Research Spotlight

Weber, J., M. Mandala, M. Del Vecchio, H. J. Gogas, A. M. Arance, C. L. Cowey, S. Dalle, M. Schenker, V. Chiarion-Sileni, I. Marquez-Rodas, J. J. Grob, M. O. Butler, M. R. Middleton, M. Maio, V. Atkinson, P. Queirolo, R. Gonzalez, R. R. Kudchadkar, M. Smylie, N. Meyer, L. Mortier, M. B. Atkins, G. V. Long, S. Bhatia, C. Lebbe, P. Rutkowski, K. Yokota, N. Yamazaki, T. M. Kim, V. de Pril, J. Sabater, A. Qureshi, J. Larkin and P. A. Ascierto (2017). “Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma.” N Engl J Med: 2017 Sep [Epub ahead of print].

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Background Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. Methods In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (>/=15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. Results At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. Conclusions Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

Pibarot, P., R. T. Hahn, N. J. Weissman, M. Arsenault, J. Beaudoin, M. Bernier, A. Dahou, O. K. Khalique, F. M. Asch, O. Toubal, J. Leipsic, P. Blanke, F. Zhang, R. Parvataneni, M. Alu, H. Herrmann, R. Makkar, M. Mack, R. Smalling, M. Leon, V. H. Thourani and S. Kodali (2017). “Association of paravalvular regurgitation with 1-year outcomes after transcatheter aortic valve replacement with the sapien 3 valve.” JAMA Cardiol: 2017 Sep [Epub ahead of print].

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Importance: Moderate/severe and even mild paravalvular regurgitation (PVR) are associated with increased mortality following transcatheter aortic valve replacement (TAVR) with first and second generations of transcatheter valves. Objective: To examine the incidence, evolution, and effect on 1-year outcomes of PVR following TAVR with a third-generation balloon-expandable transcatheter heart valve. Design, Setting, and Participants: Prespecified analysis of PVR in the Placement of Aortic Transcatheter Valves (PARTNER) II SAPIEN 3 trial, conducted between October 1, 2013, and September 3, 2014. Multicenter, nonrandomized registry of 1661 patients at intermediate or high surgical risk undergoing TAVR with the SAPIEN 3. Patients with severe, symptomatic aortic stenosis and high/intermediate surgical risk were enrolled in the registry at 51 sites in the United States and Canada. Interventions: Transcatheter aortic valve replacement with the SAPIEN 3 valve. Main Outcomes and Measures: Paravalvular regurgitation was assessed in a core laboratory at 30 days and 1 year according to a 5-class scheme: 0, none or trace; 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe. We assessed the effect of PVR on 1-year mortality and heart failure rehospitalization. Results: Among the 1661 included in the registry, 1592 received a SAPIEN 3 valve and had assessment of PVR. Of these patients, 55.7% had none-trace PVR, 32.6% had mild, 8.2% had mild to moderate, and 3.5% had at least moderate PVR at 30 days. At 1 year, 9.3% of patients had died and 14.2% had been rehospitalized. Only patients with at least moderate PVR had higher 1-year mortality (hazard ratio [HR], 2.40; 95% CI, 1.30-4.43; P = .005) and composite of mortality/rehospitalization (HR, 2.35; 95% CI, 1.52-3.62; P < .001). In a paired comparison including 1213 patients, 73% of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity of at least 1 PVR class at 1 year. Conclusions and Relevance: In this series of patients undergoing TAVR with the SAPIEN 3 valve, at least moderate PVR was rare but associated with increased risk of death and heart failure rehospitalization at 1 year. Even the upper range of the mild class in the 3-class grading scheme (ie, mild to moderate in the 5-class scheme) had no significant effect on short-term mortality or rehospitalization. Most patients with at least moderate PVR at 30 days showed a decrease of PVR severity grade at 1 year.

O’Leary, J. G., A. J. Demetris, A. Philippe, R. Freeman, J. Cai, H. Heidecke, C. Smith, B. Hart, L. W. Jennings, R. Catar, M. Everly, G. B. Klintmalm and D. Dragun (2017). “Non-hla antibodies impact on c4d staining, stellate cell activation and fibrosis in liver allografts.” Transplantation 101(10): 2399-2409.

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BACKGROUND: Recent data have shown an increased risk for rejection, fibrosis progression, and death in liver transplantation (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1 of 2000 to 4 of 2009 with known HLA DSA status for angiotensin II type-1 receptor and endothelin-1 type A receptor autoantibodies pre-LT, and year 1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death (hazard ratio [HR], 1.66; P = 0.02) especially if the HLA DSA was of the IgG3 subclass (HR, 2.28; P = 0.01). A single de novo non-HLA autoantibody was associated with an increased risk for T cell-mediated rejection or antibody-mediated rejection (68% vs 41%, P = 0.01) and fibrosis progression (HR, 1.84; P = 0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared with HLA DSA (71% vs 3%; P < 0.001). Liver sinusoidal endothelial cell activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-angiotensin II type-1 receptor and anti-endothelin-1 type A receptor autoantibodies are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to liver sinusoidal endothelial cell capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.

Palazzuoli, A., G. Ruocco, O. De Vivo, R. Nuti and P. A. McCullough (2017). “Prevalence of hyperuricemia in patients with acute heart failure with either reduced or preserved ejection fraction.” Am J Cardiol 120(7): 1146-1150.

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The relation between uric acid (UA) and heart failure has been described; however, there is little detail concerning acute heart failure (AHF) in patients with reduced versus preserved ejection fraction heart failure (HFrEF, HFpEF). We studied 324 consecutive AHF patients screened from interventional Diur-HF Trial (NCT01441245) from January 2011 to February 2016, and divided into HFrEF (EF <50%) and HFpEF (EF >/=50%). We defined hyperuricemia as serum UA >/=7.0 mg/dL in men and >/=6 mg/dL in women. Patients were followed up for 6 months after discharge. The primary outcome was heart failure hospitalization or death. Among 173 HFrEF and 151 HFpEF cases, hyperuricemia was found in 43% and 57%, respectively (p = 0.01). Hyperuricemia was also more frequent in women (74% vs 60%; p = 0.008), those with diabetes (39% vs 19%; p <0.001), hypertension (62% vs 43%; p = 0.001), and atrial fibrillation (48% vs 34%; p = 0.01). In patients with HFrEF, univariate analysis found that hyperuricemia (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.02 to 2.15; p = 0.04) and congestion score >/=3 (HR 2.83, 95% CI 1.52 to 5.28; p <0.001) were associated with the primary end point; after adjustment, only congestion score >/=3 (HR 2.08, 95% CI 1.06 to 4.10; p = 0.03) confirmed this trend. Conversely, in patients with HFpEF, hyperuricemia was the only significant predictor of the primary end point both in univariate (HR 2.25, 95% CI 1.44 to 3.50; p <0.001) and multivariate analyses (HR 2.38, 95% CI 1.32 to 4.28; p = 0.004). In conclusion, in AHF hyperuricemia is common in both in HFrEF and in HFpEF. In the HFpEF subgroup, hyperuricemia was the only independent predictor of heart failure hospitalization or death.

Packer, M. (2017). “The absence of an ideal observer: Why some clinical trials may not be what we think they are.” Circulation 136(12): 1085-1086.

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A large clinical trial typically involves a leadership committee, a sponsor, numerous geographically dispersed investigators, and a group responsible for operational functions. The leadership committee helps to define the trial hypotheses and the methods by which they are tested; however, its members personally make no observations and may not know exactly how observations are made. The sponsor invests substantial sums of money, without assurance that the hypothesis is valid and generally without direct involvement in the collection of data. The investigators are paid to recruit patients, but they may have little vested in the overall results of the trial. The operations group ensures that patients are recruited rapidly, knowing that it will be difficult to confirm whether patients were recruited appropriately or trial procedures were followed faithfully. Among these trial components, who is the ideal, fully informed and impartial observer? Could the parties (each acting in self-interest but within regulatory standards) collectively yield a flawed product? Here are a few hypothetical possibilities.