Research Spotlight

Packer, M. (2018). “Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.” Eur J Heart Fail Mar 30. [Epub ahead of print].

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Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Packer, M. (2018). “Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications.” Eur J Heart Fail Mar 22. [Epub ahead of print].

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce with favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.

O’Brien, S. M., L. Feng, X. He, Y. Xian, J. P. Jacobs, V. Badhwar, P. A. Kurlansky, A. P. Furnary, J. C. Cleveland, Jr., K. W. Lobdell, C. Vassileva, M. C. Wyler von Ballmoos, V. H. Thourani, J. S. Rankin, J. R. Edgerton, R. S. D’Agostino, N. D. Desai, F. H. Edwards and D. M. Shahian (2018). “The Society of Thoracic Surgeons 2018 Adult Cardiac Surgery Risk Models: Part 2 – Statistical Methods and Results.” Ann Thorac Surg. Mar 22. [Epub ahead of print].

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BACKGROUND: The Society of Thoracic Surgeons (STS) uses statistical models to create risk-adjusted performance metrics for Adult Cardiac Surgery Database (ACSD) participants. Because of temporal changes in patient characteristics and outcomes, evolution of surgical practice, and additional risk factors available in recent ACSD versions, completely new risk models have been developed. METHODS: Using July 2011 to June 2014 ACSD data, risk models were developed for operative mortality, stroke, renal failure, prolonged ventilation, mediastinitis /deep sternal wound infection (DSWI), reoperation, major morbidity or mortality composite, and prolonged postoperative length of stay (PLOS) or short PLOS among patients who underwent isolated coronary artery bypass grafting (CABG; n = 439,092), aortic or mitral valve surgery (n = 150,150), or combined valve + CABG (n = 81,588). Separate models were developed for each procedure and endpoint except DSWI, which was analyzed in a combined model because of its infrequency. A surgeon panel selected predictors by assessing model performance and clinical face validity of full and progressively more parsimonious models. ACSD data (July 2014 to December 2016) were used to assess model calibration and to compare discrimination with previous STS risk models. RESULTS: Calibration in the validation sample was excellent for all models except DSWI which slightly under-estimated risk and will be recalibrated in feedback reports. C-indices of new models exceeded those of the last published STS models for all populations and endpoints except stroke in valve patients. CONCLUSIONS: New STS ACSD risk models have generally excellent calibration and discrimination and are well suited for risk adjustment of STS performance metrics.

Molina, A. M., T. E. Hutson, D. Nosov, P. Tomczak, O. Lipatov, C. N. Sternberg, R. Motzer and T. Eisen (2018). “Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study.” Eur J Cancer 94: 87-94.

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BACKGROUND: Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). METHODS: Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. FINDINGS: Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade >/=3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. INTERPRETATION: This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.

Meeuwis, K. A. P., A. Potts Bleakman, P. C. M. van de Kerkhof, Y. Dutronc, C. Henneges, L. J. Kornberg and A. Menter (2018). “Prevalence of genital psoriasis in patients with psoriasis.” J Dermatolog Treat Mar 28. [Epub ahead of print].

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BACKGROUND: Psoriatic lesions in the genital area (GenPs) can cause considerable physical and emotional distress. To increase physician awareness, we estimated the GenPs prevalence among patients with psoriasis. METHODS: An English language literature search was performed. Articles reporting GenPs prevalence met the search criteria and were included. Because GenPs is rarely reported in demographics of prospective clinical trials, GenPs prevalence and baseline demographics of patients with and without GenPs in two prospective randomized phase 3b trials (NCT02561806 and NCT02634801) involving patients with moderate-to-severe psoriasis are reported. RESULTS: Overall, 600 references were screened. Eighteen articles met the search criteria. Patient populations were highly heterogeneous across articles. Broadly, the presence of GenPs was either physician-reported (physical examinations) or patient-reported (questionnaires). In the literature, GenPs prevalence at the time of reporting ranged from 7% to 42% and the prevalence of GenPs at any time during the course of psoriasis ranged from 33% to 63%. In the two prospective clinical trials, the prevalence of GenPs at the time of enrollment was 35-42%. CONCLUSION: A substantial proportion of patients experience genital lesions at some time during the course of psoriasis. Increased awareness of GenPs prevalence may drive improved assessment and treatment.