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Meta-analysis supports endoscopic surveillance of Barrett’s esophagus
Endoscopic surveillance also was associated with modest improvements in all-cause and cancer-specific mortality, said Don C. Codipilly, MD, of the Mayo Clinic in Rochester, Minn., with his associates. The Barrett’s esophagus community “eagerly” await results from the multicenter, randomized BOSS trial (Barrett’s Oesophagus Surveillance versus endoscopy at need Study), the reviewers wrote in the June issue of Gastroenterology.
Guidelines recommend endoscopic surveillance of patients with Barrett’s esophagus, but it is unclear whether this practice improves survival. Hence, the reviewers searched databases such as Ovid MEDLINE, Embase, PubMed, and Scopus for studies published since 1996 that evaluated outcomes of endoscopic surveillance in Barrett’s esophagus. Eligible studies included a case-control study of a large hospital database in northern California, 6 retrospective cohort studies of endoscopic Barrett’s esophagus surveillance, and 11 prospective and retrospective studies comparing patients with esophageal adenocarcinoma (EAC) with and without a history of Barrett’s esophagus.
The case-control study found no link between endoscopic surveillance and improved survival in Barrett’s esophagus, said the reviewers. However, the retrospective cohort studies linked regular Barrett’s esophagus endoscopic surveillance with a 40% lower risk of death from EAC, compared with incomplete or no endoscopic surveillance, which was statistically significant (risk ratio, 0.60; 95% confidence interval, 0.50-0.71). Individual results of these studies also were consistent with the results of their meta-analysis. A separate meta-analysis of the remaining studies also linked endoscopic surveillance with a significantly lower risk of EAC-related mortality (RR, 0.73; 95% CI, 0.57-0.94), but these studies had substantial heterogeneity, the investigators said.
Meta-analyses also supported endoscopic surveillance for earlier detection of EAC. Unadjusted data from four studies indicated that Barrett’s esophagus surveillance helped detect EAC while it was still early stage (stage 0 or 1) rather than later stage (RR, 2.1; 95% CI, 1.1-4.1). Similarly, patients who had already been diagnosed with Barrett’s esophagus were significantly more likely to present with early-stage EAC (RR, 5.5; 95% CI, 3.7-8.2). In contrast, enrollment in a Barrett’s esophagus surveillance program did not appear to affect the likelihood of esophagectomy.
Additional meta-analyses suggested that endoscopic surveillance of Barrett’s esophagus might confer a “potentially small” overall survival benefit, the reviewers said. A meta-analysis of adjusted data from three studies linked surveillance with a 25% reduction in risk of all-cause mortality, compared with no surveillance (hazard ratio, 0.75; 95% CI, 0.58-0.94). Having a prior Barrett’s esophagus diagnosis also was associated with a 52% decrease in all-cause mortality, compared with having symptomatic cancer (RR, 0.48; 95% CI, 0.37-0.63) in a meta-analysis of unadjusted data from 12 studies. Five studies with adjusted data linked a prior Barrett’s esophagus diagnosis with a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.45-0.76). However, individual findings varied substantially, and adjusting for lead time “almost eliminated this overall survival benefit,” the reviewers said.
The National Institutes of Health and a Public Health Service Award supported the study. Dr. Codipilly reported having no conflicts of interest. Five coinvestigators disclosed ties to Exact Sciences, C2 Therapeutics, and other companies.
SOURCE: Codipilly DC et al. Gastroenterology. 2018 Feb 17. doi: 10.1053/j.gastro.2018.02.022.
Endoscopic surveillance also was associated with modest improvements in all-cause and cancer-specific mortality, said Don C. Codipilly, MD, of the Mayo Clinic in Rochester, Minn., with his associates. The Barrett’s esophagus community “eagerly” await results from the multicenter, randomized BOSS trial (Barrett’s Oesophagus Surveillance versus endoscopy at need Study), the reviewers wrote in the June issue of Gastroenterology.
Guidelines recommend endoscopic surveillance of patients with Barrett’s esophagus, but it is unclear whether this practice improves survival. Hence, the reviewers searched databases such as Ovid MEDLINE, Embase, PubMed, and Scopus for studies published since 1996 that evaluated outcomes of endoscopic surveillance in Barrett’s esophagus. Eligible studies included a case-control study of a large hospital database in northern California, 6 retrospective cohort studies of endoscopic Barrett’s esophagus surveillance, and 11 prospective and retrospective studies comparing patients with esophageal adenocarcinoma (EAC) with and without a history of Barrett’s esophagus.
The case-control study found no link between endoscopic surveillance and improved survival in Barrett’s esophagus, said the reviewers. However, the retrospective cohort studies linked regular Barrett’s esophagus endoscopic surveillance with a 40% lower risk of death from EAC, compared with incomplete or no endoscopic surveillance, which was statistically significant (risk ratio, 0.60; 95% confidence interval, 0.50-0.71). Individual results of these studies also were consistent with the results of their meta-analysis. A separate meta-analysis of the remaining studies also linked endoscopic surveillance with a significantly lower risk of EAC-related mortality (RR, 0.73; 95% CI, 0.57-0.94), but these studies had substantial heterogeneity, the investigators said.
Meta-analyses also supported endoscopic surveillance for earlier detection of EAC. Unadjusted data from four studies indicated that Barrett’s esophagus surveillance helped detect EAC while it was still early stage (stage 0 or 1) rather than later stage (RR, 2.1; 95% CI, 1.1-4.1). Similarly, patients who had already been diagnosed with Barrett’s esophagus were significantly more likely to present with early-stage EAC (RR, 5.5; 95% CI, 3.7-8.2). In contrast, enrollment in a Barrett’s esophagus surveillance program did not appear to affect the likelihood of esophagectomy.
Additional meta-analyses suggested that endoscopic surveillance of Barrett’s esophagus might confer a “potentially small” overall survival benefit, the reviewers said. A meta-analysis of adjusted data from three studies linked surveillance with a 25% reduction in risk of all-cause mortality, compared with no surveillance (hazard ratio, 0.75; 95% CI, 0.58-0.94). Having a prior Barrett’s esophagus diagnosis also was associated with a 52% decrease in all-cause mortality, compared with having symptomatic cancer (RR, 0.48; 95% CI, 0.37-0.63) in a meta-analysis of unadjusted data from 12 studies. Five studies with adjusted data linked a prior Barrett’s esophagus diagnosis with a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.45-0.76). However, individual findings varied substantially, and adjusting for lead time “almost eliminated this overall survival benefit,” the reviewers said.
The National Institutes of Health and a Public Health Service Award supported the study. Dr. Codipilly reported having no conflicts of interest. Five coinvestigators disclosed ties to Exact Sciences, C2 Therapeutics, and other companies.
SOURCE: Codipilly DC et al. Gastroenterology. 2018 Feb 17. doi: 10.1053/j.gastro.2018.02.022.
Endoscopic surveillance also was associated with modest improvements in all-cause and cancer-specific mortality, said Don C. Codipilly, MD, of the Mayo Clinic in Rochester, Minn., with his associates. The Barrett’s esophagus community “eagerly” await results from the multicenter, randomized BOSS trial (Barrett’s Oesophagus Surveillance versus endoscopy at need Study), the reviewers wrote in the June issue of Gastroenterology.
Guidelines recommend endoscopic surveillance of patients with Barrett’s esophagus, but it is unclear whether this practice improves survival. Hence, the reviewers searched databases such as Ovid MEDLINE, Embase, PubMed, and Scopus for studies published since 1996 that evaluated outcomes of endoscopic surveillance in Barrett’s esophagus. Eligible studies included a case-control study of a large hospital database in northern California, 6 retrospective cohort studies of endoscopic Barrett’s esophagus surveillance, and 11 prospective and retrospective studies comparing patients with esophageal adenocarcinoma (EAC) with and without a history of Barrett’s esophagus.
The case-control study found no link between endoscopic surveillance and improved survival in Barrett’s esophagus, said the reviewers. However, the retrospective cohort studies linked regular Barrett’s esophagus endoscopic surveillance with a 40% lower risk of death from EAC, compared with incomplete or no endoscopic surveillance, which was statistically significant (risk ratio, 0.60; 95% confidence interval, 0.50-0.71). Individual results of these studies also were consistent with the results of their meta-analysis. A separate meta-analysis of the remaining studies also linked endoscopic surveillance with a significantly lower risk of EAC-related mortality (RR, 0.73; 95% CI, 0.57-0.94), but these studies had substantial heterogeneity, the investigators said.
Meta-analyses also supported endoscopic surveillance for earlier detection of EAC. Unadjusted data from four studies indicated that Barrett’s esophagus surveillance helped detect EAC while it was still early stage (stage 0 or 1) rather than later stage (RR, 2.1; 95% CI, 1.1-4.1). Similarly, patients who had already been diagnosed with Barrett’s esophagus were significantly more likely to present with early-stage EAC (RR, 5.5; 95% CI, 3.7-8.2). In contrast, enrollment in a Barrett’s esophagus surveillance program did not appear to affect the likelihood of esophagectomy.
Additional meta-analyses suggested that endoscopic surveillance of Barrett’s esophagus might confer a “potentially small” overall survival benefit, the reviewers said. A meta-analysis of adjusted data from three studies linked surveillance with a 25% reduction in risk of all-cause mortality, compared with no surveillance (hazard ratio, 0.75; 95% CI, 0.58-0.94). Having a prior Barrett’s esophagus diagnosis also was associated with a 52% decrease in all-cause mortality, compared with having symptomatic cancer (RR, 0.48; 95% CI, 0.37-0.63) in a meta-analysis of unadjusted data from 12 studies. Five studies with adjusted data linked a prior Barrett’s esophagus diagnosis with a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.45-0.76). However, individual findings varied substantially, and adjusting for lead time “almost eliminated this overall survival benefit,” the reviewers said.
The National Institutes of Health and a Public Health Service Award supported the study. Dr. Codipilly reported having no conflicts of interest. Five coinvestigators disclosed ties to Exact Sciences, C2 Therapeutics, and other companies.
SOURCE: Codipilly DC et al. Gastroenterology. 2018 Feb 17. doi: 10.1053/j.gastro.2018.02.022.
FROM GASTROENTEROLOGY
Key clinical point: Endoscopic surveillance of Barrett’s esophagus was associated with significantly earlier cancer detection and conferred a small survival benefit.
Major finding: Risk ratios for esophageal adenocarcinoma–specific mortality ranged from 0.60 to 0.73 and reached statistical significance.
Study details: A systematic review and meta-analysis of 18 studies.
Disclosures: The National Institutes of Health and a Public Health Service Award supported the study. Dr. Codipilly reported having no conflicts of interest. Five coinvestigators disclosed ties to Exact Sciences, C2 Therapeutics, and other companies.
Source: Codipilly DC et al. Gastroenterology. 2018 Feb 17. doi: 10.1053/j.gastro.2018.02.022.
Study eyes liver transplantation after Region 5 UNOS downstaging
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation of selected patients with hepatocellular carcinoma (HCC) is an accepted indication and associated with excellent outcomes. Until recently, criteria for liver transplantation were based on the Milan criteria that only took size and number of tumors under consideration. In this multicenter study, patients who were outside of Milan criteria were successfully downstaged to within Milan criteria with locoregional therapy and subsequently transplanted with excellent outcomes. Salient features included the following. 1) Six months waiting after the first treatment and 3 months after downstaging was required to ensure that the tumor stage remained within Milan criteria. 2) Any specific type of locoregional therapy was allowed. 3) Downstaging was possible in a majority of patients after a single treatment. 4) Patients with alpha-fetoprotein greater than 1000 ng/mL (approximately 10%) as well as presence of substantial decompensated liver disease (approximately 40%) did not have favorable outcomes. 4) On multivariable analysis, tumor biology was a stronger predictor of poor outcomes than was stage of liver disease.
Sumeet K. Asrani, MD, MSc, is associate professor in medicine and hepatologist at Baylor University Medical Center, and medical director of the Center for Advanced Liver Disease, Dallas. He has no conflicts of interest.
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
Liver transplantation led to “excellent outcomes” when performed after downstaging hepatocellular carcinoma using the UNOS (United Network for Organ Sharing) Region 5 protocol, investigators reported.
Downstaging succeeded for 58% of patients, and an estimated 87% of transplantation recipients were alive and recurrence free at 5 years, said Neil Mehta, MD, of the University of California, San Francisco, and his associates. The findings support expanding priority access to liver transplantation to include patients whose hepatocellular carcinoma (HCC) has been successfully downstaged, they said. “In the meantime, UNOS has recently approved the Region 5 downstaging protocol for receiving automatic HCC-MELD exception listing,” they wrote. The report was published in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.11.037).
This is the first multicenter study of HCC downstaging according to a uniform protocol, the researchers noted. In multivariable analyses, downstaging was significantly more likely to fail in the setting of moderate to severe (Child Pugh B or C) hepatic impairment (hazard ratio, 3.3; 95% confidence interval, 3.0 to 3.6; P less than .001) or baseline alpha-fetoprotein level above 1,000 ng/mL (HR, 1.6; 95% CI, 1.4 to 1.9; P less than .001).
The incidence of HCC in the United States is expected to keep rising for at least another decade because of epidemic levels of fatty liver disease and chronic hepatitis C, the investigators noted. Downstaging HCC with local-regional therapy is a common bridge to transplantation, and successful treatment tends to reflect favorable tumor biology, which bodes well for transplantation. However, no multicenter study had evaluated these associations. Therefore, the investigators retrospectively studied 187 patients with HCC from three centers in California who underwent downstaging according to the UNOS Region 5 protocol between 2002 and 2012.
A total of 156 patients (83%) were successfully downstaged to within Milan criteria after a median of 2.7 months (interquartile range, 1.4 to 4.9 months), said the researchers. Among patients who were successfully downstaged but did not undergo transplantation, 37 patients had tumor progression or died from liver-related causes after a median of 6 months, while 10 patients remained on the transplant list. Among the 109 patients who underwent transplantation after a median of 13 months (interquartile range 6 to 19 months), median follow-up time was 4.3 years and estimated 5-year survival was 80%, and estimated recurrence-free survival was 87%.
Fully 68% of successfully downstaged patients required only one local-regional treatment, the researchers said. The Region 5 protocol considers patients eligible for downstaging if they have a single HCC lesion measuring up to 8 cm or multiple lesions whose combined diameters do not exceed 8 cm, and no evidence of extrahepatic disease or vascular invasion on multiphase computed tomography or magnetic resonance imaging.
The protocol considers downstaging successful if it results in one lesion measuring up to 5 cm or no more than three lesions of up to 3 cm each. Thus, patients who start out with four or five lesions must have complete necrosis of at least one to two tumors. Successfully downstaged patients must remain free of acute hepatic decompensation for at least 3 consecutive months before undergoing transplantation, according to the protocol.
“Slight refinements in the inclusion criteria for downstaging seem warranted [given] that all Child’s B/C patients with pretreatment alpha-fetoprotein greater than 1000 ng/mL suffered poor outcomes when downstaging was attempted,” the investigators noted. They reported that the 1-year risk of failed downstaging was 70% among patients with both Child’s B/C cirrhosis and alpha-fetoprotein level at or above 1000 ng/mL, 32% among patients with one risk factor, and 14% among patients with no risk factors (P less than .001).
The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
SOURCE: Mehta N, et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Liver transplantation led to excellent outcomes when performed after downstaging hepatocellular carcinoma according to the UNOS (United Network for Organ Sharing) Region 5 protocol.
Major finding: Downstaging succeeded in 58% of patients. Estimated 5-year posttransplantation recurrence-free survival was 87%.
Study details: Retrospective multicenter study of 187 patients with hepatocellular carcinoma.
Disclosures: The National Institutes of Health provided partial funding. The investigators reported having no conflicts of interest.
Source: Mehta N et al. Clin Gastroenterol Hepatol. 2017 Nov 23. doi: 10.1016/j.cgh.2017.11.037.
Colonic diverticulosis not linked to mucosal inflammation, GI symptoms
Colonic diverticulosis was not associated with mucosal inflammation or gastrointestinal symptoms in a single-center, prospective study of adults undergoing their first screening colonoscopy.
After adjustment for age, sex, and body mass index, there were no significant links between diverticulosis and tumor necrosis factor, CD4+ cells, CD8+ cells, CD57+ cells, irritable bowel syndrome, or chronic abdominal pain, reported Anne F. Peery, MD, with her associates at the University of North Carolina at Chapel Hill. “Our findings strongly question the rationale for treating symptomatic uncomplicated diverticular disease with mesalamine,” they wrote in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.05.051).
Colonic diverticula affect more than half of individuals in the United States over the age of 60 years, according to the results of past studies. “Although colonic diverticulosis can be complicated by the overt inflammation of acute diverticulitis, there is some thought that colonic diverticulosis is associated with low-grade mucosal inflammation,” the researchers said. “Moreover, this low-grade diverticular inflammation is believed to contribute to chronic gastrointestinal symptoms.” However, no rigorous prospective study had tested these assertions.
Accordingly, the researchers evaluated prospective data from 619 outpatients aged 30 years and older who underwent screening colonoscopies for the first time during 2013-2015. These patients had consented to participate in a study of risk factors for colonic diverticulosis. Most were white (76%) or black (21%), and most were aged 50-59 years.
A total of 255 individuals had diverticula while 364 controls did not. Patients with diverticula tended to be older and were more often male (47% vs. 41% of controls) and overweight or obese (72% vs. 62%). After adjustment for age, sex, and body mass index, there was no evidence linking diverticulosis with tumor necrosis factor alpha expression (odds ratio, 0.9; 95% confidence interval, 0.6-1.2), CD4+ cells (OR, 1.2; 95% CI, 0.9-1.6), CD8+ cells (OR, 1.0; 95% CI, 0.7-1.3), or CD57+ cells (OR, 0.8; 95% CI, 0.6-1.1).
Among 42 patients who met Rome III criteria for irritable bowel syndrome, 11 had diverticulosis. Diverticulosis in IBS was not associated with changes in expression of the mucosal inflammatory markers interleukin-6, interleukin-10, tumor necrosis factor, CD4, CD8, or mast cell tryptase, said the researchers. A total of 63 patients had chronic abdominal pain, of whom 22 also had diverticulosis. There were no significant differences in mucosal inflammatory markers between symptomatic patients with diverticula and those without. Adjusted analysis found no association between number of diverticula and chronic abdominal pain (OR, 0.7; 95% CI, 0.4-1.2) or IBS (OR, 0.5; 95% CI, 0.3-1.1).
The number of patients with IBS in this study was small, and the researchers did not ascertain IBS symptom severity, they noted. “Although we studied several immune markers and cytokines, there are other potential markers that may be associated with chronic inflammation,” they added. “Multianalyte profiling could be used to assess an array of cytokines, and markers for macrophages (CD68), global T cells (CD3), and B cells (CD19). Whether there is utility in further studies given our negative results is debatable.”
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
SOURCE: Peery AF et al. Clin Gastroenterol Hepatol. 2017 Jun 8. doi: 10.1016/j.cgh.2017.05.051.
Colonic diverticulosis was not associated with mucosal inflammation or gastrointestinal symptoms in a single-center, prospective study of adults undergoing their first screening colonoscopy.
After adjustment for age, sex, and body mass index, there were no significant links between diverticulosis and tumor necrosis factor, CD4+ cells, CD8+ cells, CD57+ cells, irritable bowel syndrome, or chronic abdominal pain, reported Anne F. Peery, MD, with her associates at the University of North Carolina at Chapel Hill. “Our findings strongly question the rationale for treating symptomatic uncomplicated diverticular disease with mesalamine,” they wrote in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.05.051).
Colonic diverticula affect more than half of individuals in the United States over the age of 60 years, according to the results of past studies. “Although colonic diverticulosis can be complicated by the overt inflammation of acute diverticulitis, there is some thought that colonic diverticulosis is associated with low-grade mucosal inflammation,” the researchers said. “Moreover, this low-grade diverticular inflammation is believed to contribute to chronic gastrointestinal symptoms.” However, no rigorous prospective study had tested these assertions.
Accordingly, the researchers evaluated prospective data from 619 outpatients aged 30 years and older who underwent screening colonoscopies for the first time during 2013-2015. These patients had consented to participate in a study of risk factors for colonic diverticulosis. Most were white (76%) or black (21%), and most were aged 50-59 years.
A total of 255 individuals had diverticula while 364 controls did not. Patients with diverticula tended to be older and were more often male (47% vs. 41% of controls) and overweight or obese (72% vs. 62%). After adjustment for age, sex, and body mass index, there was no evidence linking diverticulosis with tumor necrosis factor alpha expression (odds ratio, 0.9; 95% confidence interval, 0.6-1.2), CD4+ cells (OR, 1.2; 95% CI, 0.9-1.6), CD8+ cells (OR, 1.0; 95% CI, 0.7-1.3), or CD57+ cells (OR, 0.8; 95% CI, 0.6-1.1).
Among 42 patients who met Rome III criteria for irritable bowel syndrome, 11 had diverticulosis. Diverticulosis in IBS was not associated with changes in expression of the mucosal inflammatory markers interleukin-6, interleukin-10, tumor necrosis factor, CD4, CD8, or mast cell tryptase, said the researchers. A total of 63 patients had chronic abdominal pain, of whom 22 also had diverticulosis. There were no significant differences in mucosal inflammatory markers between symptomatic patients with diverticula and those without. Adjusted analysis found no association between number of diverticula and chronic abdominal pain (OR, 0.7; 95% CI, 0.4-1.2) or IBS (OR, 0.5; 95% CI, 0.3-1.1).
The number of patients with IBS in this study was small, and the researchers did not ascertain IBS symptom severity, they noted. “Although we studied several immune markers and cytokines, there are other potential markers that may be associated with chronic inflammation,” they added. “Multianalyte profiling could be used to assess an array of cytokines, and markers for macrophages (CD68), global T cells (CD3), and B cells (CD19). Whether there is utility in further studies given our negative results is debatable.”
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
SOURCE: Peery AF et al. Clin Gastroenterol Hepatol. 2017 Jun 8. doi: 10.1016/j.cgh.2017.05.051.
Colonic diverticulosis was not associated with mucosal inflammation or gastrointestinal symptoms in a single-center, prospective study of adults undergoing their first screening colonoscopy.
After adjustment for age, sex, and body mass index, there were no significant links between diverticulosis and tumor necrosis factor, CD4+ cells, CD8+ cells, CD57+ cells, irritable bowel syndrome, or chronic abdominal pain, reported Anne F. Peery, MD, with her associates at the University of North Carolina at Chapel Hill. “Our findings strongly question the rationale for treating symptomatic uncomplicated diverticular disease with mesalamine,” they wrote in the June issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.05.051).
Colonic diverticula affect more than half of individuals in the United States over the age of 60 years, according to the results of past studies. “Although colonic diverticulosis can be complicated by the overt inflammation of acute diverticulitis, there is some thought that colonic diverticulosis is associated with low-grade mucosal inflammation,” the researchers said. “Moreover, this low-grade diverticular inflammation is believed to contribute to chronic gastrointestinal symptoms.” However, no rigorous prospective study had tested these assertions.
Accordingly, the researchers evaluated prospective data from 619 outpatients aged 30 years and older who underwent screening colonoscopies for the first time during 2013-2015. These patients had consented to participate in a study of risk factors for colonic diverticulosis. Most were white (76%) or black (21%), and most were aged 50-59 years.
A total of 255 individuals had diverticula while 364 controls did not. Patients with diverticula tended to be older and were more often male (47% vs. 41% of controls) and overweight or obese (72% vs. 62%). After adjustment for age, sex, and body mass index, there was no evidence linking diverticulosis with tumor necrosis factor alpha expression (odds ratio, 0.9; 95% confidence interval, 0.6-1.2), CD4+ cells (OR, 1.2; 95% CI, 0.9-1.6), CD8+ cells (OR, 1.0; 95% CI, 0.7-1.3), or CD57+ cells (OR, 0.8; 95% CI, 0.6-1.1).
Among 42 patients who met Rome III criteria for irritable bowel syndrome, 11 had diverticulosis. Diverticulosis in IBS was not associated with changes in expression of the mucosal inflammatory markers interleukin-6, interleukin-10, tumor necrosis factor, CD4, CD8, or mast cell tryptase, said the researchers. A total of 63 patients had chronic abdominal pain, of whom 22 also had diverticulosis. There were no significant differences in mucosal inflammatory markers between symptomatic patients with diverticula and those without. Adjusted analysis found no association between number of diverticula and chronic abdominal pain (OR, 0.7; 95% CI, 0.4-1.2) or IBS (OR, 0.5; 95% CI, 0.3-1.1).
The number of patients with IBS in this study was small, and the researchers did not ascertain IBS symptom severity, they noted. “Although we studied several immune markers and cytokines, there are other potential markers that may be associated with chronic inflammation,” they added. “Multianalyte profiling could be used to assess an array of cytokines, and markers for macrophages (CD68), global T cells (CD3), and B cells (CD19). Whether there is utility in further studies given our negative results is debatable.”
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
SOURCE: Peery AF et al. Clin Gastroenterol Hepatol. 2017 Jun 8. doi: 10.1016/j.cgh.2017.05.051.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Colonic diverticula were not associated with mucosal inflammation or chronic gastrointestinal symptoms.
Major finding: After adjustment for possible confounders, there were no significant associations between diverticulosis and tumor necrosis factor, CD4+ cells, CD8+ cells, CD57+ cells, irritable bowel syndrome, or chronic abdominal pain.
Study details: Single-center prospective study of 619 patients undergoing screening colonoscopies.
Disclosures: The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
Source: Peery AF et al. Clin Gastroenterol Hepatol. 2017 Jun 8. doi: 10.1016/j.cgh.2017.05.051
New criteria slightly improved melanoma staging
Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.
For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.
For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.
For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.
One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.
The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.
SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.
Compared with the seventh edition, use of the eighth AJCC Cancer Staging Manual (AJCC 8) produced “modest but significant improvements” in reproducibility and concordance when microstaging cutaneous melanoma, Peter M. Ferguson, MBChB, PhD, FRCPA, Jeffrey E. Gershenwald, MD, and Richard A. Scolyer, MD, FRCPA, wrote in an editorial accompanying the study.
But the study revealed “significant” shortcomings in reproducibility, they added. Future studies should explore the reproducibility of individual AJCC parameters and how experience and access to relevant case data affects reproducibility, they wrote.
The study used the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system instead of classifying cases by AJCC tumor categories. Consequently, pathologists collapsed several AJCC tumor subcategories into the Melanoma Pathology Study class V, which limited interpretability of results for T1b melanomas, an important threshold for recommending sentinel node biopsy. “[We] have published higher rates of concordance using AJCC 7 criteria, albeit with access to clinical information and reporting by a small number of pathologists with expertise reporting melanomas at a high-volume referral center,” the editorialists emphasized.
Dr. Ferguson and Dr. Scolyer are with the University of Sydney. Dr. Gershenwald is with the University of Texas MD Anderson Cancer Center, Houston. The editorialists disclosed support from the Robert and Lynne Grossman Family Foundation, the Michael and Patricia Booker Melanoma Research Endowment, Melanoma Institute Australia, the Deborah and John McMurtrie Melanoma Institute Australia Pathology Fellowship, and the Australian National Health and Medical Research Council Fellowship. Dr. Gershenwald disclosed ties to Merck, Syndax, Castle Biosciences, and the AJCC (JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0086 ).
Compared with the seventh edition, use of the eighth AJCC Cancer Staging Manual (AJCC 8) produced “modest but significant improvements” in reproducibility and concordance when microstaging cutaneous melanoma, Peter M. Ferguson, MBChB, PhD, FRCPA, Jeffrey E. Gershenwald, MD, and Richard A. Scolyer, MD, FRCPA, wrote in an editorial accompanying the study.
But the study revealed “significant” shortcomings in reproducibility, they added. Future studies should explore the reproducibility of individual AJCC parameters and how experience and access to relevant case data affects reproducibility, they wrote.
The study used the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system instead of classifying cases by AJCC tumor categories. Consequently, pathologists collapsed several AJCC tumor subcategories into the Melanoma Pathology Study class V, which limited interpretability of results for T1b melanomas, an important threshold for recommending sentinel node biopsy. “[We] have published higher rates of concordance using AJCC 7 criteria, albeit with access to clinical information and reporting by a small number of pathologists with expertise reporting melanomas at a high-volume referral center,” the editorialists emphasized.
Dr. Ferguson and Dr. Scolyer are with the University of Sydney. Dr. Gershenwald is with the University of Texas MD Anderson Cancer Center, Houston. The editorialists disclosed support from the Robert and Lynne Grossman Family Foundation, the Michael and Patricia Booker Melanoma Research Endowment, Melanoma Institute Australia, the Deborah and John McMurtrie Melanoma Institute Australia Pathology Fellowship, and the Australian National Health and Medical Research Council Fellowship. Dr. Gershenwald disclosed ties to Merck, Syndax, Castle Biosciences, and the AJCC (JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0086 ).
Compared with the seventh edition, use of the eighth AJCC Cancer Staging Manual (AJCC 8) produced “modest but significant improvements” in reproducibility and concordance when microstaging cutaneous melanoma, Peter M. Ferguson, MBChB, PhD, FRCPA, Jeffrey E. Gershenwald, MD, and Richard A. Scolyer, MD, FRCPA, wrote in an editorial accompanying the study.
But the study revealed “significant” shortcomings in reproducibility, they added. Future studies should explore the reproducibility of individual AJCC parameters and how experience and access to relevant case data affects reproducibility, they wrote.
The study used the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system instead of classifying cases by AJCC tumor categories. Consequently, pathologists collapsed several AJCC tumor subcategories into the Melanoma Pathology Study class V, which limited interpretability of results for T1b melanomas, an important threshold for recommending sentinel node biopsy. “[We] have published higher rates of concordance using AJCC 7 criteria, albeit with access to clinical information and reporting by a small number of pathologists with expertise reporting melanomas at a high-volume referral center,” the editorialists emphasized.
Dr. Ferguson and Dr. Scolyer are with the University of Sydney. Dr. Gershenwald is with the University of Texas MD Anderson Cancer Center, Houston. The editorialists disclosed support from the Robert and Lynne Grossman Family Foundation, the Michael and Patricia Booker Melanoma Research Endowment, Melanoma Institute Australia, the Deborah and John McMurtrie Melanoma Institute Australia Pathology Fellowship, and the Australian National Health and Medical Research Council Fellowship. Dr. Gershenwald disclosed ties to Merck, Syndax, Castle Biosciences, and the AJCC (JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0086 ).
Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.
For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.
For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.
For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.
One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.
The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.
SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.
Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.
For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.
For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.
For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.
One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.
The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.
SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.
FROM JAMA NETWORK OPEN
Key clinical point: Use of the recently updated AJCC Cancer Staging Manual, 8th edition, somewhat improved concordance and reproducibility for invasive melanoma, compared with the previous edition.
Major finding: For diagnoses of T1a invasive melanoma, concordance with consensus diagnoses rose from 44% with the AJCC 7 to 54% with the AJCC 8. For T1b, concordance rose from 72% to 78%.
Study details: Interpretations of 116 invasive melanomas by 187 pathologists.
Disclosures: The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.
Source: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.
IBD upped Parkinson’s risk in large study
Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.
The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.
Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”
Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.
To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.
In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.
Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.
Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.
SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.
Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.
The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.
Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”
Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.
To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.
In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.
Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.
Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.
SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.
Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.
The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.
Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”
Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.
To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.
In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.
Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.
Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.
SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.
FROM GUT
Key clinical point:
Major finding: After accounting for comorbidities, individuals with IBD were about 22% more likely to develop Parkinson’s disease compared with individuals without IBD (hazard ratio, 1.22; 95% confidence interval, 1.09-1.35).
Study details: A population-based cohort study of 76,477 individuals with IBD and 7.5 million unaffected persons.
Disclosures: Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.
Source: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.
For in-stent restenosis, everolimus-eluting stents topped drug-eluting balloons
For patients with coronary artery restenosis at the site of a drug-eluting stent, placing an everolimus-eluting stent was associated with a 57% lower risk of target lesion revascularization, compared with placing a drug-eluting balloon.
At 3-year follow-up in the randomized, multicenter RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial, 7.1% of patients required target lesion revascularization after EES versus 15.6% of patients after DEB (P = .015), reported Fernando Alfonso, MD, of Hospital Universitario de La Princesa, Madrid, and his associates. Consequently, the combined rate of cardiac death, myocardial infarction, and target lesion revascularization was 12.3% with EES versus 20.1% with DEB (hazard ratio, 0.57; 95% confidence interval, 0.34-0.96; P = .04). The findings were reported in JACC: Cardiovascular Interventions.
About 5%-10% of patients who receive a drug-eluting stent (DES) develop in-stent restenosis (ISR). When this happens, robust data support placing a DEB or next-generation DES, such as an EES, instead of a conventional (plain) balloon, the investigators noted. To directly compare EES versus DEB, they randomly assigned 309 patients with at least 50% lumen diameter stenosis at the DES site or involving its 5-mm edge to receive either DEB (SeQuent Please, B. Braun) with a 1.1:1 balloon-to-artery ratio (mean 18 atm [pressure]), or EES (Xience Prime, Abbott Vascular) with the same final ratio but significantly greater deployment pressure (mean 20 arm; P = .001). All patients had angina or objective evidence of ischemia without stent thrombosis, and the trial arms otherwise resembled each other clinically and demographically.
Angiography documented 100% immediate procedural success in both groups. At 1 year, rates of target lesion revascularization were 4.5% with EES and 13% with DEB, a significant difference (HR, 0.33; 95% CI, 0.14-0.79). Similarly, rates of target vessel revascularization were 8.4% and 16.2%, respectively (HR, 0.49; 95% CI, 0.25-0.97), at year 1 and 11% and 20.8%, respectively, at year 3 (HR, 0.50; 95% CI, 0.28-0.90).
Throughout the study, including at 3 years, the groups had similar rates of cardiac death (3.9% for EES vs. 3.2% for DEB), MI (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%). “Results of other composite clinical outcomes [also] were very similar,” the researchers wrote. While “both DEB and EES provide favorable long-term clinical outcomes,” patients “receiving EES benefit[ed] from a better long-term clinical outcome, mainly driven by a reduced need of target lesion and target vessel revascularization.”
Funders of the study included B. Braun and Abbott Vascular. The investigators reported having no conflicts of interest.
SOURCE: Alfonso F et al. JACC Cardiovasc Interv. 2018;11:981-91.
Three-year outcomes favored everolimus-eluting stents (EES) over drug-eluting balloons (DEBs) for treating in-stent restenosis, but this “should not be a reason to bid farewell to DEBs,” wrote Hyo-Soo Kim, MD, PhD, and Tae-Min Rhee, MD, in an editorial accompanying the study.
Both EES and DEB have excellent long-term safety, so a “simple rivalry between the [two] arms is no longer meaningful,” they wrote in JACC: Cardiovascular Interventions. “Instead, it is time to find ways to improve the efficacy of DEBs.”
The efficacy of DEB depends on the amount of antiproliferative drug delivered to the target lesion, which isn’t the case for EES, the experts noted. In past studies, independent predictors of long-term DEBs success included less than 20% residual stenosis, balloon-to-stent ratio exceeding 0.91, and inflation time above 60 seconds, they added. When all three of these criteria were met, DEBs performed as well as new-generation drug-eluting stents.
Thus, DEBs retains a treatment niche, “particularly for in-stent restenosis lesions already covered with one or more metal layers.”
Dr. Kim and Dr. Rhee are with Seoul (South Korea) National University Hospital. They reported having no conflicts of interest. These comments are from their editorial (JACC Cardiovasc Interv. 2018;11:992-4).
Three-year outcomes favored everolimus-eluting stents (EES) over drug-eluting balloons (DEBs) for treating in-stent restenosis, but this “should not be a reason to bid farewell to DEBs,” wrote Hyo-Soo Kim, MD, PhD, and Tae-Min Rhee, MD, in an editorial accompanying the study.
Both EES and DEB have excellent long-term safety, so a “simple rivalry between the [two] arms is no longer meaningful,” they wrote in JACC: Cardiovascular Interventions. “Instead, it is time to find ways to improve the efficacy of DEBs.”
The efficacy of DEB depends on the amount of antiproliferative drug delivered to the target lesion, which isn’t the case for EES, the experts noted. In past studies, independent predictors of long-term DEBs success included less than 20% residual stenosis, balloon-to-stent ratio exceeding 0.91, and inflation time above 60 seconds, they added. When all three of these criteria were met, DEBs performed as well as new-generation drug-eluting stents.
Thus, DEBs retains a treatment niche, “particularly for in-stent restenosis lesions already covered with one or more metal layers.”
Dr. Kim and Dr. Rhee are with Seoul (South Korea) National University Hospital. They reported having no conflicts of interest. These comments are from their editorial (JACC Cardiovasc Interv. 2018;11:992-4).
Three-year outcomes favored everolimus-eluting stents (EES) over drug-eluting balloons (DEBs) for treating in-stent restenosis, but this “should not be a reason to bid farewell to DEBs,” wrote Hyo-Soo Kim, MD, PhD, and Tae-Min Rhee, MD, in an editorial accompanying the study.
Both EES and DEB have excellent long-term safety, so a “simple rivalry between the [two] arms is no longer meaningful,” they wrote in JACC: Cardiovascular Interventions. “Instead, it is time to find ways to improve the efficacy of DEBs.”
The efficacy of DEB depends on the amount of antiproliferative drug delivered to the target lesion, which isn’t the case for EES, the experts noted. In past studies, independent predictors of long-term DEBs success included less than 20% residual stenosis, balloon-to-stent ratio exceeding 0.91, and inflation time above 60 seconds, they added. When all three of these criteria were met, DEBs performed as well as new-generation drug-eluting stents.
Thus, DEBs retains a treatment niche, “particularly for in-stent restenosis lesions already covered with one or more metal layers.”
Dr. Kim and Dr. Rhee are with Seoul (South Korea) National University Hospital. They reported having no conflicts of interest. These comments are from their editorial (JACC Cardiovasc Interv. 2018;11:992-4).
For patients with coronary artery restenosis at the site of a drug-eluting stent, placing an everolimus-eluting stent was associated with a 57% lower risk of target lesion revascularization, compared with placing a drug-eluting balloon.
At 3-year follow-up in the randomized, multicenter RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial, 7.1% of patients required target lesion revascularization after EES versus 15.6% of patients after DEB (P = .015), reported Fernando Alfonso, MD, of Hospital Universitario de La Princesa, Madrid, and his associates. Consequently, the combined rate of cardiac death, myocardial infarction, and target lesion revascularization was 12.3% with EES versus 20.1% with DEB (hazard ratio, 0.57; 95% confidence interval, 0.34-0.96; P = .04). The findings were reported in JACC: Cardiovascular Interventions.
About 5%-10% of patients who receive a drug-eluting stent (DES) develop in-stent restenosis (ISR). When this happens, robust data support placing a DEB or next-generation DES, such as an EES, instead of a conventional (plain) balloon, the investigators noted. To directly compare EES versus DEB, they randomly assigned 309 patients with at least 50% lumen diameter stenosis at the DES site or involving its 5-mm edge to receive either DEB (SeQuent Please, B. Braun) with a 1.1:1 balloon-to-artery ratio (mean 18 atm [pressure]), or EES (Xience Prime, Abbott Vascular) with the same final ratio but significantly greater deployment pressure (mean 20 arm; P = .001). All patients had angina or objective evidence of ischemia without stent thrombosis, and the trial arms otherwise resembled each other clinically and demographically.
Angiography documented 100% immediate procedural success in both groups. At 1 year, rates of target lesion revascularization were 4.5% with EES and 13% with DEB, a significant difference (HR, 0.33; 95% CI, 0.14-0.79). Similarly, rates of target vessel revascularization were 8.4% and 16.2%, respectively (HR, 0.49; 95% CI, 0.25-0.97), at year 1 and 11% and 20.8%, respectively, at year 3 (HR, 0.50; 95% CI, 0.28-0.90).
Throughout the study, including at 3 years, the groups had similar rates of cardiac death (3.9% for EES vs. 3.2% for DEB), MI (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%). “Results of other composite clinical outcomes [also] were very similar,” the researchers wrote. While “both DEB and EES provide favorable long-term clinical outcomes,” patients “receiving EES benefit[ed] from a better long-term clinical outcome, mainly driven by a reduced need of target lesion and target vessel revascularization.”
Funders of the study included B. Braun and Abbott Vascular. The investigators reported having no conflicts of interest.
SOURCE: Alfonso F et al. JACC Cardiovasc Interv. 2018;11:981-91.
For patients with coronary artery restenosis at the site of a drug-eluting stent, placing an everolimus-eluting stent was associated with a 57% lower risk of target lesion revascularization, compared with placing a drug-eluting balloon.
At 3-year follow-up in the randomized, multicenter RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial, 7.1% of patients required target lesion revascularization after EES versus 15.6% of patients after DEB (P = .015), reported Fernando Alfonso, MD, of Hospital Universitario de La Princesa, Madrid, and his associates. Consequently, the combined rate of cardiac death, myocardial infarction, and target lesion revascularization was 12.3% with EES versus 20.1% with DEB (hazard ratio, 0.57; 95% confidence interval, 0.34-0.96; P = .04). The findings were reported in JACC: Cardiovascular Interventions.
About 5%-10% of patients who receive a drug-eluting stent (DES) develop in-stent restenosis (ISR). When this happens, robust data support placing a DEB or next-generation DES, such as an EES, instead of a conventional (plain) balloon, the investigators noted. To directly compare EES versus DEB, they randomly assigned 309 patients with at least 50% lumen diameter stenosis at the DES site or involving its 5-mm edge to receive either DEB (SeQuent Please, B. Braun) with a 1.1:1 balloon-to-artery ratio (mean 18 atm [pressure]), or EES (Xience Prime, Abbott Vascular) with the same final ratio but significantly greater deployment pressure (mean 20 arm; P = .001). All patients had angina or objective evidence of ischemia without stent thrombosis, and the trial arms otherwise resembled each other clinically and demographically.
Angiography documented 100% immediate procedural success in both groups. At 1 year, rates of target lesion revascularization were 4.5% with EES and 13% with DEB, a significant difference (HR, 0.33; 95% CI, 0.14-0.79). Similarly, rates of target vessel revascularization were 8.4% and 16.2%, respectively (HR, 0.49; 95% CI, 0.25-0.97), at year 1 and 11% and 20.8%, respectively, at year 3 (HR, 0.50; 95% CI, 0.28-0.90).
Throughout the study, including at 3 years, the groups had similar rates of cardiac death (3.9% for EES vs. 3.2% for DEB), MI (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%). “Results of other composite clinical outcomes [also] were very similar,” the researchers wrote. While “both DEB and EES provide favorable long-term clinical outcomes,” patients “receiving EES benefit[ed] from a better long-term clinical outcome, mainly driven by a reduced need of target lesion and target vessel revascularization.”
Funders of the study included B. Braun and Abbott Vascular. The investigators reported having no conflicts of interest.
SOURCE: Alfonso F et al. JACC Cardiovasc Interv. 2018;11:981-91.
FROM JACC: CARDIOVASCULAR INTERVENTIONS
Key clinical point: Everolimus-eluting stents outperformed drug-eluting balloons for patients with restenosis of coronary arteries following initial drug-eluting stent placement.
Major finding: Three-year rates of target lesion revascularization were 7.1% with EES and 15.6% with DEB (P = .015). Consequently, the combined rate of cardiac death, myocardial infarction, and target lesion revascularization was significantly lower with EES (12.3% vs. 20.1% with DEB; P = .04).
Study details: Randomized multicenter trial of 309 patients with blinded outcomes assessment (RIBS IV).
Disclosures: Funders included B. Braun Surgical and Abbott Vascular. The investigators reported having no conflicts of interest.
Source: Alfonso F et al. JACC Cardiovasc Interv. 2018;11:981-91.
CANVAS: Canagliflozin improved renal outcomes in diabetes
AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.
“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.
In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.
Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).
The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).
Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m2) or reduced (less than 60 ml/min per 1.73 m2). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m2 and 49 mL/min per 1.73 m2, respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m2) or reduced (–2.83 mL/min/1.73 m2 ) baseline kidney function (P = 0.21).
Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).
Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.
No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m2) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.
Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.
SOURCE: Neuen BL et al. SCM 2018.
AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.
“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.
In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.
Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).
The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).
Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m2) or reduced (less than 60 ml/min per 1.73 m2). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m2 and 49 mL/min per 1.73 m2, respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m2) or reduced (–2.83 mL/min/1.73 m2 ) baseline kidney function (P = 0.21).
Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).
Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.
No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m2) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.
Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.
SOURCE: Neuen BL et al. SCM 2018.
AUSTIN, TEX. – Canagliflozin can improve renal outcomes in patients with type 2 diabetes, even when they have mild or moderate kidney disease, new data from the CANVAS program suggested.
“The effect of canagliflozin on composite renal outcomes was large, particularly in people with preserved kidney function,” Brendon L. Neuen, MBBS, of University of New South Wales, Sydney, and his associates wrote in a poster. Baseline renal function also did not appear to affect the safety of canagliflozin, the investigators reported at a meeting sponsored by the National Kidney Foundation.
In patients with diabetes mellitus, increased proximal reabsorption of glucose and sodium decreases the amount of sodium reaching the macula densa in the distal convoluted tubule. This results in reduced use of adenosine triphosphate for sodium reabsorption, which thereby decreases adenosine release and vasoconstriction of afferent arterioles. Left unchecked, this dampening of the tubuloglomerular feedback mechanism increases glomerular filtration and leads to diabetic nephropathy.
Sodium glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance) help mitigate this pathology by vasoconstricting afferent arterioles. Previously, in an exploratory analysis of the multicenter, placebo-controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, empagliflozin led to modest but statistically significant long-term reductions in urinary albumin secretion for diabetic patients, regardless of their baseline urinary albumin to creatinine ratio (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). Treatment with empagliflozin also significantly reduced the risk of developing microalbuminuria or macroalbuminuria (P less than .0001).
The multicenter, double-blind, placebo-controlled CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) trials included more than 10,000 adults with type 2 diabetes and high cardiovascular risk. In the primary analysis, canagliflozin significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with placebo (N Engl J Med. 2017 Aug 17;377[7]:644-57).
Dr. Neuen and his associates compared the effects of canagliflozin on renal outcomes and safety among CANVAS patients whose estimated glomerular filtration rate (eGFR) was preserved (greater than 60 mL/min per 1.73 m2) or reduced (less than 60 ml/min per 1.73 m2). Actual mean eGFRs in each of these groups were 83 mL/min per 1.73 m2 and 49 mL/min per 1.73 m2, respectively. Compared with placebo, canagliflozin acutely reduced eGFR in patients with either preserved (average, –2.2 mL/min per 1.73 m2) or reduced (–2.83 mL/min/1.73 m2 ) baseline kidney function (P = 0.21).
Among patients with preserved function at baseline, canagliflozin was associated with a statistically significant 47% decrease in risk of renal death, end-stage kidney disease, or a 40% or greater drop in eGFR (hazard ratio, 0.53; 95% confidence interval, 0.39-0.73). Canagliflozin also showed renal benefits for patients with reduced kidney function, but the effect did not reach statistical significance (HR, 0.76; 95% CI, 0.49-1.17). Findings were similar when the researchers tweaked the composite renal endpoint by replacing the eGFR criterion with doubling of serum creatinine (HR, 0.42; 95% CI, 0.23-0.75 and HR, 0.81; 95% CI, 0.37-1.77, respectively).
Canagliflozin has a black box warning for amputation risk. There was no indication that early renal function further increased this risk, the researchers reported. CANVAS patients who received canagliflozin underwent amputations (usually at the level of the toe or metatarsal) at rates of 6.3 per 1,000 person-years overall, 5.6 per 1,000 person-years in the setting of preserved kidney function, and 9.9 per 1,000 person-years in the setting of reduced kidney function. Rates in the placebo group were 3.4, 3.0, and 4.8 amputations per 1,000 person-years, respectively. Additionally, baseline renal status did not significantly affect risk of fracture, serious kidney-related adverse events, or serious acute kidney injury. Patients with baseline renal insufficiency were at increased risk of developing serious hyperkalemia (HR, 2.11; P = .06), but these events were uncommon in both treatment groups.
No CANVAS patient had stage 4 or worse kidney disease (eGFR less than 30 mL/min per 1.73 m2) at enrollment, the researchers noted. The ongoing phase 3 CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial will shed more light on canagliflozin in the setting of renal disease, they added. This multicenter, double-blind trial compares canagliflozin with placebo in more than 4,000 patients with diabetic nephropathy. Results are expected in 2019.
Janssen funded the CANVAS and CANVAS-R trials. Disclosures were not provided.
SOURCE: Neuen BL et al. SCM 2018.
REPORTING FROM SCM 18
Key clinical point: Canagliflozin improved kidney function and renal outcomes in patients with type 2 diabetes.
Major finding: Reduction in risk of a composite endpoint (end-stage kidney disease, renal death, or at least 40% decline in eGFR) was 47% for patients with preserved baseline kidney function and 24% for patients with reduced baseline function.
Study details: Multicenter, double-blind, placebo-controlled trials of 10,140 patients (CANVAS and CANVAS-R).
Disclosures: Janssen funded the CANVAS and CANVAS-R trials.
Source: Neuen BL et al. SCM 2018.
Study supports observation for select cases of porcelain gallbladder
Some adults with porcelain gallbladder may be eligible to forgo prophylactic cholecystectomy, suggest the results of a single-center retrospective study.
Over 1.7 years of median follow-up (range, 0 to 12.7 years), the observational group had no detected gallbladder malignancies and 4% developed adverse events versus 13% in the prophylactic cholecystectomy group (P = .15), wrote Haley DesJardins and her associates at Tufts University, Boston. The report was published in the Journal of the American College of Surgery.
The findings “still raise concern about an association between gallbladder wall calcifications and gallbladder malignancies, and therefore still suggest the need for cholecystectomy in the young, healthy, or symptomatic patient,” the researchers wrote. Nonetheless, surveillance for patients “who are poor surgical candidates is a reasonable approach, with a low risk of malignancy over a limited time frame.”
The investigators suggest that surgeons consider intervention when symptoms and workup points to gallbladder malignancy. But consider avoiding prophylactic cholecystectomy in patients with “limited life expectancy and significant comorbidities,” they emphasized. “Based on the results of this study, the act of prophylactic cholecystectomy for every single patient with gallbladder wall calcifications seems obsolete.”
The study comprised 113 patients with porcelain gallbladder diagnosed between 2004 and 2016. Radiographic reviews identified 70 definite cases and 43 “highly probable” cases. In all, 90 patients started out with observation only, of whom 26% with abdominal pain did not have cholecystectomy because of “significant comorbidities.” Four patients (4.4%) in the observational group subsequently underwent cholecystectomy for biliary colic, as part of liver transplantation, or for prophylactic reasons. None developed complications. In all, 11% developed new gallstones on follow-up imaging and 8% showed progression from focal to diffuse porcelain bladder, the researchers said. None developed gallbladder malignancy during 1.7 years of median follow-up.
Histopathologies of the operative group identified two cases of gallbladder malignancy, of which one was detected on initial imaging. “This patient had a mass at the gallbladder infundibulum extending into the hepatic duct bifurcation,” the researchers explained. “It was not entirely evident whether the resected adenocarcinoma was originating from the gallbladder or from the bile duct. For the purpose of this study, this patient was listed as [having] gallbladder cancer.” The second case consisted of metastatic squamous cell gallbladder carcinoma.
The investigators concluded that “while it is seemingly very reasonable to observe asymptomatic patients with limited life expectancy and significant comorbidities, the decision to proceed with prophylactic cholecystectomy versus observation remains in the hands of the treating physician and patient; especially since absolute criteria or cut-offs cannot be defined at this point.”
No external funding sources were reported. The researchers reported having no conflicts of interest.
SOURCE: DesJardins H et al. J Am Coll Surg. 2018 Apr 22. doi: 10.1016/j.jamcollsurg.2017.11.026.
Some adults with porcelain gallbladder may be eligible to forgo prophylactic cholecystectomy, suggest the results of a single-center retrospective study.
Over 1.7 years of median follow-up (range, 0 to 12.7 years), the observational group had no detected gallbladder malignancies and 4% developed adverse events versus 13% in the prophylactic cholecystectomy group (P = .15), wrote Haley DesJardins and her associates at Tufts University, Boston. The report was published in the Journal of the American College of Surgery.
The findings “still raise concern about an association between gallbladder wall calcifications and gallbladder malignancies, and therefore still suggest the need for cholecystectomy in the young, healthy, or symptomatic patient,” the researchers wrote. Nonetheless, surveillance for patients “who are poor surgical candidates is a reasonable approach, with a low risk of malignancy over a limited time frame.”
The investigators suggest that surgeons consider intervention when symptoms and workup points to gallbladder malignancy. But consider avoiding prophylactic cholecystectomy in patients with “limited life expectancy and significant comorbidities,” they emphasized. “Based on the results of this study, the act of prophylactic cholecystectomy for every single patient with gallbladder wall calcifications seems obsolete.”
The study comprised 113 patients with porcelain gallbladder diagnosed between 2004 and 2016. Radiographic reviews identified 70 definite cases and 43 “highly probable” cases. In all, 90 patients started out with observation only, of whom 26% with abdominal pain did not have cholecystectomy because of “significant comorbidities.” Four patients (4.4%) in the observational group subsequently underwent cholecystectomy for biliary colic, as part of liver transplantation, or for prophylactic reasons. None developed complications. In all, 11% developed new gallstones on follow-up imaging and 8% showed progression from focal to diffuse porcelain bladder, the researchers said. None developed gallbladder malignancy during 1.7 years of median follow-up.
Histopathologies of the operative group identified two cases of gallbladder malignancy, of which one was detected on initial imaging. “This patient had a mass at the gallbladder infundibulum extending into the hepatic duct bifurcation,” the researchers explained. “It was not entirely evident whether the resected adenocarcinoma was originating from the gallbladder or from the bile duct. For the purpose of this study, this patient was listed as [having] gallbladder cancer.” The second case consisted of metastatic squamous cell gallbladder carcinoma.
The investigators concluded that “while it is seemingly very reasonable to observe asymptomatic patients with limited life expectancy and significant comorbidities, the decision to proceed with prophylactic cholecystectomy versus observation remains in the hands of the treating physician and patient; especially since absolute criteria or cut-offs cannot be defined at this point.”
No external funding sources were reported. The researchers reported having no conflicts of interest.
SOURCE: DesJardins H et al. J Am Coll Surg. 2018 Apr 22. doi: 10.1016/j.jamcollsurg.2017.11.026.
Some adults with porcelain gallbladder may be eligible to forgo prophylactic cholecystectomy, suggest the results of a single-center retrospective study.
Over 1.7 years of median follow-up (range, 0 to 12.7 years), the observational group had no detected gallbladder malignancies and 4% developed adverse events versus 13% in the prophylactic cholecystectomy group (P = .15), wrote Haley DesJardins and her associates at Tufts University, Boston. The report was published in the Journal of the American College of Surgery.
The findings “still raise concern about an association between gallbladder wall calcifications and gallbladder malignancies, and therefore still suggest the need for cholecystectomy in the young, healthy, or symptomatic patient,” the researchers wrote. Nonetheless, surveillance for patients “who are poor surgical candidates is a reasonable approach, with a low risk of malignancy over a limited time frame.”
The investigators suggest that surgeons consider intervention when symptoms and workup points to gallbladder malignancy. But consider avoiding prophylactic cholecystectomy in patients with “limited life expectancy and significant comorbidities,” they emphasized. “Based on the results of this study, the act of prophylactic cholecystectomy for every single patient with gallbladder wall calcifications seems obsolete.”
The study comprised 113 patients with porcelain gallbladder diagnosed between 2004 and 2016. Radiographic reviews identified 70 definite cases and 43 “highly probable” cases. In all, 90 patients started out with observation only, of whom 26% with abdominal pain did not have cholecystectomy because of “significant comorbidities.” Four patients (4.4%) in the observational group subsequently underwent cholecystectomy for biliary colic, as part of liver transplantation, or for prophylactic reasons. None developed complications. In all, 11% developed new gallstones on follow-up imaging and 8% showed progression from focal to diffuse porcelain bladder, the researchers said. None developed gallbladder malignancy during 1.7 years of median follow-up.
Histopathologies of the operative group identified two cases of gallbladder malignancy, of which one was detected on initial imaging. “This patient had a mass at the gallbladder infundibulum extending into the hepatic duct bifurcation,” the researchers explained. “It was not entirely evident whether the resected adenocarcinoma was originating from the gallbladder or from the bile duct. For the purpose of this study, this patient was listed as [having] gallbladder cancer.” The second case consisted of metastatic squamous cell gallbladder carcinoma.
The investigators concluded that “while it is seemingly very reasonable to observe asymptomatic patients with limited life expectancy and significant comorbidities, the decision to proceed with prophylactic cholecystectomy versus observation remains in the hands of the treating physician and patient; especially since absolute criteria or cut-offs cannot be defined at this point.”
No external funding sources were reported. The researchers reported having no conflicts of interest.
SOURCE: DesJardins H et al. J Am Coll Surg. 2018 Apr 22. doi: 10.1016/j.jamcollsurg.2017.11.026.
FROM JOURNAL OF THE AMERICAN COLLEGE OF SURGERY
Key clinical point: Observation is an option for select patients with porcelain gallbladder .
Major finding: Rates of adverse events were 4% with observation and 13% with surgery (P = .15).
Study details: Single-center retrospective cohort study of 113 patients.
Disclosures: No external funding sources were reported. The researchers reported having no conflicts of interest.
Source: DesJardins H et al. J Am Coll Surg. 2018 Apr 22. doi: 10.1016/j.jamcollsurg.2017.11.026.
As-needed budesonide-formoterol prevented exacerbations in mild asthma
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.
“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.
Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.
Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”
Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
according to the results of two large, double-blind, 52-week, randomized phase 3 trials.
In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.
Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.
In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).
Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.
In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.
Results from both trials suggested that as-needed budesonide-formoterol provided better symptom control than did terbutaline but worse symptom control than did twice-daily budesonide. In SYGMA1, the change from baseline on the Asthma Control Questionnaire-5 (ACQ-5) favored budesonide-formoterol over terbutaline by an average of 0.15 units and similarly favored twice-daily budesonide over budesonide-formoterol. In SYGMA2, the budesonide maintenance group averaged 0.11 units greater improvement on the ACQ-5 and 0.10 better improvement on the standardized Asthma Quality of Life Questionnaire, compared with as-needed budesonide-formoterol recipients.
Finally, lung function assessments favored as-needed budesonide-formoterol over terbutaline but not over maintenance budesonide. SYGMA1, mean changes (from baseline) in FEV1 before bronchodilator use were 11.2 mL with terbutaline, 65.0 mL with budesonide-formoterol, and 119.3 mL with maintenance budesonide. In SYGMA2, these values were 104 mL with budesonide-formoterol and 136.6 mL with maintenance budesonide.
AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
SOURCES: O’Byrne PM et al. N Engl J Med. 2018;378(20):1865-76.Bateman ED et al. N Engl J Med. 2018;378(20):1877-87.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: As-needed budesonide-formoterol (Symbicort) prevented exacerbations in patients with mild persistent asthma.
Major finding: In the SYGMA1 trial, the regimen outperformed as-needed terbutaline for asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (RR, 0.36; 95% CI, 0.27-0.49). In SYGMA2, the regimen was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% confidence limit, 1.16).
Study details: SYGMA1 and SYGMA2, randomized phase 3 trials of 8,012 patients aged 12 years and older with mild persistent asthma.
Disclosures: AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.
Sources: O’Byrne PM et al. N Engl J Med. 2018 May 17;378(20);1865-76. Bateman ED et al. N Engl J Med. 2018 May 17;378(20):1877-87.
Restrictive fluids tied to kidney injury after major abdominal surgery
among high-risk patients undergoing major abdominal surgery and led to a significantly increased risk of acute kidney injury, researchers reported.
In an international, randomized trial with 366 median days of follow-up, estimated 1-year rates of disability-free survival were 81.9% with the restrictive intravenous fluid regimen and 82.3% with the liberal regimen (hazard ratio for death or disability, 1.05; P = .61), according to Paul S. Myles, MPH, DSc, and his associates.
Rates of acute renal injury were 8.6% in the restrictive IV fluid group and 5.0% with the liberal fluid therapy (P less than .001), the researchers reported online May 10 in the New England Journal of Medicine.
Guidelines recommend a restrictive intravenous fluid strategy to promote early recovery after major abdominal surgery, noted Dr. Myles of Alfred Hospital in Melbourne and his colleagues. “However, the supporting evidence is limited, and there is concern about impaired organ perfusion.”
Therefore, they randomly assigned, 3,000 patients to receive either the restrictive fluid regimen or a liberal regimen during major abdominal surgery and up to 24 hours after. Median intravenous volume was 3.7 L (interquartile range, 2.9-4.9 L) in the restrictive group and 6.1 L (IQR, 5.0-7.4 L) in the liberal fluid group. All patients were deemed high risk based on their age (at least 70 years) or because they had heart disease, diabetes, kidney disease, or morbid obesity.
Patients who received the restrictive regimen had higher rates of surgical site infection (16.5% vs. 13.6% with liberal fluids; P = .02) and were more likely to receive renal replacement therapy (0.9% vs. 0.3%; P = .048). However, these trends were no longer significant after the researchers controlled for the effects of testing for multiple variables.
“Our findings should not be used to support excessive administration of intravenous fluid,” the researchers cautioned. “Rather, they show that a regimen that includes a modestly liberal administration of fluid is safer than a restrictive regimen.”
Funders included the Australian National Health and Medical Research Council (NHMRC), the Health Research Council of New Zealand, the Australian and New Zealand College of Anaesthetists, and Monash University, Melbourne. Dr. Myles reported receiving grant support from NHMRC. He had no other disclosures.
SOURCE: Myles PS et al. New Engl J Med. 2018 May 10. doi: 10.1056/NEJMoa1801601.
Effective blinding was impossible in this randomized study, wrote Birgitte Brandstrup, PhD, in an accompanying editorial. Differences in fluid volume cause symptoms that clinicians can easily identify, she noted.
She recalled the 1990s, when “surgical patients received so much intravenous saline on the day of surgery that they often gained 4 to 6 kg, and by postoperative day 2 or 3, [and] pulmonary congestion and cardiac arrhythmias were commonplace.” Subsequent trials changed this practice, and patients in the current study received much less fluid than they would have in the old days, she noted.
Nonetheless, the findings indicate “that physiologic principles remain valid: Both hypovolemia and oliguria must be recognized and treated with fluid.” While that does not justify excessive perioperative fluid therapy, “a modestly liberal fluid regimen is safer than a truly restrictive regimen.”
Dr. Brandstrup is with the department of surgery at Holbaek (Denmark) Hospital. She reported having no relevant conflicts of interest. These comments recap her editorial (New Engl J Med. 2018 May 10. doi: 10.1056/NEJMe1805615).
Effective blinding was impossible in this randomized study, wrote Birgitte Brandstrup, PhD, in an accompanying editorial. Differences in fluid volume cause symptoms that clinicians can easily identify, she noted.
She recalled the 1990s, when “surgical patients received so much intravenous saline on the day of surgery that they often gained 4 to 6 kg, and by postoperative day 2 or 3, [and] pulmonary congestion and cardiac arrhythmias were commonplace.” Subsequent trials changed this practice, and patients in the current study received much less fluid than they would have in the old days, she noted.
Nonetheless, the findings indicate “that physiologic principles remain valid: Both hypovolemia and oliguria must be recognized and treated with fluid.” While that does not justify excessive perioperative fluid therapy, “a modestly liberal fluid regimen is safer than a truly restrictive regimen.”
Dr. Brandstrup is with the department of surgery at Holbaek (Denmark) Hospital. She reported having no relevant conflicts of interest. These comments recap her editorial (New Engl J Med. 2018 May 10. doi: 10.1056/NEJMe1805615).
Effective blinding was impossible in this randomized study, wrote Birgitte Brandstrup, PhD, in an accompanying editorial. Differences in fluid volume cause symptoms that clinicians can easily identify, she noted.
She recalled the 1990s, when “surgical patients received so much intravenous saline on the day of surgery that they often gained 4 to 6 kg, and by postoperative day 2 or 3, [and] pulmonary congestion and cardiac arrhythmias were commonplace.” Subsequent trials changed this practice, and patients in the current study received much less fluid than they would have in the old days, she noted.
Nonetheless, the findings indicate “that physiologic principles remain valid: Both hypovolemia and oliguria must be recognized and treated with fluid.” While that does not justify excessive perioperative fluid therapy, “a modestly liberal fluid regimen is safer than a truly restrictive regimen.”
Dr. Brandstrup is with the department of surgery at Holbaek (Denmark) Hospital. She reported having no relevant conflicts of interest. These comments recap her editorial (New Engl J Med. 2018 May 10. doi: 10.1056/NEJMe1805615).
among high-risk patients undergoing major abdominal surgery and led to a significantly increased risk of acute kidney injury, researchers reported.
In an international, randomized trial with 366 median days of follow-up, estimated 1-year rates of disability-free survival were 81.9% with the restrictive intravenous fluid regimen and 82.3% with the liberal regimen (hazard ratio for death or disability, 1.05; P = .61), according to Paul S. Myles, MPH, DSc, and his associates.
Rates of acute renal injury were 8.6% in the restrictive IV fluid group and 5.0% with the liberal fluid therapy (P less than .001), the researchers reported online May 10 in the New England Journal of Medicine.
Guidelines recommend a restrictive intravenous fluid strategy to promote early recovery after major abdominal surgery, noted Dr. Myles of Alfred Hospital in Melbourne and his colleagues. “However, the supporting evidence is limited, and there is concern about impaired organ perfusion.”
Therefore, they randomly assigned, 3,000 patients to receive either the restrictive fluid regimen or a liberal regimen during major abdominal surgery and up to 24 hours after. Median intravenous volume was 3.7 L (interquartile range, 2.9-4.9 L) in the restrictive group and 6.1 L (IQR, 5.0-7.4 L) in the liberal fluid group. All patients were deemed high risk based on their age (at least 70 years) or because they had heart disease, diabetes, kidney disease, or morbid obesity.
Patients who received the restrictive regimen had higher rates of surgical site infection (16.5% vs. 13.6% with liberal fluids; P = .02) and were more likely to receive renal replacement therapy (0.9% vs. 0.3%; P = .048). However, these trends were no longer significant after the researchers controlled for the effects of testing for multiple variables.
“Our findings should not be used to support excessive administration of intravenous fluid,” the researchers cautioned. “Rather, they show that a regimen that includes a modestly liberal administration of fluid is safer than a restrictive regimen.”
Funders included the Australian National Health and Medical Research Council (NHMRC), the Health Research Council of New Zealand, the Australian and New Zealand College of Anaesthetists, and Monash University, Melbourne. Dr. Myles reported receiving grant support from NHMRC. He had no other disclosures.
SOURCE: Myles PS et al. New Engl J Med. 2018 May 10. doi: 10.1056/NEJMoa1801601.
among high-risk patients undergoing major abdominal surgery and led to a significantly increased risk of acute kidney injury, researchers reported.
In an international, randomized trial with 366 median days of follow-up, estimated 1-year rates of disability-free survival were 81.9% with the restrictive intravenous fluid regimen and 82.3% with the liberal regimen (hazard ratio for death or disability, 1.05; P = .61), according to Paul S. Myles, MPH, DSc, and his associates.
Rates of acute renal injury were 8.6% in the restrictive IV fluid group and 5.0% with the liberal fluid therapy (P less than .001), the researchers reported online May 10 in the New England Journal of Medicine.
Guidelines recommend a restrictive intravenous fluid strategy to promote early recovery after major abdominal surgery, noted Dr. Myles of Alfred Hospital in Melbourne and his colleagues. “However, the supporting evidence is limited, and there is concern about impaired organ perfusion.”
Therefore, they randomly assigned, 3,000 patients to receive either the restrictive fluid regimen or a liberal regimen during major abdominal surgery and up to 24 hours after. Median intravenous volume was 3.7 L (interquartile range, 2.9-4.9 L) in the restrictive group and 6.1 L (IQR, 5.0-7.4 L) in the liberal fluid group. All patients were deemed high risk based on their age (at least 70 years) or because they had heart disease, diabetes, kidney disease, or morbid obesity.
Patients who received the restrictive regimen had higher rates of surgical site infection (16.5% vs. 13.6% with liberal fluids; P = .02) and were more likely to receive renal replacement therapy (0.9% vs. 0.3%; P = .048). However, these trends were no longer significant after the researchers controlled for the effects of testing for multiple variables.
“Our findings should not be used to support excessive administration of intravenous fluid,” the researchers cautioned. “Rather, they show that a regimen that includes a modestly liberal administration of fluid is safer than a restrictive regimen.”
Funders included the Australian National Health and Medical Research Council (NHMRC), the Health Research Council of New Zealand, the Australian and New Zealand College of Anaesthetists, and Monash University, Melbourne. Dr. Myles reported receiving grant support from NHMRC. He had no other disclosures.
SOURCE: Myles PS et al. New Engl J Med. 2018 May 10. doi: 10.1056/NEJMoa1801601.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Compared with a liberal fluid regimen, restricting fluids did not improve disability-free survival and was tied to a significantly increased risk of acute kidney injury among high-risk patients undergoing major abdominal surgery.
Major finding: Rates of acute renal injury were 8.6% with restrictive fluids and 5.0% with liberal fluids.
Study details: International randomized trial of 3,000 patients undergoing major abdominal surgery.
Disclosures: Funders included the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, the Australian and New Zealand College of Anaesthetists, and Monash University, Melbourne. Dr. Myles reported receiving grant support from NHMRC. He had no other disclosures.
Source: Myles PS et al. New Engl J Med. 2018 May 10. doi: 10.1056/NEJMoa1801601
