Research Spotlight

Posted July 15th 2018

Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2018). “Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.” Int J Cardiol 261: 130-133.

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BACKGROUND: Current guidelines for the treatment of heart failure strongly recommend the use of inhibitors of the renin-angiotensin system and sympathetic nervous system in all patients with a reduced ejection fraction who can tolerate these drugs. Yet, there is no consensus about the efficacy of low doses of these drugs or the likely shape of the dose-response relationship for these agents. METHODS: Inferences were made by examining the effects of drugs in placebo-controlled trials before the protocol-specified opportunity for uptitration and by reassessing the results of large-scale trials with active comparators that inadvertently produced different intensities of neurohormonal blockade. RESULTS: In the case of inhibitors of the renin-angiotensin system, low starting doses appear to be effective in many patients, and 3-5 fold increases in dose do not have a mortality advantage over low doses. By contrast, in the case of beta-adrenergic blockers, although low starting doses appear effective in improving outcomes, achievement of target doses may yield substantial incremental mortality benefits, even such doses are accompanied by only small additional decreases in heart rate. CONCLUSION: When treating patients with heart failure to reduce mortality, the totality of evidence supports a relatively flat dose-response relationship for inhibitors of the renin-angiotensin system but a steep dose-response relationship for beta-adrenergic receptor blockers.


Posted July 15th 2018

Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2018). “Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control.” Diabetes Obes Metab 20(7): 1766-1769.

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Current guidelines for diabetes recommend that physicians attain a glycated haemoglobin (HbA1c) concentration less than or equal to 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies in patients with chronic heart failure that examined the relationship between the level of HbA1c and risk of death specified whether HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, the mortality rate was not higher among those with an HbA1c concentration <7.0%. By contrast, in patients who were treated with insulin, sulphonylureas and thiazolidinediones, an inverse or U-shaped relationship between HbA1c and the risk of death was generally observed, and mortality was lowest in patients with both heart failure and diabetes if the level of HbA1c was >7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c <7.0%.


Posted July 15th 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.

Milton Packer M.D.

Milton Packer M.D.

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.


Posted July 15th 2018

Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small-Cell Lung Cancer Patients Treated in the Community Practice Setting.

Eric Nadler M.D.

Eric Nadler M.D.

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.


Posted July 15th 2018

TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Murcia, O., R. Jover, C. Egoavil, L. Perez-Carbonell, M. Juarez, E. Hernandez-Illan, E. Rojas, C. Alenda, F. Balaguer, M. Andreu, X. Llor, A. Castells, C. R. Boland and A. Goel (2018). “TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer.” Clin Cancer Res 24(12): 2820-2827.

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Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank P = 0.6]. In stage II-III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% CI, 0.52-1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank P = 0.7).Conclusions:TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer.