Research Spotlight

Packer, M., J. J. V. McMurray, H. Krum, W. Kiowski, B. M. Massie, A. Caspi, C. M. Pratt, M. C. Petrie, D. DeMets, I. Kobrin, S. Roux and K. Swedberg (2017). “Long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure: Primary results of the enable trials.” JACC Heart Fail 5(5): 317-326.

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OBJECTIVES: The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND: Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. METHODS: In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. RESULTS: Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. CONCLUSIONS: Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

Zurawski, G., X. Shen, S. Zurawski, G. D. Tomaras, D. C. Montefiori, M. Roederer, G. Ferrari, C. Lacabaratz, P. Klucar, Z. Wang, K. E. Foulds, S. F. Kao, X. Yu, A. Sato, N. L. Yates, C. LaBranche, S. Stanfield-Oakley, K. Kibler, B. Jacobs, A. Salazar, S. Self, W. Fulp, R. Gottardo, L. Galmin, D. Weiss, A. Cristillo, G. Pantaleo and Y. Levy (2017). “Superiority in rhesus macaques of targeting hiv-1 env gp140 to cd40 versus lox-1 in combination with replication-competent nyvac-kc for induction of env-specific antibody and t cell responses.” J Virol 91(9): e01596-01616.

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We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.

Blanke, P., J. K. Park, P. Grayburn, C. Naoum, K. Ong, K. Kohli, B. L. Norgaard, J. G. Webb, J. Popma, D. Boshell, P. Sorajja, D. Muller and J. Leipsic (2017). “Left ventricular access point determination for a coaxial approach to the mitral annular landing zone in transcatheter mitral valve replacement.” J Cardiovasc Comput Tomogr: Apr [Epub ahead of print].

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INTRODUCTION: To facilitate coaxial device deployment in transcatheter mitral valve replacement (TMVR), a coaxial approach to the mitral annular plane is needed. We sought to establish a method to determine an ‘orthogonal’ left ventricular (LV) access point for transapical TMVR and to quantitatively characterize its location in patients with severe mitral regurgitation using cardiac computed tomography. METHODS: Cardiac CT data sets of 54 patients with moderate-severe mitral regurgitation evaluated for potential TMVR were analyzed. The D-shaped mitral annular contour was segmented and a 2-dimensional annular plane was derived, allowing for subsequent definition of the perpendicularly oriented mitral annular trajectory. The ‘orthogonal’ LV access point was defined as the transection point of mitral trajectory with the LV epicardial surface. The location of the access point was quantified by its epicardial distance from the true apex and by the rotational offset from a 3-chamber view. RESULTS: LV access points orthogonal to the mitral annular plane were most frequently located in the anterolateral (n = 22, 40.7%) and anterior (n = 16, 29.6%), less frequently anteroseptal (n = 6, 11.1%) and inferolateral (n = 5, 9.3%) ventricular segment; none inferior or inferoseptal. The mean distance to the LV apex was 17.6 +/- 7.7 mm. The mean forward rotational offset from the 3-chamber view was 96.4 +/- 43.4 degrees , relating to a mean forward rotational offset of 6.4 +/- 43.4 degrees in regard to a hypothetical, secondary 90 degrees x-plane view. No significant difference between patients with degenerative mitral valve disease or functional mitral regurgitation was observed. CONCLUSION: The location of the LV access point that provides an orthogonal trajectory to the mitral annular plane exhibits relevant inter-individual variability. It is commonly not identical with the true apex, and frequently localized in the anterolateral or anterior ventricular segments.

Blanke, P., P. Pibarot, R. Hahn, N. Weissman, S. Kodali, V. Thourani, R. Parvataneni, D. Dvir, C. Naoum, B. L. Norgaard, P. Douglas, W. Jaber, O. K. Khalique, H. Jilaihawi, M. Mack, C. Smith, M. Leon, J. Webb and J. Leipsic (2017). “Computed tomography-based oversizing degrees and incidence of paravalvular regurgitation of a new generation transcatheter heart valve.” JACC Cardiovasc Interv 10(8): 810-820.

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OBJECTIVES: The aim of the study was to investigate the influence of the extent of computed tomography (CT)-based area and perimeter oversizing on the incidence and severity of paravalvular aortic regurgitation (PAR) for the Edwards SAPIEN 3 (Edwards Lifesciences, Irvine, California) device, using CT data and echocardiographic outcome data of the PARTNER II (Placement of AoRTic TraNscathetER Valves Trial II) SAPIEN 3 intermediate-risk cohort. BACKGROUND: Transcatheter heart valve (THV) sizing algorithms are device specific, requiring refinements for new valve designs. METHODS: A total of 835 intermediate-risk patients with severe, symptomatic aortic stenosis enrolled in a multicenter, nonrandomized registry at 57 sites in the United States and Canada with available systolic CT data and echocardiographic follow-up were included in this analysis. THV size selection was primarily CT guided based on annular area. Area-based and perimeter-based oversizing was calculated using systolic annular CT dimensions and nominal dimensions of the implanted THV size. PAR was assessed at 30 days according to a 5-class scheme. RESULTS: Mean oversizing by area was 7.7 +/- 9.4% and mean oversizing by perimeter was 1.7 +/- 4.4%. An inverse proportional relationship between degree of oversizing and frequency and severity of PAR was observed for both area and perimeter oversizing. Perimeter and area oversizing confer similar predictive capacity in regard to the occurrence of PAR after THV implantation (area under the curve: 0.78 [95% confidence interval: 0.70 to 0.85] vs. area under the curve: 0.78 [95% confidence interval: 0.72 to 0.85]; p < 0.0001). No aortic root ruptures were observed. CONCLUSIONS: For the SAPIEN 3 THV, the frequency and extent of PAR is inversely related to the degree of oversizing with acceptable rates of PAR being achieved at lower degrees of oversizing. Perimeter and area oversizing confer similar predictive capacity in regard to the occurrence of PAR after implantation of the SAPIEN 3 THV. Therefore, the SAPIEN 3 THV may offer the opportunity to reduce the risk of annular rupture associated with more significant degrees of oversizing in borderline annular anatomy.

Blum, J. L., P. J. Flynn, G. Yothers, L. Asmar, C. E. Geyer, Jr., S. A. Jacobs, N. J. Robert, J. O. Hopkins, J. A. O’Shaughnessy, C. T. Dang, H. L. Gomez, L. Fehrenbacher, S. J. Vukelja, A. P. Lyss, D. Paul, A. M. Brufsky, J. H. Jeong, L. H. Colangelo, S. M. Swain, E. P. Mamounas, S. E. Jones and N. Wolmark (2017). “Anthracyclines in early breast cancer: The abc trials-usor 06-090, nsabp b-46-i/usor 07132, and nsabp b-49 (nrg oncology).” J Clin Oncol: Apr [Epub ahead of print].

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Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.