. Douglas, N. J. Weissman, S. K. Kodali, V. H. Thourani, H. Jilaihawi, O. Khalique, C. R. Smith, S. H. Kueh, M. Ohana, R. Grover, C. Naoum, A. Crowley, W. A. Jaber, M. C. Alu, R. Parvataneni, M. Mack, J. G. Webb, M. B. Leon and J. A. Leipsic (2017). “Ct-defined prosthesis-patient mismatch downgrades frequency and severity, and demonstrates no association with adverse outcomes after tavr.” JACC Cardiovasc Interv: 2017 Jul [Epub ahead of print].

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OBJECTIVES: This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis-patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). BACKGROUND: PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. METHODS: A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (>/=0.65 and

Lewis, E. F., B. L. Claggett, J. J. V. McMurray, M. Packer, M. P. Lefkowitz, J. L. Rouleau, J. Liu, V. C. Shi, M. R. Zile, A. S. Desai, S. D. Solomon and K. Swedberg (2017). “Health-related quality of life outcomes in paradigm-hf.” Circ Heart Fail 10(8): 1-16.

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BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (>/=5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.