Will Pass

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.

For patients, including patients who are physicians, knowledge isn’t power, according to investigators.

megaflopp/Thinkstock

A literature review and retrospective analysis of more than 35,000 physicians treated as patients revealed minimal associations between level of medical knowledge and quality of health outcomes, reported Michael D. Frakes, PhD, of Duke University, Durham, N.C., and colleagues. The study findings stand in opposition to the “widely prevailing view” that information and medical knowledge among patients are integral to realizing high-quality, low-cost health care, the investigators noted.

“[This] research is particularly relevant to modern discussions and debates about the consumer-driven health care movement and the use of plans with high deductibles and high copayments to encourage greater patient and consumer involvement in health care decision making,” Dr. Frakes said in an interview. “Recent research has suggested that the financial incentives created by such structures discourage the use of both low-value care and high-value care. Some have argued that greater disclosure of information to patients may address this concern and steer patients towards high-value decisions. Our results cast doubt on the potential for information initiatives alone to meet this aim.”

The study is one of the first of its kind, the investigators noted in the National Bureau of Economic Research working paper. Other than a 2016 publication that found that physician mothers were less likely to have cesarean sections (Am Econ J: Econ Policy. 2016;8[1]:115-41), “there is no work which has been able to study the role of physicians as patients,” they wrote.

To fill this gap, the investigators turned to a unique data source: The Military Health System, which provides insurance to active and retired military personnel and their families. Military Health System spending exceeds $50 billion per year, constituting a major portion of American health care expenditures, and with more than 35,000 military physicians treated as patients, the dataset is highly relevant and powerful. The investigators objectively evaluated health outcomes by focusing on evidence-based, measurable clinical decisions deemed “high value” or “low value,” comparing how the frequency of these choices related with physician versus nonphysician patient status.

Coauthor Jonathan Gruber, PhD, of the Massachusetts Institute of Technology in Cambridge, Mass., explained this methodology in an interview. “The literature is clear that high-value care has positive health outcomes with relatively small increases in health care spending, and that low-value care has no impact on health outcomes with large increases in spending.”

“One concern with this analysis, of course, is that physicians may be of different health statuses and have different tastes for medical interventions than nonphysicians,” the investigators wrote. They addressed this problem in five ways, by focusing on widely accepted medical standards that apply to all patients; examining both high- and low-value care to eliminate one-sided bias; controlling for underlying health differences across groups; comparing physicians with other military officers to account for underlying tastes; and evaluating military officer dependents in comparison with physician dependents, the latter of whom may benefit from medical knowledge by virtue of personal relationship.

“Our results suggest that physicians do only slightly better than nonphysicians,” the investigators wrote, “but not by much and not always.” Low-value care was slightly less common among physicians, but this difference was described as “modest.” Analysis of high-value care was more mixed, with some results supporting equivalence between groups and others pointing to a slightly higher rate of high-value care among physician patients.

“These results provide a rough boundary on the extent to which additional information disclosure [beyond prevailing levels] can be expected to improve the delivery of health care in the U.S.,” the investigators wrote. “[M]ost of the explanation behind the over- and underutilization of low- and high-value services likely arises from factors other than informational deficiencies of patients.”

“Perhaps one interpretation of these findings is that patients remain generally deferential to the care recommendations of their treating physicians, even in the case of near fully informed patients,” the investigators wrote, noting that this interpretation aligns with a recent working paper that found that physicians play a greater role in selecting the site of MRI scans than patient cost-sharing factors.

Looking to the future, Dr. Gruber said that he and his colleagues plan on exploring “what drives this lack of response among physicians [as patients].”

The study was funded by the National Institute on Aging. The investigators reported no conflicts of interest.

SOURCE: Frakes MD et al. Natl Bur Econ Res. 2019 Jul. doi: 10.3386/w26038.

This article was updated 8/6/19.

For patients, including patients who are physicians, knowledge isn’t power, according to investigators.

megaflopp/Thinkstock

A literature review and retrospective analysis of more than 35,000 physicians treated as patients revealed minimal associations between level of medical knowledge and quality of health outcomes, reported Michael D. Frakes, PhD, of Duke University, Durham, N.C., and colleagues. The study findings stand in opposition to the “widely prevailing view” that information and medical knowledge among patients are integral to realizing high-quality, low-cost health care, the investigators noted.

“[This] research is particularly relevant to modern discussions and debates about the consumer-driven health care movement and the use of plans with high deductibles and high copayments to encourage greater patient and consumer involvement in health care decision making,” Dr. Frakes said in an interview. “Recent research has suggested that the financial incentives created by such structures discourage the use of both low-value care and high-value care. Some have argued that greater disclosure of information to patients may address this concern and steer patients towards high-value decisions. Our results cast doubt on the potential for information initiatives alone to meet this aim.”

The study is one of the first of its kind, the investigators noted in the National Bureau of Economic Research working paper. Other than a 2016 publication that found that physician mothers were less likely to have cesarean sections (Am Econ J: Econ Policy. 2016;8[1]:115-41), “there is no work which has been able to study the role of physicians as patients,” they wrote.

To fill this gap, the investigators turned to a unique data source: The Military Health System, which provides insurance to active and retired military personnel and their families. Military Health System spending exceeds $50 billion per year, constituting a major portion of American health care expenditures, and with more than 35,000 military physicians treated as patients, the dataset is highly relevant and powerful. The investigators objectively evaluated health outcomes by focusing on evidence-based, measurable clinical decisions deemed “high value” or “low value,” comparing how the frequency of these choices related with physician versus nonphysician patient status.

Coauthor Jonathan Gruber, PhD, of the Massachusetts Institute of Technology in Cambridge, Mass., explained this methodology in an interview. “The literature is clear that high-value care has positive health outcomes with relatively small increases in health care spending, and that low-value care has no impact on health outcomes with large increases in spending.”

“One concern with this analysis, of course, is that physicians may be of different health statuses and have different tastes for medical interventions than nonphysicians,” the investigators wrote. They addressed this problem in five ways, by focusing on widely accepted medical standards that apply to all patients; examining both high- and low-value care to eliminate one-sided bias; controlling for underlying health differences across groups; comparing physicians with other military officers to account for underlying tastes; and evaluating military officer dependents in comparison with physician dependents, the latter of whom may benefit from medical knowledge by virtue of personal relationship.

“Our results suggest that physicians do only slightly better than nonphysicians,” the investigators wrote, “but not by much and not always.” Low-value care was slightly less common among physicians, but this difference was described as “modest.” Analysis of high-value care was more mixed, with some results supporting equivalence between groups and others pointing to a slightly higher rate of high-value care among physician patients.

“These results provide a rough boundary on the extent to which additional information disclosure [beyond prevailing levels] can be expected to improve the delivery of health care in the U.S.,” the investigators wrote. “[M]ost of the explanation behind the over- and underutilization of low- and high-value services likely arises from factors other than informational deficiencies of patients.”

“Perhaps one interpretation of these findings is that patients remain generally deferential to the care recommendations of their treating physicians, even in the case of near fully informed patients,” the investigators wrote, noting that this interpretation aligns with a recent working paper that found that physicians play a greater role in selecting the site of MRI scans than patient cost-sharing factors.

Looking to the future, Dr. Gruber said that he and his colleagues plan on exploring “what drives this lack of response among physicians [as patients].”

The study was funded by the National Institute on Aging. The investigators reported no conflicts of interest.

SOURCE: Frakes MD et al. Natl Bur Econ Res. 2019 Jul. doi: 10.3386/w26038.

This article was updated 8/6/19.

For patients, including patients who are physicians, knowledge isn’t power, according to investigators.

megaflopp/Thinkstock

A literature review and retrospective analysis of more than 35,000 physicians treated as patients revealed minimal associations between level of medical knowledge and quality of health outcomes, reported Michael D. Frakes, PhD, of Duke University, Durham, N.C., and colleagues. The study findings stand in opposition to the “widely prevailing view” that information and medical knowledge among patients are integral to realizing high-quality, low-cost health care, the investigators noted.

“[This] research is particularly relevant to modern discussions and debates about the consumer-driven health care movement and the use of plans with high deductibles and high copayments to encourage greater patient and consumer involvement in health care decision making,” Dr. Frakes said in an interview. “Recent research has suggested that the financial incentives created by such structures discourage the use of both low-value care and high-value care. Some have argued that greater disclosure of information to patients may address this concern and steer patients towards high-value decisions. Our results cast doubt on the potential for information initiatives alone to meet this aim.”

The study is one of the first of its kind, the investigators noted in the National Bureau of Economic Research working paper. Other than a 2016 publication that found that physician mothers were less likely to have cesarean sections (Am Econ J: Econ Policy. 2016;8[1]:115-41), “there is no work which has been able to study the role of physicians as patients,” they wrote.

To fill this gap, the investigators turned to a unique data source: The Military Health System, which provides insurance to active and retired military personnel and their families. Military Health System spending exceeds $50 billion per year, constituting a major portion of American health care expenditures, and with more than 35,000 military physicians treated as patients, the dataset is highly relevant and powerful. The investigators objectively evaluated health outcomes by focusing on evidence-based, measurable clinical decisions deemed “high value” or “low value,” comparing how the frequency of these choices related with physician versus nonphysician patient status.

Coauthor Jonathan Gruber, PhD, of the Massachusetts Institute of Technology in Cambridge, Mass., explained this methodology in an interview. “The literature is clear that high-value care has positive health outcomes with relatively small increases in health care spending, and that low-value care has no impact on health outcomes with large increases in spending.”

“One concern with this analysis, of course, is that physicians may be of different health statuses and have different tastes for medical interventions than nonphysicians,” the investigators wrote. They addressed this problem in five ways, by focusing on widely accepted medical standards that apply to all patients; examining both high- and low-value care to eliminate one-sided bias; controlling for underlying health differences across groups; comparing physicians with other military officers to account for underlying tastes; and evaluating military officer dependents in comparison with physician dependents, the latter of whom may benefit from medical knowledge by virtue of personal relationship.

“Our results suggest that physicians do only slightly better than nonphysicians,” the investigators wrote, “but not by much and not always.” Low-value care was slightly less common among physicians, but this difference was described as “modest.” Analysis of high-value care was more mixed, with some results supporting equivalence between groups and others pointing to a slightly higher rate of high-value care among physician patients.

“These results provide a rough boundary on the extent to which additional information disclosure [beyond prevailing levels] can be expected to improve the delivery of health care in the U.S.,” the investigators wrote. “[M]ost of the explanation behind the over- and underutilization of low- and high-value services likely arises from factors other than informational deficiencies of patients.”

“Perhaps one interpretation of these findings is that patients remain generally deferential to the care recommendations of their treating physicians, even in the case of near fully informed patients,” the investigators wrote, noting that this interpretation aligns with a recent working paper that found that physicians play a greater role in selecting the site of MRI scans than patient cost-sharing factors.

Looking to the future, Dr. Gruber said that he and his colleagues plan on exploring “what drives this lack of response among physicians [as patients].”

The study was funded by the National Institute on Aging. The investigators reported no conflicts of interest.

SOURCE: Frakes MD et al. Natl Bur Econ Res. 2019 Jul. doi: 10.3386/w26038.

This article was updated 8/6/19.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.

In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.

There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.

They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.

Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.

“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.

Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).

Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).

Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.

“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”

The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.

SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.

For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.

In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.

There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.

They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.

Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.

“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.

Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).

Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).

Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.

“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”

The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.

SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.

For patients with testicular diffuse large B-cell lymphoma (T-DLBCL), intravenous central nervous system (CNS)–directed chemotherapy and prophylactic treatment of the contralateral testis offer the best survival outcomes, according to findings from a recent retrospective analysis.

In contrast, intrathecal chemotherapy offered no benefit, reported lead author Susanna Mannisto, MD, of Helsinki University Hospital in Finland, and her colleagues. Survival advantages gained by CNS-directed chemotherapy were generally due to control of systemic disease rather than prevention of CNS progression, they noted.

There have not been randomized trials conducted specifically in T-DLBCL and treatment guidelines are currently based on phase 2 trials. Treatment for T-DLBCL typically involves cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab (R–CHOP), with the addition of CNS prophylaxis with either intravenous or intrathecal methotrexate or cytarabine (AraC) in eligible patients. “Thus far, however, no prospective randomised studies on the benefit of this approach have been published,” the investigators wrote. The study is in the European Journal of Cancer.

They drew data from the Danish Lymphoma Registry and three Southern Finland University Hospitals. Out of 235 patients diagnosed with T-DLBCL between 1987 and 2013, 192 (82%) were treated with curative anthracycline-based chemotherapy. As some cases dated back to 1987, about one-third (36%) were treated before rituximab was available. A slightly higher proportion received intravenous CNS-directed chemotherapy (40%). Due to data availability, 189 patients were included in the survival analysis.

Results of multivariate analyses showed that CNS-directed chemotherapy (intravenous methotrexate, high-dose AraC, or both), was associated with an approximately 58% decreased risk of death across the entire population (hazard ratio [HR] for overall survival, 0.419; 95% confidence interval, 0.256-0.686; P = .001), with elderly patients realizing the greatest benefit.

“[I]t is important to note that we did not observe reduction in the CNS recurrence rate, but rather a better control of the systemic disease, suggesting that R–CHOP alone may not be a sufficient therapy for the patients with testicular DLBCL involvement,” the investigators wrote.

Intrathecal CNS-targeted therapy did not correlate with improved survival in the study. Likewise, for the entire population, rituximab did not boost survival; however, for high risk patients (International Prognostic Index, 3-5), immunochemotherapy did provide a better rate of 5-year disease-specific survival than that of conventional chemotherapy (44% vs 14%; P = .019).

Treatment of the contralateral testis was worthwhile for the entire population, with a 46% decreased risk of death (HR for overall survival, 0.514, 95% CI, 0.338-0.782; P = .002).

Shortest overall survival times, regardless of treatment type, were reported among patients with poor performance status, elevated lactate dehydrogenase (LDH), primary T-DLBCL, more extranodal sites, higher International Prognostic Index, and patients older than 70 years.

“[O]ur results recommend aggressive chemotherapy with [intravenous high-dose methotrexate and/or high-dose AraC] for better control of systemic disease for eligible patients,” the investigators concluded. “In addition, treatment of the contralateral testis with either radiotherapy or orchiectomy should be included in the management strategy of patients with T-DLBCL.”

The study was funded by the Academy of Finland, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and others. The investigators reported additional relationships with Pfizer, Takeda, Roche, Sanofi, and others.

SOURCE: Mannisto S et al. Eur J Cancer. 2019 May 10. doi: 10.1016/j.ejca.2019.04.004.

Triple therapy with an inhaled corticosteroid is particularly helpful for patients with chronic obstructive pulmonary disease (COPD) who have high baseline eosinophil counts, a trial involving more than 10,000 patients found.

Former smokers received greater benefit from inhaled corticosteroids (ICS) than did current smokers, reported lead author Steven Pascoe, MBBS, of GlaxoSmithKline and colleagues. The investigators noted that these findings can help personalize therapy for patients with COPD, which can be challenging to treat because of its heterogeneity. The study was published in Lancet Respiratory Medicine.

The phase 3 IMPACT trial compared single-inhaler fluticasone furoate–umeclidinium–vilanterol with umeclidinium-vilanterol and fluticasone furoate–vilanterol in patients with moderate to very severe COPD at high risk of exacerbation. Of the 10,333 patients involved, approximately one-quarter (26%) had one or more severe exacerbations in the previous year and half (47%) had two or more moderate exacerbations in the same time period. All patients were symptomatic and were aged 40 years or older. A variety of baseline and demographic patient characteristics were recorded, including blood eosinophil count, smoking status, and others. Responses to therapy were measured with trough forced expiratory volume in 1 second (FEV₁), symptom scoring, and a quality of life questionnaire.

After 52 weeks, results showed that higher baseline eosinophil counts were associated with progressively greater benefits in favor of triple therapy. For patients with baseline blood eosinophil counts of at least 310 cells per mcL, triple therapy was associated with about half as many moderate and severe exacerbations as treatment with umeclidinium-vilanterol (rate ratio = 0.56; 95% confidence interval, 0.47-0.66). For patients with less than 90 cells per mcL at baseline, the rate ratio for the same two regimens was 0.88, but with a confidence interval crossing 1 (0.74-1.04). For fluticasone furoate–vilanterol vs. umeclidinium-vilanterol, high baseline eosinophil count again demonstrated its predictive power for ICS efficacy, again with an associated rate ratio of 0.56 (0.47-0.66), compared with 1.09 (0.91-1.29) for patients below the lower threshold. Symptom scoring, quality of life, and FEV₁ followed a similar trend, although the investigators noted that this was “less marked” for FEV₁. Although the trend held regardless of smoking status, benefits were more pronounced among former smokers than current smokers.

“In former smokers, ICS benefits were observed at all blood eosinophil counts when comparing triple therapy with umeclidinium-vilanterol, whereas in current smokers no ICS benefit was observed at lower eosinophil counts, less than approximately 200 eosinophils per [mcL],” the investigators wrote.

“Overall, these results show the potential use of blood eosinophil counts in conjunction with smoking status to predict the magnitude of ICS response within a dual or triple-combination therapy,” the investigators concluded. “Future approaches to the pharmacological management of COPD should move beyond the simple dichotomization of each clinical or biomarker variable, toward more complex algorithms that integrate the interactions between important variables including exacerbation history, smoking status, and blood eosinophil counts.”

The study was funded by GlaxoSmithKline. The investigators disclosed additional relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, and others.

SOURCE: Pascoe S et al. Lancet Resp Med. 2019 Jul 4. doi: 10.1016/S2213-2600(19)30190-0.

Triple therapy with an inhaled corticosteroid is particularly helpful for patients with chronic obstructive pulmonary disease (COPD) who have high baseline eosinophil counts, a trial involving more than 10,000 patients found.

Former smokers received greater benefit from inhaled corticosteroids (ICS) than did current smokers, reported lead author Steven Pascoe, MBBS, of GlaxoSmithKline and colleagues. The investigators noted that these findings can help personalize therapy for patients with COPD, which can be challenging to treat because of its heterogeneity. The study was published in Lancet Respiratory Medicine.

The phase 3 IMPACT trial compared single-inhaler fluticasone furoate–umeclidinium–vilanterol with umeclidinium-vilanterol and fluticasone furoate–vilanterol in patients with moderate to very severe COPD at high risk of exacerbation. Of the 10,333 patients involved, approximately one-quarter (26%) had one or more severe exacerbations in the previous year and half (47%) had two or more moderate exacerbations in the same time period. All patients were symptomatic and were aged 40 years or older. A variety of baseline and demographic patient characteristics were recorded, including blood eosinophil count, smoking status, and others. Responses to therapy were measured with trough forced expiratory volume in 1 second (FEV₁), symptom scoring, and a quality of life questionnaire.

After 52 weeks, results showed that higher baseline eosinophil counts were associated with progressively greater benefits in favor of triple therapy. For patients with baseline blood eosinophil counts of at least 310 cells per mcL, triple therapy was associated with about half as many moderate and severe exacerbations as treatment with umeclidinium-vilanterol (rate ratio = 0.56; 95% confidence interval, 0.47-0.66). For patients with less than 90 cells per mcL at baseline, the rate ratio for the same two regimens was 0.88, but with a confidence interval crossing 1 (0.74-1.04). For fluticasone furoate–vilanterol vs. umeclidinium-vilanterol, high baseline eosinophil count again demonstrated its predictive power for ICS efficacy, again with an associated rate ratio of 0.56 (0.47-0.66), compared with 1.09 (0.91-1.29) for patients below the lower threshold. Symptom scoring, quality of life, and FEV₁ followed a similar trend, although the investigators noted that this was “less marked” for FEV₁. Although the trend held regardless of smoking status, benefits were more pronounced among former smokers than current smokers.

“In former smokers, ICS benefits were observed at all blood eosinophil counts when comparing triple therapy with umeclidinium-vilanterol, whereas in current smokers no ICS benefit was observed at lower eosinophil counts, less than approximately 200 eosinophils per [mcL],” the investigators wrote.

“Overall, these results show the potential use of blood eosinophil counts in conjunction with smoking status to predict the magnitude of ICS response within a dual or triple-combination therapy,” the investigators concluded. “Future approaches to the pharmacological management of COPD should move beyond the simple dichotomization of each clinical or biomarker variable, toward more complex algorithms that integrate the interactions between important variables including exacerbation history, smoking status, and blood eosinophil counts.”

The study was funded by GlaxoSmithKline. The investigators disclosed additional relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, and others.

SOURCE: Pascoe S et al. Lancet Resp Med. 2019 Jul 4. doi: 10.1016/S2213-2600(19)30190-0.

Triple therapy with an inhaled corticosteroid is particularly helpful for patients with chronic obstructive pulmonary disease (COPD) who have high baseline eosinophil counts, a trial involving more than 10,000 patients found.

Former smokers received greater benefit from inhaled corticosteroids (ICS) than did current smokers, reported lead author Steven Pascoe, MBBS, of GlaxoSmithKline and colleagues. The investigators noted that these findings can help personalize therapy for patients with COPD, which can be challenging to treat because of its heterogeneity. The study was published in Lancet Respiratory Medicine.

The phase 3 IMPACT trial compared single-inhaler fluticasone furoate–umeclidinium–vilanterol with umeclidinium-vilanterol and fluticasone furoate–vilanterol in patients with moderate to very severe COPD at high risk of exacerbation. Of the 10,333 patients involved, approximately one-quarter (26%) had one or more severe exacerbations in the previous year and half (47%) had two or more moderate exacerbations in the same time period. All patients were symptomatic and were aged 40 years or older. A variety of baseline and demographic patient characteristics were recorded, including blood eosinophil count, smoking status, and others. Responses to therapy were measured with trough forced expiratory volume in 1 second (FEV₁), symptom scoring, and a quality of life questionnaire.

After 52 weeks, results showed that higher baseline eosinophil counts were associated with progressively greater benefits in favor of triple therapy. For patients with baseline blood eosinophil counts of at least 310 cells per mcL, triple therapy was associated with about half as many moderate and severe exacerbations as treatment with umeclidinium-vilanterol (rate ratio = 0.56; 95% confidence interval, 0.47-0.66). For patients with less than 90 cells per mcL at baseline, the rate ratio for the same two regimens was 0.88, but with a confidence interval crossing 1 (0.74-1.04). For fluticasone furoate–vilanterol vs. umeclidinium-vilanterol, high baseline eosinophil count again demonstrated its predictive power for ICS efficacy, again with an associated rate ratio of 0.56 (0.47-0.66), compared with 1.09 (0.91-1.29) for patients below the lower threshold. Symptom scoring, quality of life, and FEV₁ followed a similar trend, although the investigators noted that this was “less marked” for FEV₁. Although the trend held regardless of smoking status, benefits were more pronounced among former smokers than current smokers.

“In former smokers, ICS benefits were observed at all blood eosinophil counts when comparing triple therapy with umeclidinium-vilanterol, whereas in current smokers no ICS benefit was observed at lower eosinophil counts, less than approximately 200 eosinophils per [mcL],” the investigators wrote.

“Overall, these results show the potential use of blood eosinophil counts in conjunction with smoking status to predict the magnitude of ICS response within a dual or triple-combination therapy,” the investigators concluded. “Future approaches to the pharmacological management of COPD should move beyond the simple dichotomization of each clinical or biomarker variable, toward more complex algorithms that integrate the interactions between important variables including exacerbation history, smoking status, and blood eosinophil counts.”

The study was funded by GlaxoSmithKline. The investigators disclosed additional relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, and others.

SOURCE: Pascoe S et al. Lancet Resp Med. 2019 Jul 4. doi: 10.1016/S2213-2600(19)30190-0.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.