Research Spotlight

Sabate, M. and M. Mack (2020). “Very Late Outcomes After Stent Implantation: It Is Time to Target the Nontarget Sites.” J Am Coll Cardiol 75(6): 605-607.

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Coronary stents were initially designed to prevent acute vessel closure after balloon dilatation. Soon after their introduction, it became obvious that the benefit of metallic stents further extended beyond the acute angiographic result. As a matter of fact, seminal randomized controlled trials demonstrated reductions in binary restenosis and subsequently, in target lesion revascularization rates. Technology evolved from bare-metal stents (BMS) to first-generation drug-eluting stents (DES), with the aim to design more efficacious devices (i.e., with higher suppression of neointimal proliferation) to be used in all types of lesions and clinical scenarios. However, this first-generation DES carried very late safety concerns related to stent thrombosis that could be associated with delayed neointimal healing, chronic inflammatory reaction to polymer, and development of in-stent neoatherosclerosis, among others. DES evolved to a second-generation, which was demonstrated to have a much improved safety profile compared with both first-generation DES and BMS (4). Consequently, second-generation DES are now recommended as the default technique in recent myocardial revascularization guidelines. Although several trials have reported very late outcomes following stent implantation, their analysis should be taken as merely hypothesis-generating due to lack of power to demonstrate differences in hard events. Therefore, the individual patient-data pooled analysis involving a total of 25,032 patients from 19 large-scale, randomized, metallic stent trials reported in this issue of the Journal is most welcome. (Excerpt from text of this commentary, p. 605; refers to M.V. Madhavan, A.J. Kirtane, B. Redfors, et al. Stent-related adverse events >1 year after percutaneous coronary intervention.; no abstract available.)

Rorth, R., P. S. Jhund, M. B. Yilmaz, S. L. Kristensen, P. Welsh, A. S. Desai, L. Kober, M. F. Prescott, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2020). “Comparison of BNP and NT-proBNP in Patients With Heart Failure and Reduced Ejection Fraction.” Circ Heart Fail Epub 2020 Feb 17.

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BACKGROUND: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). METHODS: Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction /=150 pg/mL or NT-proBNP >/=600 pg/mL (for patients with HF hospitalization within 12 months, BNP >/=100 pg/mL or NT-proBNP >/=400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate <30 mL/min per 1.73 m(2) was a key exclusion criterion. RESULTS: The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217-4003) and BNP 318 (Q1, Q3: 207-559), and the ratio, calculated from the raw data, was approximately 6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33-1.49) per 1 SD increase, P<0.0001; NT-proBNP, 1.45 (1.36-1.54); P<0.0001. CONCLUSIONS: The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction.

Roger, S. D., P. T. Lavin, E. V. Lerma, P. A. McCullough, J. Butler, B. S. Spinowitz, S. von Haehling, M. Kosiborod, J. Zhao, S. Fishbane and D. K. Packham (2020). “Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study.” Nephrol Dial Transplant Feb 6. [Epub ahead of print].

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BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD. METHODS: Adults with serum K+ >/=5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for /=30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). RESULTS: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, >/=30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and >/=30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 >/=30 mL/min/1.73 m2 subgroup. CONCLUSIONS: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

Roger, S. D., P. T. Lavin, E. V. Lerma, P. A. McCullough, J. Butler, B. S. Spinowitz, S. von Haehling, M. Kosiborod, J. Zhao, S. Fishbane and D. K. Packham (2020). “Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study.” Nephrol Dial Transplant Feb 6. [Epub ahead of print].

Full text of this article.

BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD. METHODS: Adults with serum K+ >/=5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for /=30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). RESULTS: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, >/=30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and >/=30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 >/=30 mL/min/1.73 m2 subgroup. CONCLUSIONS: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

Reardon, D. A., A. Desjardins, J. J. Vredenburgh, D. M. O’Rourke, D. D. Tran, K. L. Fink, L. B. Nabors, G. Li, D. A. Bota, R. V. Lukas, L. S. Ashby, J. P. Duic, M. M. Mrugala, S. Cruickshank, L. Vitale, Y. He, J. A. Green, M. J. Yellin, C. D. Turner, T. Keler, T. A. Davis and J. H. Sampson (2020). “Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.” Clin Cancer Res Feb 7. [Epub ahead of print].

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PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naive patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for >/=6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (>/=1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.