Pharmacology

Over-the-counter medications, food supplements, and other drugs may interact with antiretroviral therapy (ART) in people living with HIV and be harmful, an industry-sponsored clinical survey from Denmark reports.

“Our study confirms that polypharmacy and being on a protease inhibitor–based regimen increase the risk of potential drug-drug interactions [PDDIs] considerably and highlights the importance of questioning people living with HIV [PLWH] about dietary supplement intake,” the authors, led by Michaela Tinggaard, MD, Copenhagen University Hospital, wrote in HIV Medicine.

“Potential drug-drug interactions were common among our study population. Although the clinical significance of the majority of the identified PDDIs may be low, most of them were avoidable through a change or discontinuation of the comedication, a change in ART or by spacing drugs,” they added.

Senior author Thomas Benfield, MD, DTMH, DMSc, a professor of infectious diseases at the University of Copenhagen, and colleagues collected information on prescription medication, over-the-counter medication, and dietary supplements from adults living with HIV who received ART from two outpatient clinics.

The researchers estimated the prevalence of non-HIV comedications, and they used the University of Liverpool HIV Drug Interactions database to identify potential drug-drug interactions. They evaluated PDDIs and used logistic regression models to investigate links between PDDIs and relevant variables.

The study included 337 people living with HIV receiving ART. The median age was 53 years, 77% of them were male, and 96% were virally suppressed, with HIV-RNA viral load less than 50 copies/mL.

Overall, 26% of participants received five or more comedications, and 56% took dietary supplements.

In the medication lists of 52% of patients, the authors identified coadministration of drugs that required dose adjustment or monitoring; 4.5% of patients were taking drugs that should not be coadministered.

The researchers detected several factors that independently predicted PDDIs:

• Male sex (odds ratio, 1.9; 95% confidence interval, 1.0-3.4)
• Being on a protease inhibitor (OR, 4.3; 95% CI, 1.9-9.7)
• Receiving five or more comedications (OR, 3.3; 95% CI, 1.5-7.2)
• Taking over-the-counter medications (OR, 1.9; 95% CI, 1.1-3.3)
• Taking dietary supplements (OR, 2.0; 95% CI, 1.2-3.3)

Comorbidities and OTC medications increase in aging people with HIV

Indira Brar, MD, an infectious diseases senior staff physician and the medical director of HIV services at Henry Ford Health in Detroit, called the study and important resource for educating providers and patients about over-the-counter drugs.

“The main strength of the study is that it includes a decent number of aging patients living with HIV, the age group in which we worry about drug interactions,” she said in an interview.

“As patients get older, they have increased comorbidities. As comorbidities increase, the number of medications increases. As the number of medications increases, the drug interactions increase,” said Dr. Brar, who was not involved in the study. “Also, as patients get older, they tend to take more over-the-counter drugs.”

Dr. Brar explained how drug-drug interactions can harm patients.

“Drugs added to a patient who is already on ART could decrease the level of the ART and cause the patient to develop a drug-resistant HIV infection,” she said. “Or the ART the patient is on can increase the levels of the new drugs that have been added, and that could have potential toxicity and side effects.

“Food supplements, including multivitamins, calcium, and magnesium, are often overlooked because we think they’re benign. But these drugs can bind our new antiretrovirals, the integrase inhibitors. They can decrease their levels in the patient and cause drug-resistant HIV infection.

“In our clinic, we always tell our patients to please call us before they take any medication, so we can make sure there is no drug interaction,” Dr. Brar said.

Nan Wang, PharmD, a clinical pharmacy specialist at University Hospitals Cleveland Medical Center, noted in an email that drug-drug interactions with ARTs are common.

“Understanding the prevalence of antiretroviral drug interactions in a patient population can help identify certain medications that require enhanced vigilance and can guide our clinical interventions,” said Dr. Wang, who was not associated with the research.

Joseph Alvarnas, MD, a hematologist and oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said that this is “a methodologically sound and well-designed study that’s a timely, important reminder that providers need to think carefully and comprehensively when caring for their patients living with HIV.”

Dr. Alvarnas, who was not involved in the study, said that, with the widespread availability of ART, HIV has become a chronic, manageable condition in an aging population.

“ART agents, particularly the ritonavir-boosted protease inhibitors, increase the likelihood of patients having a potentially significant drug-drug interaction with one of their chronic care medications,” he added. “Even seemingly low-risk supplements such as multivitamins may result in a negative impact upon effective ART treatment of PLWH.”

“The essential next step is that these findings are integrated carefully into decision-support systems, electronic health record prescribing systems, and pharmacy safety-check systems to ensure that we reduce the risk of patient harm,” Dr. Alvarnas advised.

Dr. Benfield and several study coauthors reported financial relationships with GlaxoSmithKline and other pharmaceutical companies. Other coauthors, as well as Dr. Alvarnas, Dr. Brar, and Dr. Wang, reported no relevant financial relationships. The study was supported by GlaxoSmithKline.

A version of this article first appeared on Medscape.com.

Over-the-counter medications, food supplements, and other drugs may interact with antiretroviral therapy (ART) in people living with HIV and be harmful, an industry-sponsored clinical survey from Denmark reports.

“Our study confirms that polypharmacy and being on a protease inhibitor–based regimen increase the risk of potential drug-drug interactions [PDDIs] considerably and highlights the importance of questioning people living with HIV [PLWH] about dietary supplement intake,” the authors, led by Michaela Tinggaard, MD, Copenhagen University Hospital, wrote in HIV Medicine.

“Potential drug-drug interactions were common among our study population. Although the clinical significance of the majority of the identified PDDIs may be low, most of them were avoidable through a change or discontinuation of the comedication, a change in ART or by spacing drugs,” they added.

Senior author Thomas Benfield, MD, DTMH, DMSc, a professor of infectious diseases at the University of Copenhagen, and colleagues collected information on prescription medication, over-the-counter medication, and dietary supplements from adults living with HIV who received ART from two outpatient clinics.

The researchers estimated the prevalence of non-HIV comedications, and they used the University of Liverpool HIV Drug Interactions database to identify potential drug-drug interactions. They evaluated PDDIs and used logistic regression models to investigate links between PDDIs and relevant variables.

The study included 337 people living with HIV receiving ART. The median age was 53 years, 77% of them were male, and 96% were virally suppressed, with HIV-RNA viral load less than 50 copies/mL.

Overall, 26% of participants received five or more comedications, and 56% took dietary supplements.

In the medication lists of 52% of patients, the authors identified coadministration of drugs that required dose adjustment or monitoring; 4.5% of patients were taking drugs that should not be coadministered.

The researchers detected several factors that independently predicted PDDIs:

• Male sex (odds ratio, 1.9; 95% confidence interval, 1.0-3.4)
• Being on a protease inhibitor (OR, 4.3; 95% CI, 1.9-9.7)
• Receiving five or more comedications (OR, 3.3; 95% CI, 1.5-7.2)
• Taking over-the-counter medications (OR, 1.9; 95% CI, 1.1-3.3)
• Taking dietary supplements (OR, 2.0; 95% CI, 1.2-3.3)

Comorbidities and OTC medications increase in aging people with HIV

Indira Brar, MD, an infectious diseases senior staff physician and the medical director of HIV services at Henry Ford Health in Detroit, called the study and important resource for educating providers and patients about over-the-counter drugs.

“The main strength of the study is that it includes a decent number of aging patients living with HIV, the age group in which we worry about drug interactions,” she said in an interview.

“As patients get older, they have increased comorbidities. As comorbidities increase, the number of medications increases. As the number of medications increases, the drug interactions increase,” said Dr. Brar, who was not involved in the study. “Also, as patients get older, they tend to take more over-the-counter drugs.”

Dr. Brar explained how drug-drug interactions can harm patients.

“Drugs added to a patient who is already on ART could decrease the level of the ART and cause the patient to develop a drug-resistant HIV infection,” she said. “Or the ART the patient is on can increase the levels of the new drugs that have been added, and that could have potential toxicity and side effects.

“Food supplements, including multivitamins, calcium, and magnesium, are often overlooked because we think they’re benign. But these drugs can bind our new antiretrovirals, the integrase inhibitors. They can decrease their levels in the patient and cause drug-resistant HIV infection.

“In our clinic, we always tell our patients to please call us before they take any medication, so we can make sure there is no drug interaction,” Dr. Brar said.

Nan Wang, PharmD, a clinical pharmacy specialist at University Hospitals Cleveland Medical Center, noted in an email that drug-drug interactions with ARTs are common.

“Understanding the prevalence of antiretroviral drug interactions in a patient population can help identify certain medications that require enhanced vigilance and can guide our clinical interventions,” said Dr. Wang, who was not associated with the research.

Joseph Alvarnas, MD, a hematologist and oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said that this is “a methodologically sound and well-designed study that’s a timely, important reminder that providers need to think carefully and comprehensively when caring for their patients living with HIV.”

Dr. Alvarnas, who was not involved in the study, said that, with the widespread availability of ART, HIV has become a chronic, manageable condition in an aging population.

“ART agents, particularly the ritonavir-boosted protease inhibitors, increase the likelihood of patients having a potentially significant drug-drug interaction with one of their chronic care medications,” he added. “Even seemingly low-risk supplements such as multivitamins may result in a negative impact upon effective ART treatment of PLWH.”

“The essential next step is that these findings are integrated carefully into decision-support systems, electronic health record prescribing systems, and pharmacy safety-check systems to ensure that we reduce the risk of patient harm,” Dr. Alvarnas advised.

Dr. Benfield and several study coauthors reported financial relationships with GlaxoSmithKline and other pharmaceutical companies. Other coauthors, as well as Dr. Alvarnas, Dr. Brar, and Dr. Wang, reported no relevant financial relationships. The study was supported by GlaxoSmithKline.

A version of this article first appeared on Medscape.com.

Over-the-counter medications, food supplements, and other drugs may interact with antiretroviral therapy (ART) in people living with HIV and be harmful, an industry-sponsored clinical survey from Denmark reports.

“Our study confirms that polypharmacy and being on a protease inhibitor–based regimen increase the risk of potential drug-drug interactions [PDDIs] considerably and highlights the importance of questioning people living with HIV [PLWH] about dietary supplement intake,” the authors, led by Michaela Tinggaard, MD, Copenhagen University Hospital, wrote in HIV Medicine.

“Potential drug-drug interactions were common among our study population. Although the clinical significance of the majority of the identified PDDIs may be low, most of them were avoidable through a change or discontinuation of the comedication, a change in ART or by spacing drugs,” they added.

Senior author Thomas Benfield, MD, DTMH, DMSc, a professor of infectious diseases at the University of Copenhagen, and colleagues collected information on prescription medication, over-the-counter medication, and dietary supplements from adults living with HIV who received ART from two outpatient clinics.

The researchers estimated the prevalence of non-HIV comedications, and they used the University of Liverpool HIV Drug Interactions database to identify potential drug-drug interactions. They evaluated PDDIs and used logistic regression models to investigate links between PDDIs and relevant variables.

The study included 337 people living with HIV receiving ART. The median age was 53 years, 77% of them were male, and 96% were virally suppressed, with HIV-RNA viral load less than 50 copies/mL.

Overall, 26% of participants received five or more comedications, and 56% took dietary supplements.

In the medication lists of 52% of patients, the authors identified coadministration of drugs that required dose adjustment or monitoring; 4.5% of patients were taking drugs that should not be coadministered.

The researchers detected several factors that independently predicted PDDIs:

• Male sex (odds ratio, 1.9; 95% confidence interval, 1.0-3.4)
• Being on a protease inhibitor (OR, 4.3; 95% CI, 1.9-9.7)
• Receiving five or more comedications (OR, 3.3; 95% CI, 1.5-7.2)
• Taking over-the-counter medications (OR, 1.9; 95% CI, 1.1-3.3)
• Taking dietary supplements (OR, 2.0; 95% CI, 1.2-3.3)

Comorbidities and OTC medications increase in aging people with HIV

Indira Brar, MD, an infectious diseases senior staff physician and the medical director of HIV services at Henry Ford Health in Detroit, called the study and important resource for educating providers and patients about over-the-counter drugs.

“The main strength of the study is that it includes a decent number of aging patients living with HIV, the age group in which we worry about drug interactions,” she said in an interview.

“As patients get older, they have increased comorbidities. As comorbidities increase, the number of medications increases. As the number of medications increases, the drug interactions increase,” said Dr. Brar, who was not involved in the study. “Also, as patients get older, they tend to take more over-the-counter drugs.”

Dr. Brar explained how drug-drug interactions can harm patients.

“Drugs added to a patient who is already on ART could decrease the level of the ART and cause the patient to develop a drug-resistant HIV infection,” she said. “Or the ART the patient is on can increase the levels of the new drugs that have been added, and that could have potential toxicity and side effects.

“Food supplements, including multivitamins, calcium, and magnesium, are often overlooked because we think they’re benign. But these drugs can bind our new antiretrovirals, the integrase inhibitors. They can decrease their levels in the patient and cause drug-resistant HIV infection.

“In our clinic, we always tell our patients to please call us before they take any medication, so we can make sure there is no drug interaction,” Dr. Brar said.

Nan Wang, PharmD, a clinical pharmacy specialist at University Hospitals Cleveland Medical Center, noted in an email that drug-drug interactions with ARTs are common.

“Understanding the prevalence of antiretroviral drug interactions in a patient population can help identify certain medications that require enhanced vigilance and can guide our clinical interventions,” said Dr. Wang, who was not associated with the research.

Joseph Alvarnas, MD, a hematologist and oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said that this is “a methodologically sound and well-designed study that’s a timely, important reminder that providers need to think carefully and comprehensively when caring for their patients living with HIV.”

Dr. Alvarnas, who was not involved in the study, said that, with the widespread availability of ART, HIV has become a chronic, manageable condition in an aging population.

“ART agents, particularly the ritonavir-boosted protease inhibitors, increase the likelihood of patients having a potentially significant drug-drug interaction with one of their chronic care medications,” he added. “Even seemingly low-risk supplements such as multivitamins may result in a negative impact upon effective ART treatment of PLWH.”

“The essential next step is that these findings are integrated carefully into decision-support systems, electronic health record prescribing systems, and pharmacy safety-check systems to ensure that we reduce the risk of patient harm,” Dr. Alvarnas advised.

Dr. Benfield and several study coauthors reported financial relationships with GlaxoSmithKline and other pharmaceutical companies. Other coauthors, as well as Dr. Alvarnas, Dr. Brar, and Dr. Wang, reported no relevant financial relationships. The study was supported by GlaxoSmithKline.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – Nearly half of all patients with severe, uncontrolled asthma who received a full course of the biologic agent tezepelumab (Tezspire) in the NAVIGATOR trial had a complete response to treatment at 1 year, results of a prespecified exploratory analysis indicated.

Among 471 patients assigned to tezepelumab who completed the on-treatment period of the phase 3 randomized trial, 46% had a complete response at 52 weeks, compared with 24% of patients assigned to placebo.

Complete response was defined as reduction in exacerbations of at least 50% over the previous year, improvement from baseline in Asthma Control Questionnaire 6 (ACQ-6) total score of at least 0.5 points, improvement in prebronchodilator forced expiratory volume in 1 second (pre-BD FEV₁), and physician-assessed Clinical Global Impression measure of clinical change (CGI-C) score.

“These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma,” said Njira Lugogo, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

Dr. Lugogo presented results of the exploratory analysis at the American Thoracic Society’s international conference.
 

Exacerbations reduced, lung function improved

Primary results from NAVIGATOR, published in The New England Journal of Medicine, showed that patients with severe, uncontrolled asthma randomly assigned to tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life compared with patients assigned to placebo.

The investigators noted that approximately 10% of patients with asthma have symptoms and exacerbations despite maximal standard-of-care controller therapy.

Tezepelumab is a human monoclonal antibody that inhibits action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that is released in response to airborne triggers of asthma. TSLP is a major contributor to initiation and persistence of airway inflammation, Dr. Lugogo said.

The on-treatment analysis looked at all patients in the trial who completed 52 weeks of treatment and had complete data for all criteria studied.

The odds ratios (OR) for patients on tezepelumab achieving each of the response criteria are shown in the table.

Exacerbations explored

In a separate presentation, Christopher S. Ambrose, MD, MBA, of AstraZeneca in Gaithersburg, Md., presented information from investigator-narrative descriptions of all hospitalization events related to asthma exacerbations (mild, moderate, or severe) that occurred while the investigator was blinded to each patient’s treatment assignment in NAVIGATOR.

In all, 39 of 531 patients (7.3%) assigned to placebo had a total of 78 exacerbations requiring hospitalization, compared with 13 of 528 patients (2.5%) assigned to tezepelumab. The latter group had a total of 14 exacerbations requiring hospitalization during the study.

Among hospitalized patients, 32 of the 39 assigned to placebo had severe, incapacitating exacerbations, compared with 5 of 13 assigned to tezepelumab.

Reported symptoms were generally similar between hospitalized patients in the two treatment groups, although there appeared to be trends toward lower incidence of dyspnea, fever, and tachycardia with tezepelumab.

Health care resource utilization, a surrogate marker for disease burden, was substantially lower for patients assigned to tezepelumab.

Infections were the most common triggers of exacerbations in both groups.

“These data provide further evidence that tezepelumab can reduce the burden of disease of severe uncontrolled asthma, both to patients and to health care systems,” Dr. Ambrose said.
 

Head-to-head studies needed

Although there have been no head-to-head comparisons of biologic agents for asthma to date, results of these studies suggest that tezepelumab has efficacy similar to that of other agents for reducing exacerbation, said Fernando Holguin, MD, MPH, from the University of Colorado at Denver, Aurora, who comoderated the oral session where the data were presented but was not involved in the study.

Biologic agents appear to be slightly more effective against type 2 inflammation in asthma, “but in general I think we give it to a broader severe population, so that’s exciting,” he told this news organization.

Comoderator Amisha Barochia, MBBS, MHS, of the National Institutes of Health, Bethesda, Md., told this news organization that head-to-head trials of biologic agents would provide important clinical information going forward.

“Should we switch to a different biologic or add a second biologic? Those are questions we need answers for,” she said.

The NAVIGATOR trial is funded by AstraZeneca and Amgen. Dr. Lugogo disclosed financial relationships with both companies. Dr. Holguin and Dr. Barochia have disclosed no financial relationships relevant to the studies presented.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – Nearly half of all patients with severe, uncontrolled asthma who received a full course of the biologic agent tezepelumab (Tezspire) in the NAVIGATOR trial had a complete response to treatment at 1 year, results of a prespecified exploratory analysis indicated.

Among 471 patients assigned to tezepelumab who completed the on-treatment period of the phase 3 randomized trial, 46% had a complete response at 52 weeks, compared with 24% of patients assigned to placebo.

Complete response was defined as reduction in exacerbations of at least 50% over the previous year, improvement from baseline in Asthma Control Questionnaire 6 (ACQ-6) total score of at least 0.5 points, improvement in prebronchodilator forced expiratory volume in 1 second (pre-BD FEV₁), and physician-assessed Clinical Global Impression measure of clinical change (CGI-C) score.

“These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma,” said Njira Lugogo, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

Dr. Lugogo presented results of the exploratory analysis at the American Thoracic Society’s international conference.
 

Exacerbations reduced, lung function improved

Primary results from NAVIGATOR, published in The New England Journal of Medicine, showed that patients with severe, uncontrolled asthma randomly assigned to tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life compared with patients assigned to placebo.

The investigators noted that approximately 10% of patients with asthma have symptoms and exacerbations despite maximal standard-of-care controller therapy.

Tezepelumab is a human monoclonal antibody that inhibits action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that is released in response to airborne triggers of asthma. TSLP is a major contributor to initiation and persistence of airway inflammation, Dr. Lugogo said.

The on-treatment analysis looked at all patients in the trial who completed 52 weeks of treatment and had complete data for all criteria studied.

The odds ratios (OR) for patients on tezepelumab achieving each of the response criteria are shown in the table.

Exacerbations explored

In a separate presentation, Christopher S. Ambrose, MD, MBA, of AstraZeneca in Gaithersburg, Md., presented information from investigator-narrative descriptions of all hospitalization events related to asthma exacerbations (mild, moderate, or severe) that occurred while the investigator was blinded to each patient’s treatment assignment in NAVIGATOR.

In all, 39 of 531 patients (7.3%) assigned to placebo had a total of 78 exacerbations requiring hospitalization, compared with 13 of 528 patients (2.5%) assigned to tezepelumab. The latter group had a total of 14 exacerbations requiring hospitalization during the study.

Among hospitalized patients, 32 of the 39 assigned to placebo had severe, incapacitating exacerbations, compared with 5 of 13 assigned to tezepelumab.

Reported symptoms were generally similar between hospitalized patients in the two treatment groups, although there appeared to be trends toward lower incidence of dyspnea, fever, and tachycardia with tezepelumab.

Health care resource utilization, a surrogate marker for disease burden, was substantially lower for patients assigned to tezepelumab.

Infections were the most common triggers of exacerbations in both groups.

“These data provide further evidence that tezepelumab can reduce the burden of disease of severe uncontrolled asthma, both to patients and to health care systems,” Dr. Ambrose said.
 

Head-to-head studies needed

Although there have been no head-to-head comparisons of biologic agents for asthma to date, results of these studies suggest that tezepelumab has efficacy similar to that of other agents for reducing exacerbation, said Fernando Holguin, MD, MPH, from the University of Colorado at Denver, Aurora, who comoderated the oral session where the data were presented but was not involved in the study.

Biologic agents appear to be slightly more effective against type 2 inflammation in asthma, “but in general I think we give it to a broader severe population, so that’s exciting,” he told this news organization.

Comoderator Amisha Barochia, MBBS, MHS, of the National Institutes of Health, Bethesda, Md., told this news organization that head-to-head trials of biologic agents would provide important clinical information going forward.

“Should we switch to a different biologic or add a second biologic? Those are questions we need answers for,” she said.

The NAVIGATOR trial is funded by AstraZeneca and Amgen. Dr. Lugogo disclosed financial relationships with both companies. Dr. Holguin and Dr. Barochia have disclosed no financial relationships relevant to the studies presented.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – Nearly half of all patients with severe, uncontrolled asthma who received a full course of the biologic agent tezepelumab (Tezspire) in the NAVIGATOR trial had a complete response to treatment at 1 year, results of a prespecified exploratory analysis indicated.

Among 471 patients assigned to tezepelumab who completed the on-treatment period of the phase 3 randomized trial, 46% had a complete response at 52 weeks, compared with 24% of patients assigned to placebo.

Complete response was defined as reduction in exacerbations of at least 50% over the previous year, improvement from baseline in Asthma Control Questionnaire 6 (ACQ-6) total score of at least 0.5 points, improvement in prebronchodilator forced expiratory volume in 1 second (pre-BD FEV₁), and physician-assessed Clinical Global Impression measure of clinical change (CGI-C) score.

“These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma,” said Njira Lugogo, MD, of the division of pulmonary and critical care medicine at the University of Michigan, Ann Arbor.

Dr. Lugogo presented results of the exploratory analysis at the American Thoracic Society’s international conference.
 

Exacerbations reduced, lung function improved

Primary results from NAVIGATOR, published in The New England Journal of Medicine, showed that patients with severe, uncontrolled asthma randomly assigned to tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life compared with patients assigned to placebo.

The investigators noted that approximately 10% of patients with asthma have symptoms and exacerbations despite maximal standard-of-care controller therapy.

Tezepelumab is a human monoclonal antibody that inhibits action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that is released in response to airborne triggers of asthma. TSLP is a major contributor to initiation and persistence of airway inflammation, Dr. Lugogo said.

The on-treatment analysis looked at all patients in the trial who completed 52 weeks of treatment and had complete data for all criteria studied.

The odds ratios (OR) for patients on tezepelumab achieving each of the response criteria are shown in the table.

Exacerbations explored

In a separate presentation, Christopher S. Ambrose, MD, MBA, of AstraZeneca in Gaithersburg, Md., presented information from investigator-narrative descriptions of all hospitalization events related to asthma exacerbations (mild, moderate, or severe) that occurred while the investigator was blinded to each patient’s treatment assignment in NAVIGATOR.

In all, 39 of 531 patients (7.3%) assigned to placebo had a total of 78 exacerbations requiring hospitalization, compared with 13 of 528 patients (2.5%) assigned to tezepelumab. The latter group had a total of 14 exacerbations requiring hospitalization during the study.

Among hospitalized patients, 32 of the 39 assigned to placebo had severe, incapacitating exacerbations, compared with 5 of 13 assigned to tezepelumab.

Reported symptoms were generally similar between hospitalized patients in the two treatment groups, although there appeared to be trends toward lower incidence of dyspnea, fever, and tachycardia with tezepelumab.

Health care resource utilization, a surrogate marker for disease burden, was substantially lower for patients assigned to tezepelumab.

Infections were the most common triggers of exacerbations in both groups.

“These data provide further evidence that tezepelumab can reduce the burden of disease of severe uncontrolled asthma, both to patients and to health care systems,” Dr. Ambrose said.
 

Head-to-head studies needed

Although there have been no head-to-head comparisons of biologic agents for asthma to date, results of these studies suggest that tezepelumab has efficacy similar to that of other agents for reducing exacerbation, said Fernando Holguin, MD, MPH, from the University of Colorado at Denver, Aurora, who comoderated the oral session where the data were presented but was not involved in the study.

Biologic agents appear to be slightly more effective against type 2 inflammation in asthma, “but in general I think we give it to a broader severe population, so that’s exciting,” he told this news organization.

Comoderator Amisha Barochia, MBBS, MHS, of the National Institutes of Health, Bethesda, Md., told this news organization that head-to-head trials of biologic agents would provide important clinical information going forward.

“Should we switch to a different biologic or add a second biologic? Those are questions we need answers for,” she said.

The NAVIGATOR trial is funded by AstraZeneca and Amgen. Dr. Lugogo disclosed financial relationships with both companies. Dr. Holguin and Dr. Barochia have disclosed no financial relationships relevant to the studies presented.

A version of this article first appeared on Medscape.com.

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded an emergency use authorization (EUA), allowing the Pfizer-BioNTech COVID-19 booster shot for children ages 5 to 11 who are at least 5 months out from their first vaccine series.

According to the most recent data from the Centers for Disease Control and Prevention, 28.6% of children in this age group have received both initial doses of Pfizer’s COVID-19 vaccine, and 35.3% have received their first dose.

Pfizer’s vaccine trial involving 4,500 children showed few side effects among children younger than 12 who received a booster, or third dose, according to a company statement.

Pfizer asked the FDA for an amended authorization in April, after submitting data showing that a third dose in children between 5 and 11 raised antibodies targeting the Omicron variant by 36 times.

“While it has largely been the case that COVID-19 tends to be less severe in children than adults, the omicron wave has seen more kids getting sick with the disease and being hospitalized, and children may also experience longer-term effects, even following initially mild disease,” FDA Commissioner Robert M. Califf, MD, said in a news release.

A study done by the New York State Department of Health showed the effectiveness of Pfizer’s two-dose vaccine series fell from 68% to 12% 4-5 months after the second dose was given to children 5 to 11 during the Omicron surge. A CDC study published in March also showed that the Pfizer shot reduced the risk of Omicron by 31% in children 5 to 11, a significantly lower rate than for kids 12 to 15, who had a 59% risk reduction after receiving two doses.

To some experts, this data suggest an even greater need for children under 12 to be eligible for a third dose.

“Since authorizing the vaccine for children down to 5 years of age in October 2021, emerging data suggest that vaccine effectiveness against COVID-19 wanes after the second dose of the vaccine in all authorized populations,” says Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research.

The CDC still needs to sign off on the shots before they can be allowed. The agency’s Advisory Committee on Immunization Practices is set to meet on May 19 to discuss boosters in this age group.

FDA advisory panels plan to meet next month to discuss allowing Pfizer’s and Moderna’s COVID-19 vaccines for children under 6 years old.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has expanded an emergency use authorization (EUA), allowing the Pfizer-BioNTech COVID-19 booster shot for children ages 5 to 11 who are at least 5 months out from their first vaccine series.

According to the most recent data from the Centers for Disease Control and Prevention, 28.6% of children in this age group have received both initial doses of Pfizer’s COVID-19 vaccine, and 35.3% have received their first dose.

Pfizer’s vaccine trial involving 4,500 children showed few side effects among children younger than 12 who received a booster, or third dose, according to a company statement.

Pfizer asked the FDA for an amended authorization in April, after submitting data showing that a third dose in children between 5 and 11 raised antibodies targeting the Omicron variant by 36 times.

“While it has largely been the case that COVID-19 tends to be less severe in children than adults, the omicron wave has seen more kids getting sick with the disease and being hospitalized, and children may also experience longer-term effects, even following initially mild disease,” FDA Commissioner Robert M. Califf, MD, said in a news release.

A study done by the New York State Department of Health showed the effectiveness of Pfizer’s two-dose vaccine series fell from 68% to 12% 4-5 months after the second dose was given to children 5 to 11 during the Omicron surge. A CDC study published in March also showed that the Pfizer shot reduced the risk of Omicron by 31% in children 5 to 11, a significantly lower rate than for kids 12 to 15, who had a 59% risk reduction after receiving two doses.

To some experts, this data suggest an even greater need for children under 12 to be eligible for a third dose.

“Since authorizing the vaccine for children down to 5 years of age in October 2021, emerging data suggest that vaccine effectiveness against COVID-19 wanes after the second dose of the vaccine in all authorized populations,” says Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research.

The CDC still needs to sign off on the shots before they can be allowed. The agency’s Advisory Committee on Immunization Practices is set to meet on May 19 to discuss boosters in this age group.

FDA advisory panels plan to meet next month to discuss allowing Pfizer’s and Moderna’s COVID-19 vaccines for children under 6 years old.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has expanded an emergency use authorization (EUA), allowing the Pfizer-BioNTech COVID-19 booster shot for children ages 5 to 11 who are at least 5 months out from their first vaccine series.

According to the most recent data from the Centers for Disease Control and Prevention, 28.6% of children in this age group have received both initial doses of Pfizer’s COVID-19 vaccine, and 35.3% have received their first dose.

Pfizer’s vaccine trial involving 4,500 children showed few side effects among children younger than 12 who received a booster, or third dose, according to a company statement.

Pfizer asked the FDA for an amended authorization in April, after submitting data showing that a third dose in children between 5 and 11 raised antibodies targeting the Omicron variant by 36 times.

“While it has largely been the case that COVID-19 tends to be less severe in children than adults, the omicron wave has seen more kids getting sick with the disease and being hospitalized, and children may also experience longer-term effects, even following initially mild disease,” FDA Commissioner Robert M. Califf, MD, said in a news release.

A study done by the New York State Department of Health showed the effectiveness of Pfizer’s two-dose vaccine series fell from 68% to 12% 4-5 months after the second dose was given to children 5 to 11 during the Omicron surge. A CDC study published in March also showed that the Pfizer shot reduced the risk of Omicron by 31% in children 5 to 11, a significantly lower rate than for kids 12 to 15, who had a 59% risk reduction after receiving two doses.

To some experts, this data suggest an even greater need for children under 12 to be eligible for a third dose.

“Since authorizing the vaccine for children down to 5 years of age in October 2021, emerging data suggest that vaccine effectiveness against COVID-19 wanes after the second dose of the vaccine in all authorized populations,” says Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research.

The CDC still needs to sign off on the shots before they can be allowed. The agency’s Advisory Committee on Immunization Practices is set to meet on May 19 to discuss boosters in this age group.

FDA advisory panels plan to meet next month to discuss allowing Pfizer’s and Moderna’s COVID-19 vaccines for children under 6 years old.

A version of this article first appeared on WebMD.com.

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Something different appears to be going on when an older adult develops inflammatory bowel disease (IBD), and now researchers offer more evidence that antibiotics could be playing a role.

Most studies to date have assessed a link between antibiotics and IBD in younger patients, lead researcher Adam S. Faye, MD, said during a media briefing that previewed select research for the annual Digestive Disease Week® (DDW).

The impact of antibiotic use on the incidence of IBD in older adults is really unknown, he added.

In contrast to younger people with IBD, who tend to have a strong family history or genetic predisposition to developing Crohn’s disease or ulcerative colitis, the cause is likely different in older populations.

“There’s clearly something in the environment that’s driving this new older-onset IBD,” said Dr. Faye, who is an assistant professor of medicine and population health at New York University.
 

Antibiotics as a contributing link

Dr. Faye and colleagues took a closer look at antibiotics as contributing to this link. They studied 2.3 million patient records in Denmark’s national medical registry from 2000 to 2018. They identified people aged 60 years and older who were newly diagnosed with IBD, and they then assessed the number, frequency, and timing of any antibiotic prescriptions.

They found that IBD was 27% more likely in this age group if the patients had received any antibiotic prescription.

They also found that the chance of developing IBD was higher as the number of antibiotic prescriptions increased. For example, IBD was 55% more likely if a person had received two prescriptions, and it was 96% more likely with four prescriptions. The risk really jumped with five or more antibiotic prescriptions – a person with this many prescriptions was more than 2.3 times (236%) more likely to be diagnosed with IBD than those who had not been prescribed antibiotics in the prior 5 years.

Not all antibiotics were equal, however. For example, the investigators found no link with nitrofurantoin, an antibiotic commonly prescribed for urinary tract infections. In contrast, all other antibiotic agents that were evaluated, and especially fluoroquinolones, nitroimidazoles, and macrolides, were associated with IBD.

Timing made some difference.

“The risk was highest if antibiotics were prescribed within the 1- to 2-year period before diagnosis, and it declined as you go farther out. But the risks persist,” Dr. Faye said. He noted that they even found that risk was elevated 10 years out.

The investigators also considered whether the antibiotic agent or infection was behind the association.

Dr. Faye cited previous research, again in younger people with IBD, that revealed that “infections plus antibiotics substantially increase the odds or risk of developing IBD more than the infection alone.

“So there really does seem to be something that the antibiotics are doing here,” Dr. Faye said.

A leading theory is that antibiotics disrupt the gut microbiota and increase the risk for developing IBD. “But, obviously, it’s quite complicated,” he said.
 

Clinical implications

The findings suggest that older people who may have IBD should be screened for prior antibiotic use, Dr. Faye said.

“This is a result that really has important implications for diagnosing older adults with new gastrointestinal symptoms,” he said. “Inflammatory bowel disease often can be overlooked in older adults because there’s a lot of different diagnoses you’re thinking of.”

IBD “should be considered, especially if you have a patient who’s reporting multiple courses of antibiotics in the last few years,” he added.

The results suggest another reason that antimicrobial stewardship programs should promote judicial use of these agents beyond concerns about resistance.

“We think of antibiotic stewardship to prevent the development of multidrug-resistant organisms, but we should be thinking about it to also prevent the development of inflammatory bowel disease,” Dr. Faye said.

Although this study adds to the evidence implicating antibiotics and expands the concept to an older population, “we really don’t have a great handle on what all of the environmental and other factors are,” he said.

Some researchers point to smoking and diet, among other factors, but the interplay remains unknown, Dr. Faye added.

The study is important because the incidence of IBD is increasing within the older population, “and this is one of the first studies to look at it,” he said.

Dr. Faye and colleagues plan to start a new study to evaluate other environmental factors.

“Hopefully, we’ll have more within the next few years to report,” he said.
 

Shedding more light on older-onset IBD worldwide

“It’s a well-done study,” Aline Charabaty, MD, said in a comment. “We are seeing that there’s an increase of incidence of IBD in the entire population, but even more so in the elderly.”

IBD is likely caused by a combination of factors, including genetics, environmental influences, and dysfunction of the gut immune system, agreed Dr. Charabaty, who is an assistant clinical professor in the division of gastroenterology at Johns Hopkins University, Baltimore.

The research “goes along with other studies that we’ve done in the pediatric and adult populations that show antibiotics exposure increases the risk of developing inflammatory bowel disease,” she said.

For a broader perspective of the study’s findings, Dr. Faye was asked during the media briefing if the results of this Danish registry study would be generalizable to the U.S. population.

“The simplest answer is we’ll need to redo this study within the U.S. to make absolutely sure,” Dr. Faye said. She noted that prior studies in the United States and elsewhere have found a risk associated with antibiotics, although again these studies focused on younger patients.

Dr. Charabaty was more certain that the findings were meaningful outside of Denmark.

“I definitely think this will apply to our U.S. population,” added Dr. Charabaty, who is also the clinical director of the IBD Center at Johns Hopkins–Sibley Memorial Hospital, Washington. “We have very similar practices in terms of how we approach antibiotic use.

“This could be one of the risk factors that’s promoting an increase in IBD everywhere,” she added.

The study was conducted in partnership with the Danish National Center of Excellence PREDICT Program. Dr. Faye and Dr. Charabaty did not report any conflicts of interest related to this study.

A version of this article first appeared on Medscape.com.

Something different appears to be going on when an older adult develops inflammatory bowel disease (IBD), and now researchers offer more evidence that antibiotics could be playing a role.

Most studies to date have assessed a link between antibiotics and IBD in younger patients, lead researcher Adam S. Faye, MD, said during a media briefing that previewed select research for the annual Digestive Disease Week® (DDW).

The impact of antibiotic use on the incidence of IBD in older adults is really unknown, he added.

In contrast to younger people with IBD, who tend to have a strong family history or genetic predisposition to developing Crohn’s disease or ulcerative colitis, the cause is likely different in older populations.

“There’s clearly something in the environment that’s driving this new older-onset IBD,” said Dr. Faye, who is an assistant professor of medicine and population health at New York University.
 

Antibiotics as a contributing link

Dr. Faye and colleagues took a closer look at antibiotics as contributing to this link. They studied 2.3 million patient records in Denmark’s national medical registry from 2000 to 2018. They identified people aged 60 years and older who were newly diagnosed with IBD, and they then assessed the number, frequency, and timing of any antibiotic prescriptions.

They found that IBD was 27% more likely in this age group if the patients had received any antibiotic prescription.

They also found that the chance of developing IBD was higher as the number of antibiotic prescriptions increased. For example, IBD was 55% more likely if a person had received two prescriptions, and it was 96% more likely with four prescriptions. The risk really jumped with five or more antibiotic prescriptions – a person with this many prescriptions was more than 2.3 times (236%) more likely to be diagnosed with IBD than those who had not been prescribed antibiotics in the prior 5 years.

Not all antibiotics were equal, however. For example, the investigators found no link with nitrofurantoin, an antibiotic commonly prescribed for urinary tract infections. In contrast, all other antibiotic agents that were evaluated, and especially fluoroquinolones, nitroimidazoles, and macrolides, were associated with IBD.

Timing made some difference.

“The risk was highest if antibiotics were prescribed within the 1- to 2-year period before diagnosis, and it declined as you go farther out. But the risks persist,” Dr. Faye said. He noted that they even found that risk was elevated 10 years out.

The investigators also considered whether the antibiotic agent or infection was behind the association.

Dr. Faye cited previous research, again in younger people with IBD, that revealed that “infections plus antibiotics substantially increase the odds or risk of developing IBD more than the infection alone.

“So there really does seem to be something that the antibiotics are doing here,” Dr. Faye said.

A leading theory is that antibiotics disrupt the gut microbiota and increase the risk for developing IBD. “But, obviously, it’s quite complicated,” he said.
 

Clinical implications

The findings suggest that older people who may have IBD should be screened for prior antibiotic use, Dr. Faye said.

“This is a result that really has important implications for diagnosing older adults with new gastrointestinal symptoms,” he said. “Inflammatory bowel disease often can be overlooked in older adults because there’s a lot of different diagnoses you’re thinking of.”

IBD “should be considered, especially if you have a patient who’s reporting multiple courses of antibiotics in the last few years,” he added.

The results suggest another reason that antimicrobial stewardship programs should promote judicial use of these agents beyond concerns about resistance.

“We think of antibiotic stewardship to prevent the development of multidrug-resistant organisms, but we should be thinking about it to also prevent the development of inflammatory bowel disease,” Dr. Faye said.

Although this study adds to the evidence implicating antibiotics and expands the concept to an older population, “we really don’t have a great handle on what all of the environmental and other factors are,” he said.

Some researchers point to smoking and diet, among other factors, but the interplay remains unknown, Dr. Faye added.

The study is important because the incidence of IBD is increasing within the older population, “and this is one of the first studies to look at it,” he said.

Dr. Faye and colleagues plan to start a new study to evaluate other environmental factors.

“Hopefully, we’ll have more within the next few years to report,” he said.
 

Shedding more light on older-onset IBD worldwide

“It’s a well-done study,” Aline Charabaty, MD, said in a comment. “We are seeing that there’s an increase of incidence of IBD in the entire population, but even more so in the elderly.”

IBD is likely caused by a combination of factors, including genetics, environmental influences, and dysfunction of the gut immune system, agreed Dr. Charabaty, who is an assistant clinical professor in the division of gastroenterology at Johns Hopkins University, Baltimore.

The research “goes along with other studies that we’ve done in the pediatric and adult populations that show antibiotics exposure increases the risk of developing inflammatory bowel disease,” she said.

For a broader perspective of the study’s findings, Dr. Faye was asked during the media briefing if the results of this Danish registry study would be generalizable to the U.S. population.

“The simplest answer is we’ll need to redo this study within the U.S. to make absolutely sure,” Dr. Faye said. She noted that prior studies in the United States and elsewhere have found a risk associated with antibiotics, although again these studies focused on younger patients.

Dr. Charabaty was more certain that the findings were meaningful outside of Denmark.

“I definitely think this will apply to our U.S. population,” added Dr. Charabaty, who is also the clinical director of the IBD Center at Johns Hopkins–Sibley Memorial Hospital, Washington. “We have very similar practices in terms of how we approach antibiotic use.

“This could be one of the risk factors that’s promoting an increase in IBD everywhere,” she added.

The study was conducted in partnership with the Danish National Center of Excellence PREDICT Program. Dr. Faye and Dr. Charabaty did not report any conflicts of interest related to this study.

A version of this article first appeared on Medscape.com.

Something different appears to be going on when an older adult develops inflammatory bowel disease (IBD), and now researchers offer more evidence that antibiotics could be playing a role.

Most studies to date have assessed a link between antibiotics and IBD in younger patients, lead researcher Adam S. Faye, MD, said during a media briefing that previewed select research for the annual Digestive Disease Week® (DDW).

The impact of antibiotic use on the incidence of IBD in older adults is really unknown, he added.

In contrast to younger people with IBD, who tend to have a strong family history or genetic predisposition to developing Crohn’s disease or ulcerative colitis, the cause is likely different in older populations.

“There’s clearly something in the environment that’s driving this new older-onset IBD,” said Dr. Faye, who is an assistant professor of medicine and population health at New York University.
 

Antibiotics as a contributing link

Dr. Faye and colleagues took a closer look at antibiotics as contributing to this link. They studied 2.3 million patient records in Denmark’s national medical registry from 2000 to 2018. They identified people aged 60 years and older who were newly diagnosed with IBD, and they then assessed the number, frequency, and timing of any antibiotic prescriptions.

They found that IBD was 27% more likely in this age group if the patients had received any antibiotic prescription.

They also found that the chance of developing IBD was higher as the number of antibiotic prescriptions increased. For example, IBD was 55% more likely if a person had received two prescriptions, and it was 96% more likely with four prescriptions. The risk really jumped with five or more antibiotic prescriptions – a person with this many prescriptions was more than 2.3 times (236%) more likely to be diagnosed with IBD than those who had not been prescribed antibiotics in the prior 5 years.

Not all antibiotics were equal, however. For example, the investigators found no link with nitrofurantoin, an antibiotic commonly prescribed for urinary tract infections. In contrast, all other antibiotic agents that were evaluated, and especially fluoroquinolones, nitroimidazoles, and macrolides, were associated with IBD.

Timing made some difference.

“The risk was highest if antibiotics were prescribed within the 1- to 2-year period before diagnosis, and it declined as you go farther out. But the risks persist,” Dr. Faye said. He noted that they even found that risk was elevated 10 years out.

The investigators also considered whether the antibiotic agent or infection was behind the association.

Dr. Faye cited previous research, again in younger people with IBD, that revealed that “infections plus antibiotics substantially increase the odds or risk of developing IBD more than the infection alone.

“So there really does seem to be something that the antibiotics are doing here,” Dr. Faye said.

A leading theory is that antibiotics disrupt the gut microbiota and increase the risk for developing IBD. “But, obviously, it’s quite complicated,” he said.
 

Clinical implications

The findings suggest that older people who may have IBD should be screened for prior antibiotic use, Dr. Faye said.

“This is a result that really has important implications for diagnosing older adults with new gastrointestinal symptoms,” he said. “Inflammatory bowel disease often can be overlooked in older adults because there’s a lot of different diagnoses you’re thinking of.”

IBD “should be considered, especially if you have a patient who’s reporting multiple courses of antibiotics in the last few years,” he added.

The results suggest another reason that antimicrobial stewardship programs should promote judicial use of these agents beyond concerns about resistance.

“We think of antibiotic stewardship to prevent the development of multidrug-resistant organisms, but we should be thinking about it to also prevent the development of inflammatory bowel disease,” Dr. Faye said.

Although this study adds to the evidence implicating antibiotics and expands the concept to an older population, “we really don’t have a great handle on what all of the environmental and other factors are,” he said.

Some researchers point to smoking and diet, among other factors, but the interplay remains unknown, Dr. Faye added.

The study is important because the incidence of IBD is increasing within the older population, “and this is one of the first studies to look at it,” he said.

Dr. Faye and colleagues plan to start a new study to evaluate other environmental factors.

“Hopefully, we’ll have more within the next few years to report,” he said.
 

Shedding more light on older-onset IBD worldwide

“It’s a well-done study,” Aline Charabaty, MD, said in a comment. “We are seeing that there’s an increase of incidence of IBD in the entire population, but even more so in the elderly.”

IBD is likely caused by a combination of factors, including genetics, environmental influences, and dysfunction of the gut immune system, agreed Dr. Charabaty, who is an assistant clinical professor in the division of gastroenterology at Johns Hopkins University, Baltimore.

The research “goes along with other studies that we’ve done in the pediatric and adult populations that show antibiotics exposure increases the risk of developing inflammatory bowel disease,” she said.

For a broader perspective of the study’s findings, Dr. Faye was asked during the media briefing if the results of this Danish registry study would be generalizable to the U.S. population.

“The simplest answer is we’ll need to redo this study within the U.S. to make absolutely sure,” Dr. Faye said. She noted that prior studies in the United States and elsewhere have found a risk associated with antibiotics, although again these studies focused on younger patients.

Dr. Charabaty was more certain that the findings were meaningful outside of Denmark.

“I definitely think this will apply to our U.S. population,” added Dr. Charabaty, who is also the clinical director of the IBD Center at Johns Hopkins–Sibley Memorial Hospital, Washington. “We have very similar practices in terms of how we approach antibiotic use.

“This could be one of the risk factors that’s promoting an increase in IBD everywhere,” she added.

The study was conducted in partnership with the Danish National Center of Excellence PREDICT Program. Dr. Faye and Dr. Charabaty did not report any conflicts of interest related to this study.

A version of this article first appeared on Medscape.com.

A new study questions the conventional wisdom of using steroids and anti-inflammatory drugs like ibuprofen to treat low back pain if exercise and other nondrug therapies don’t work right away.

Those medications offer relief from acute pain but may actually increase a person’s chances of developing chronic pain, said the investigators for a study published in Science Translational Medicine. The study results indicate that inflammation is a normal part of recovering from a painful injury and that inhibiting inflammation may result in more-difficult-to-treat chronic pain.

“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs,” Jeffrey Mogil, PhD, a psychology professor at McGill University, Montreal, said in a school news release. “But we found that this short-term fix could lead to longer-term problems.”

Researchers looked at low back pain because it’s so common, with 25% of U.S. adults saying they had low back pain in the previous 3 months, according to the Centers for Disease Control and Prevention. Acute back pain is defined as lasting less than 4 weeks while chronic back pain lasts more than 12 weeks.

By examining blood samples, researchers discovered that people whose low back pain was resolved had high inflammation driven by neutrophils, a type of white blood cell that helps the body fight infection, the study said.

“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” Dr. Mogil said in the news release.

The research team found that blocking neutrophils in mice prolonged pain in the animals up to 10-fold. Pain also was prolonged when the mice were given anti-inflammatory drugs and steroids, the news release says.

McGill University said other studies support the findings. The school cited an analysis of 500,000 people in the United Kingdom. The analysis found that those taking anti-inflammatory drugs for pain were more likely to have pain 2 to 10 years later.

While saying the study suggests it’s time to reconsider how pain is treated, the researchers called for clinical trials on humans, not just observations of people with low back pain.

Experts warned about accepting the results without further investigation.

“It’s intriguing but requires further study,” Steven J. Atlas, MD, director of the Primary Care Research & Quality Improvement Network at Massachusetts General Hospital, Boston, told The New York Times.

A version of this article first appeared on WebMD.com.

A new study questions the conventional wisdom of using steroids and anti-inflammatory drugs like ibuprofen to treat low back pain if exercise and other nondrug therapies don’t work right away.

Those medications offer relief from acute pain but may actually increase a person’s chances of developing chronic pain, said the investigators for a study published in Science Translational Medicine. The study results indicate that inflammation is a normal part of recovering from a painful injury and that inhibiting inflammation may result in more-difficult-to-treat chronic pain.

“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs,” Jeffrey Mogil, PhD, a psychology professor at McGill University, Montreal, said in a school news release. “But we found that this short-term fix could lead to longer-term problems.”

Researchers looked at low back pain because it’s so common, with 25% of U.S. adults saying they had low back pain in the previous 3 months, according to the Centers for Disease Control and Prevention. Acute back pain is defined as lasting less than 4 weeks while chronic back pain lasts more than 12 weeks.

By examining blood samples, researchers discovered that people whose low back pain was resolved had high inflammation driven by neutrophils, a type of white blood cell that helps the body fight infection, the study said.

“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” Dr. Mogil said in the news release.

The research team found that blocking neutrophils in mice prolonged pain in the animals up to 10-fold. Pain also was prolonged when the mice were given anti-inflammatory drugs and steroids, the news release says.

McGill University said other studies support the findings. The school cited an analysis of 500,000 people in the United Kingdom. The analysis found that those taking anti-inflammatory drugs for pain were more likely to have pain 2 to 10 years later.

While saying the study suggests it’s time to reconsider how pain is treated, the researchers called for clinical trials on humans, not just observations of people with low back pain.

Experts warned about accepting the results without further investigation.

“It’s intriguing but requires further study,” Steven J. Atlas, MD, director of the Primary Care Research & Quality Improvement Network at Massachusetts General Hospital, Boston, told The New York Times.

A version of this article first appeared on WebMD.com.

A new study questions the conventional wisdom of using steroids and anti-inflammatory drugs like ibuprofen to treat low back pain if exercise and other nondrug therapies don’t work right away.

Those medications offer relief from acute pain but may actually increase a person’s chances of developing chronic pain, said the investigators for a study published in Science Translational Medicine. The study results indicate that inflammation is a normal part of recovering from a painful injury and that inhibiting inflammation may result in more-difficult-to-treat chronic pain.

“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs,” Jeffrey Mogil, PhD, a psychology professor at McGill University, Montreal, said in a school news release. “But we found that this short-term fix could lead to longer-term problems.”

Researchers looked at low back pain because it’s so common, with 25% of U.S. adults saying they had low back pain in the previous 3 months, according to the Centers for Disease Control and Prevention. Acute back pain is defined as lasting less than 4 weeks while chronic back pain lasts more than 12 weeks.

By examining blood samples, researchers discovered that people whose low back pain was resolved had high inflammation driven by neutrophils, a type of white blood cell that helps the body fight infection, the study said.

“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” Dr. Mogil said in the news release.

The research team found that blocking neutrophils in mice prolonged pain in the animals up to 10-fold. Pain also was prolonged when the mice were given anti-inflammatory drugs and steroids, the news release says.

McGill University said other studies support the findings. The school cited an analysis of 500,000 people in the United Kingdom. The analysis found that those taking anti-inflammatory drugs for pain were more likely to have pain 2 to 10 years later.

While saying the study suggests it’s time to reconsider how pain is treated, the researchers called for clinical trials on humans, not just observations of people with low back pain.

Experts warned about accepting the results without further investigation.

“It’s intriguing but requires further study,” Steven J. Atlas, MD, director of the Primary Care Research & Quality Improvement Network at Massachusetts General Hospital, Boston, told The New York Times.

A version of this article first appeared on WebMD.com.

Patients who mix a diuretic and renin-angiotensin system (RAS) inhibitor with a nonsteroidal anti-inflammatory drug (NSAID) could face a higher risk of developing acute kidney injury (AKI), a new analysis confirms.

The study also looked at risk factors associated with the effect of triple therapy with these agents, which has been called “triple whammy” AKI.

“It’s not that everyone who happens to take this combination of drugs is going to have problems,” Anita Layton, PhD, University of Waterloo, Ontario, said in a statement. “But the research shows it’s enough of a problem that you should exercise caution.”

The study was published online in Mathematical Biosciences.   

In an earlier study, triple therapy with a diuretic, RAS inhibitor, and NSAID was associated with a 31% increased risk for AKI, relative to diuretic and RAS inhibitor therapy only.  

However, the factors that predispose some patients to develop “triple whammy” AKI are unclear.

To better understand the mechanism by which triple therapy increases risk for AKI, Dr. Layton and colleagues used computational models to gauge interactions between concurrent use of a diuretic, a RAS inhibitor, and an NSAID.

They identified dehydration and high sensitivity to drug treatment as key contributing factors to the development of triple whammy AKI.

Their model simulations suggested that low water intake, the myogenic response (that is, the reflex response of arteries and arterioles to changes in blood pressure to maintain consistent blood flow), and drug sensitivity “may predispose patients with hypertension to develop triple whammy-induced AKI,” they wrote.

“We hypothesize that individuals with an impaired myogenic response may be particularly susceptible to triple whammy AKI. Additionally, increased drug sensitivity or low water intake can predispose patients to triple whammy AKI,” they added.

In the absence of additional risk factors, there was no indication of an elevated risk for AKI when an angiotensin-converting enzyme (ACE) inhibitor and NSAID are combined, the study team said. 

In contrast, when an ACE inhibitor, diuretic, and NSAID are combined, critical blood pressure and glomerular filtration rate (GFR) regulatory mechanisms are simultaneously interrupted, they reported.

“Perhaps not unexpectedly, model simulations indicate that triple treatment reduces GFR more than single or double treatments in all individuals. However, under triple treatment, urine volume and GFR have not been predicted to fall sufficiently far to indicate AKI,” they wrote. “This result is consistent with the fact that only a fraction of individuals develop AKI following triple treatment.”

They expect, therefore, that hypertensive patients who are otherwise healthy will be able to withstand triple treatment, in the absence of these aggravating factors, the researchers concluded.

Nonetheless, it’s wise to “always be careful when mixing medications,” Dr. Layton told this news organization.

She noted that “triple whammy AKI is known among kidney researchers and nephrologists. To what extent nonspecialists are aware, it isn’t clear.

“More importantly,” Dr. Layton said, “NSAIDs can be obtained over the counter, and triple whammy AKI isn’t common knowledge outside of the medical community.”

This research was supported by the Canada 150 Research Chair program and by the Natural Sciences and Engineering Research Council of Canada. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

Patients who mix a diuretic and renin-angiotensin system (RAS) inhibitor with a nonsteroidal anti-inflammatory drug (NSAID) could face a higher risk of developing acute kidney injury (AKI), a new analysis confirms.

The study also looked at risk factors associated with the effect of triple therapy with these agents, which has been called “triple whammy” AKI.

“It’s not that everyone who happens to take this combination of drugs is going to have problems,” Anita Layton, PhD, University of Waterloo, Ontario, said in a statement. “But the research shows it’s enough of a problem that you should exercise caution.”

The study was published online in Mathematical Biosciences.   

In an earlier study, triple therapy with a diuretic, RAS inhibitor, and NSAID was associated with a 31% increased risk for AKI, relative to diuretic and RAS inhibitor therapy only.  

However, the factors that predispose some patients to develop “triple whammy” AKI are unclear.

To better understand the mechanism by which triple therapy increases risk for AKI, Dr. Layton and colleagues used computational models to gauge interactions between concurrent use of a diuretic, a RAS inhibitor, and an NSAID.

They identified dehydration and high sensitivity to drug treatment as key contributing factors to the development of triple whammy AKI.

Their model simulations suggested that low water intake, the myogenic response (that is, the reflex response of arteries and arterioles to changes in blood pressure to maintain consistent blood flow), and drug sensitivity “may predispose patients with hypertension to develop triple whammy-induced AKI,” they wrote.

“We hypothesize that individuals with an impaired myogenic response may be particularly susceptible to triple whammy AKI. Additionally, increased drug sensitivity or low water intake can predispose patients to triple whammy AKI,” they added.

In the absence of additional risk factors, there was no indication of an elevated risk for AKI when an angiotensin-converting enzyme (ACE) inhibitor and NSAID are combined, the study team said. 

In contrast, when an ACE inhibitor, diuretic, and NSAID are combined, critical blood pressure and glomerular filtration rate (GFR) regulatory mechanisms are simultaneously interrupted, they reported.

“Perhaps not unexpectedly, model simulations indicate that triple treatment reduces GFR more than single or double treatments in all individuals. However, under triple treatment, urine volume and GFR have not been predicted to fall sufficiently far to indicate AKI,” they wrote. “This result is consistent with the fact that only a fraction of individuals develop AKI following triple treatment.”

They expect, therefore, that hypertensive patients who are otherwise healthy will be able to withstand triple treatment, in the absence of these aggravating factors, the researchers concluded.

Nonetheless, it’s wise to “always be careful when mixing medications,” Dr. Layton told this news organization.

She noted that “triple whammy AKI is known among kidney researchers and nephrologists. To what extent nonspecialists are aware, it isn’t clear.

“More importantly,” Dr. Layton said, “NSAIDs can be obtained over the counter, and triple whammy AKI isn’t common knowledge outside of the medical community.”

This research was supported by the Canada 150 Research Chair program and by the Natural Sciences and Engineering Research Council of Canada. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

Patients who mix a diuretic and renin-angiotensin system (RAS) inhibitor with a nonsteroidal anti-inflammatory drug (NSAID) could face a higher risk of developing acute kidney injury (AKI), a new analysis confirms.

The study also looked at risk factors associated with the effect of triple therapy with these agents, which has been called “triple whammy” AKI.

“It’s not that everyone who happens to take this combination of drugs is going to have problems,” Anita Layton, PhD, University of Waterloo, Ontario, said in a statement. “But the research shows it’s enough of a problem that you should exercise caution.”

The study was published online in Mathematical Biosciences.   

In an earlier study, triple therapy with a diuretic, RAS inhibitor, and NSAID was associated with a 31% increased risk for AKI, relative to diuretic and RAS inhibitor therapy only.  

However, the factors that predispose some patients to develop “triple whammy” AKI are unclear.

To better understand the mechanism by which triple therapy increases risk for AKI, Dr. Layton and colleagues used computational models to gauge interactions between concurrent use of a diuretic, a RAS inhibitor, and an NSAID.

They identified dehydration and high sensitivity to drug treatment as key contributing factors to the development of triple whammy AKI.

Their model simulations suggested that low water intake, the myogenic response (that is, the reflex response of arteries and arterioles to changes in blood pressure to maintain consistent blood flow), and drug sensitivity “may predispose patients with hypertension to develop triple whammy-induced AKI,” they wrote.

“We hypothesize that individuals with an impaired myogenic response may be particularly susceptible to triple whammy AKI. Additionally, increased drug sensitivity or low water intake can predispose patients to triple whammy AKI,” they added.

In the absence of additional risk factors, there was no indication of an elevated risk for AKI when an angiotensin-converting enzyme (ACE) inhibitor and NSAID are combined, the study team said. 

In contrast, when an ACE inhibitor, diuretic, and NSAID are combined, critical blood pressure and glomerular filtration rate (GFR) regulatory mechanisms are simultaneously interrupted, they reported.

“Perhaps not unexpectedly, model simulations indicate that triple treatment reduces GFR more than single or double treatments in all individuals. However, under triple treatment, urine volume and GFR have not been predicted to fall sufficiently far to indicate AKI,” they wrote. “This result is consistent with the fact that only a fraction of individuals develop AKI following triple treatment.”

They expect, therefore, that hypertensive patients who are otherwise healthy will be able to withstand triple treatment, in the absence of these aggravating factors, the researchers concluded.

Nonetheless, it’s wise to “always be careful when mixing medications,” Dr. Layton told this news organization.

She noted that “triple whammy AKI is known among kidney researchers and nephrologists. To what extent nonspecialists are aware, it isn’t clear.

“More importantly,” Dr. Layton said, “NSAIDs can be obtained over the counter, and triple whammy AKI isn’t common knowledge outside of the medical community.”

This research was supported by the Canada 150 Research Chair program and by the Natural Sciences and Engineering Research Council of Canada. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

A version of this article first appeared on Medscape.com.

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

A version of this article first appeared on Medscape.com.

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

A version of this article first appeared on Medscape.com.