Research Spotlight

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 20(7): 1100-1105.

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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 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.

Nadler, E., J. L. Espirito, M. Pavilack, M. Boyd, A. Vergara-Silva and A. Fernandes (2018). “Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small-Cell Lung Cancer Patients Treated in the Community Practice Setting.” Clin Lung Cancer 19(4): 360-370.

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INTRODUCTION: Multiple therapeutic options now exist for metastatic non-small-cell lung cancer (mNSCLC). In this study we evaluated treatment patterns and outcomes in mNSCLC patients who received first-line (1L), second-line (2L), and third-line (3L) therapy. PATIENTS AND METHODS: A retrospective, observational cohort study was conducted using an electronic health record database of mNSCLC patients who received initial treatment from January 2012 through April 2016, with follow-up through June 2016. Patient characteristics and treatment patterns were characterized. Overall survival (OS) was assessed using the Kaplan-Meier method. RESULTS: We identified 10,689 1L patients. Median age was 68 years, and 5816 (54%) were male. Most patients (6337; 59%) had a performance status of 1, and 8282 (77%) had nonsquamous histology. 1L treatment was chemotherapy in 9969 (93%) patients, and targeted therapy in 685 (6%). Median OS (mOS) for all patients in 1L was 12.3 months (95% confidence interval [CI], 11.9-12.7), and 24.3 months in 1L patients receiving targeted therapy. Among patients who received 2L therapy (n = 4235), 2790 (66%), 718 (17%), and 727 (17%) received chemotherapy, targeted therapy, and immunotherapy, respectively. mOS from 2L therapy was 9.6 months (95% CI, 9.1-10.1). In patients receiving 3L therapy (n = 1580), 921 (58%), 355 (22%), and 304 (19%) received chemotherapy, targeted therapy, and immunotherapy, respectively. mOS from 3L therapy was 8.2 months (95% CI, 7.3-8.7). CONCLUSION: Targeted therapy and immunotherapy was most frequently used in the 2L and 3L setting during the study time frame. Survival differences observed according to treatment types are likely because of biologic differences, and suggest that patients with actionable mutations have a survival advantage.

Mullins, B. P., C. J. Kramer, B. J. Bartel, J. S. Catlin and R. E. Gilder (2018). “Comparison of the Nephrotoxicity of Vancomycin in Combination With Cefepime, Meropenem, or Piperacillin/Tazobactam: A Prospective, Multicenter Study.” Ann Pharmacother 52(7): 639-644.

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BACKGROUND: Patients often receive broad-spectrum antibiotics for nosocomial infections commonly with activity against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Previous retrospective and/or single-center studies have suggested that the combination of vancomycin and piperacillin/tazobactam might be associated with an increased risk of acute kidney injury. OBJECTIVES: To compare the incidence of nephrotoxicity in patients receiving intravenous vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam. METHODS: This was a prospective, multicenter observational study of patients receiving vancomycin in combination with piperacillin/tazobactam versus cefepime or meropenem. Adult patients 18 years of age or older who were hospitalized and received 72 or more hours of intravenous vancomycin and 72 hours or more of cefepime, meropenem, or piperacillin/tazobactam were eligible. Patient and medication characteristics were examined for the 242 patients included. RESULTS: The incidence of acute kidney injury for patients treated with vancomycin and piperacillin/tazobactam was significantly higher than for those treated with vancomycin and cefepime or meropenem, 29.8% versus 8.8%, respectively, P < 0.001. Binary logistic regression demonstrated that patients receiving vancomycin and piperacillin/tazobactam were 6.7 times more likely to develop acute kidney injury compared with the other cohort. CONCLUSIONS: The combination of vancomycin with piperacillin/tazobactam significantly increases the risk of acute kidney injury compared with other broad-spectrum antibiotic combinations. Clinicians should be vigilant when employing this regimen.

Morisset, J., Y. Mageto and G. Raghu (2018). “Mortality in interstitial lung disease: do race and skin colour matter?” Eur Respir J 51(6).

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Adegunsoye et al. have described how African-Americans with interstitial lung disease (ILD) exhibit a unique clinical phenotype and raised several further challenging and exciting questions about the rationale behind those differences. Their report surfaces important considerations in understanding the incidence, prevalence, clinical manifestation and outcomes of patients with ILD of different race, colour and ethnicity, besides cultural, socioeconomic and regional variabilities. It is hoped that this work will provoke studies aiming to better understand the role of race and ethnicity along with the intrinsic and extrinsic factors in the individuals manifesting ILD. Further research exploring the mechanistic and pathobiological pathways responsible for the clinical difference between races and ultimately leading to a more comprehensive and personalised care of patients with ILD is warranted. (Excerpt from text, p. 3; no abstract available.)

Mirchi, A., F. Pelletier, L. T. Tran, S. Keller, N. Braverman, D. Tonduti, A. Vanderver, A. Pizzino, M. E. Dilenge, C. Poulin, M. Shevell, A. Majnemer, G. Sebire, M. Srour, B. Osterman, R. M. Boucher, M. Vanasse, E. Rossignol, J. Mitchell, S. Venkateswaran, D. Pohl, M. Kauffman, R. Schiffmann, C. Goizet, S. Moutton, F. Roncarolo and G. Bernard (2018). “Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy.” Pediatr Neurol 84: 21-26.

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BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.