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Fluoroquinolones can cause fatal hypoglycemia, FDA warns
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Antiamyloid antibody slowed Alzheimer’s progression while clearing brain amyloid
An antibody that targets clumps of soluble amyloid-beta before they aggregate into plaques has passed its phase 2 challenge, posting statistically significant results on a combined measure of cognition and function while decreasing amyloid deposition in the brain.
Full data won’t be released until a late-breaker session on July 25 at the Alzheimer’s Association International Conference in Chicago, so it’s still impossible to fully dissect the 18-month, dose exploration study. But according to codevelopers Eisai and Biogen, the significant clinical improvements accrued to the highest dose tested (10 mg/kg intravenously, twice a month) and were evident as early as 6 months. Amyloid cleared in a dose-dependent manner as well.
Although there is no available information on P values or effect sizes, the trial design designated success as at least a 25% reduction in the rate of decline over 1 year, relative to placebo.
In an interview, Lynn Kramer, MD, of Eisai declined to give further details. “I will say, however, that we believe these changes are clinically meaningful,” said Dr. Kramer, chief medical officer of the company’s neurology division.
These results make BAN2401 the first antiamyloid antibody to score significant results in both cognition and amyloid brain imaging a clinical trial, and warrant tempered optimism, according to Keith Fargo, PhD, director of scientific programs for the Alzheimer’s Association.
“We can’t know whether this is a breakthrough until we get past phase 3,” Dr. Fargo said in an interview. “In drug development, you’re never done until you’re done.”
Richard J. Caselli, MD, agreed with the tempered enthusiasm.
“This is very encouraging, but we await the full data and ultimately the phase 3 trial,” said Dr. Caselli, professor of neurology the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. “I would also say that 25% slowing in disease progression is nice and unprecedented but clinically not exactly earth shattering. If it holds up in phase 3, the cost-benefit will need to be carefully weighed.”
Nevertheless, the publicly available data seem to lay a firm foundation for future studies, he said. “It’s unusual to see this kind of clarity in both clinical and biomarker results in a phase 2. There’s a history of large drug companies taking things from phase 2 to phase 3 on data that have been less clear than this, teasing out results from subgroups or using biomarker but not clinical data to make a decision on moving forward.”
The BAN2401 research team staked this commitment in the 2016 paper describing the study methodology. “They wanted to have clear evidence on both biomarker and clinical efficacy to allow them to make a decision [to move into phase 3],” Dr. Fargo said. “I don’t know if they are or not, but I’d be surprised if they don’t, and I think they would be on solid footing.”
BAN2401 selectively binds to amyloid-beta protofibrils – large AB oligomers that are still soluble – and targets them for clearance. It was originally developed by Swedish biopharma company BioArctic; Eisai acquired the molecule in 2007 and entered the Biogen deal in 2014.
The study randomized 856 patients with mild cognitive impairment or early Alzheimer’s dementia to six treatment arms: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. All patients had PET-confirmed amyloid brain pathology, a key baseline requirement; only one other antiamyloid agent (Biogen’s antiamyloid antibody aducanumab) has completed a phase 2 study in a purely amyloid-positive cohort. Before PET imaging, patients with non-Alzheimer’s pathology comprised up to 30% of Alzheimer’s drug studies, which researchers say confounded results and likely contributed to the long string of antiamyloid failures.
The coprimary endpoints were reduction of brain amyloid on PET scan and slowing of progression as measured by the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai. ADCOMS combines measures from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), Clinical Dementia Rating Sum of Boxes (CDR-sb), and the Mini-Mental State Examination (MMSE). In devising ADCOMS, researchers chose individual components of each tool that are most likely to change in very-early-stage disease. The scale was validated retrospectively in 1,160 patients who were included in four datasets. This is the first time it’s been used in an Alzheimer’s study.
The BAN2401 trial employed a Bayesian adaptive randomization, a computer-driven algorithm designed to drive patients to the two most effective doses. Often seen in trials of faster-progressing diseases, like cancer, it is unusual in Alzheimer’s studies, Dr. Fargo said.
“I would say it’s unorthodox, but it doesn’t give me heartburn. It’s an adaptive trial design that’s been considered hard to do in the AD field, because the changes between placebo and treatment groups tend to be very slow. In studies that have a very clear biomarker endpoint, like tumor size for example, that everyone can agree on, you can quickly see which treatment arm is most effective. In general, we haven’t been able to do this in AD because the signal changes so slowly.”
The BAN2401 algorithm assessed outcomes monthly, and reallocated incoming subjects according to the most recent efficacy data. But the 12-month primary endpoint assessment, a widely publicized failure, was “unfortunate,” Dr. Fargo said.
“This study had a built-in 12-month endpoint, at which time the sponsor could declare either futility or early success, and stop it for either one.” If neither was achieved, the study was to continue for 18 months and reassess outcomes. This was the situation Eisai and Biogen encountered in December when they announced that BAN2401 had failed to achieve its clinical and imaging endpoints but that the study would continue as planned. That news generated a large amount of negative press for the companies – which saw stock prices plunge – and contributed to media and consumer confusion about the trial design’s validity, Dr. Fargo said.
The 18-month data released on July 5 also included some information on adverse events. Amyloid-related imaging abnormalities, both edematous and hemorrhagic (ARIA-E and ARIA-H) occurred in an undisclosed number of patients. Dr. Kramer said ARIA occurred in “not more than 10% in any of the treatment arms” and in less than 15% of patients who carried an apolipoprotein E e4 allele. Only a portion of these patients were included in the final analysis, and this may have influenced the results somewhat negatively, Dr. Kramer said. In the first years of the study, before ARIA was understood to be largely subclinical and self-resolving, any patient who developed it was dropped.
“We initially dropped every patient who had ARIA, and this is one of the issues that actually make the observed effect [of BAN2401] probably a little bit conservative. Patients with ARIA are typically responding to amyloid removal, and they could be expected to do better.”
An antibody that targets clumps of soluble amyloid-beta before they aggregate into plaques has passed its phase 2 challenge, posting statistically significant results on a combined measure of cognition and function while decreasing amyloid deposition in the brain.
Full data won’t be released until a late-breaker session on July 25 at the Alzheimer’s Association International Conference in Chicago, so it’s still impossible to fully dissect the 18-month, dose exploration study. But according to codevelopers Eisai and Biogen, the significant clinical improvements accrued to the highest dose tested (10 mg/kg intravenously, twice a month) and were evident as early as 6 months. Amyloid cleared in a dose-dependent manner as well.
Although there is no available information on P values or effect sizes, the trial design designated success as at least a 25% reduction in the rate of decline over 1 year, relative to placebo.
In an interview, Lynn Kramer, MD, of Eisai declined to give further details. “I will say, however, that we believe these changes are clinically meaningful,” said Dr. Kramer, chief medical officer of the company’s neurology division.
These results make BAN2401 the first antiamyloid antibody to score significant results in both cognition and amyloid brain imaging a clinical trial, and warrant tempered optimism, according to Keith Fargo, PhD, director of scientific programs for the Alzheimer’s Association.
“We can’t know whether this is a breakthrough until we get past phase 3,” Dr. Fargo said in an interview. “In drug development, you’re never done until you’re done.”
Richard J. Caselli, MD, agreed with the tempered enthusiasm.
“This is very encouraging, but we await the full data and ultimately the phase 3 trial,” said Dr. Caselli, professor of neurology the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. “I would also say that 25% slowing in disease progression is nice and unprecedented but clinically not exactly earth shattering. If it holds up in phase 3, the cost-benefit will need to be carefully weighed.”
Nevertheless, the publicly available data seem to lay a firm foundation for future studies, he said. “It’s unusual to see this kind of clarity in both clinical and biomarker results in a phase 2. There’s a history of large drug companies taking things from phase 2 to phase 3 on data that have been less clear than this, teasing out results from subgroups or using biomarker but not clinical data to make a decision on moving forward.”
The BAN2401 research team staked this commitment in the 2016 paper describing the study methodology. “They wanted to have clear evidence on both biomarker and clinical efficacy to allow them to make a decision [to move into phase 3],” Dr. Fargo said. “I don’t know if they are or not, but I’d be surprised if they don’t, and I think they would be on solid footing.”
BAN2401 selectively binds to amyloid-beta protofibrils – large AB oligomers that are still soluble – and targets them for clearance. It was originally developed by Swedish biopharma company BioArctic; Eisai acquired the molecule in 2007 and entered the Biogen deal in 2014.
The study randomized 856 patients with mild cognitive impairment or early Alzheimer’s dementia to six treatment arms: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. All patients had PET-confirmed amyloid brain pathology, a key baseline requirement; only one other antiamyloid agent (Biogen’s antiamyloid antibody aducanumab) has completed a phase 2 study in a purely amyloid-positive cohort. Before PET imaging, patients with non-Alzheimer’s pathology comprised up to 30% of Alzheimer’s drug studies, which researchers say confounded results and likely contributed to the long string of antiamyloid failures.
The coprimary endpoints were reduction of brain amyloid on PET scan and slowing of progression as measured by the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai. ADCOMS combines measures from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), Clinical Dementia Rating Sum of Boxes (CDR-sb), and the Mini-Mental State Examination (MMSE). In devising ADCOMS, researchers chose individual components of each tool that are most likely to change in very-early-stage disease. The scale was validated retrospectively in 1,160 patients who were included in four datasets. This is the first time it’s been used in an Alzheimer’s study.
The BAN2401 trial employed a Bayesian adaptive randomization, a computer-driven algorithm designed to drive patients to the two most effective doses. Often seen in trials of faster-progressing diseases, like cancer, it is unusual in Alzheimer’s studies, Dr. Fargo said.
“I would say it’s unorthodox, but it doesn’t give me heartburn. It’s an adaptive trial design that’s been considered hard to do in the AD field, because the changes between placebo and treatment groups tend to be very slow. In studies that have a very clear biomarker endpoint, like tumor size for example, that everyone can agree on, you can quickly see which treatment arm is most effective. In general, we haven’t been able to do this in AD because the signal changes so slowly.”
The BAN2401 algorithm assessed outcomes monthly, and reallocated incoming subjects according to the most recent efficacy data. But the 12-month primary endpoint assessment, a widely publicized failure, was “unfortunate,” Dr. Fargo said.
“This study had a built-in 12-month endpoint, at which time the sponsor could declare either futility or early success, and stop it for either one.” If neither was achieved, the study was to continue for 18 months and reassess outcomes. This was the situation Eisai and Biogen encountered in December when they announced that BAN2401 had failed to achieve its clinical and imaging endpoints but that the study would continue as planned. That news generated a large amount of negative press for the companies – which saw stock prices plunge – and contributed to media and consumer confusion about the trial design’s validity, Dr. Fargo said.
The 18-month data released on July 5 also included some information on adverse events. Amyloid-related imaging abnormalities, both edematous and hemorrhagic (ARIA-E and ARIA-H) occurred in an undisclosed number of patients. Dr. Kramer said ARIA occurred in “not more than 10% in any of the treatment arms” and in less than 15% of patients who carried an apolipoprotein E e4 allele. Only a portion of these patients were included in the final analysis, and this may have influenced the results somewhat negatively, Dr. Kramer said. In the first years of the study, before ARIA was understood to be largely subclinical and self-resolving, any patient who developed it was dropped.
“We initially dropped every patient who had ARIA, and this is one of the issues that actually make the observed effect [of BAN2401] probably a little bit conservative. Patients with ARIA are typically responding to amyloid removal, and they could be expected to do better.”
An antibody that targets clumps of soluble amyloid-beta before they aggregate into plaques has passed its phase 2 challenge, posting statistically significant results on a combined measure of cognition and function while decreasing amyloid deposition in the brain.
Full data won’t be released until a late-breaker session on July 25 at the Alzheimer’s Association International Conference in Chicago, so it’s still impossible to fully dissect the 18-month, dose exploration study. But according to codevelopers Eisai and Biogen, the significant clinical improvements accrued to the highest dose tested (10 mg/kg intravenously, twice a month) and were evident as early as 6 months. Amyloid cleared in a dose-dependent manner as well.
Although there is no available information on P values or effect sizes, the trial design designated success as at least a 25% reduction in the rate of decline over 1 year, relative to placebo.
In an interview, Lynn Kramer, MD, of Eisai declined to give further details. “I will say, however, that we believe these changes are clinically meaningful,” said Dr. Kramer, chief medical officer of the company’s neurology division.
These results make BAN2401 the first antiamyloid antibody to score significant results in both cognition and amyloid brain imaging a clinical trial, and warrant tempered optimism, according to Keith Fargo, PhD, director of scientific programs for the Alzheimer’s Association.
“We can’t know whether this is a breakthrough until we get past phase 3,” Dr. Fargo said in an interview. “In drug development, you’re never done until you’re done.”
Richard J. Caselli, MD, agreed with the tempered enthusiasm.
“This is very encouraging, but we await the full data and ultimately the phase 3 trial,” said Dr. Caselli, professor of neurology the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. “I would also say that 25% slowing in disease progression is nice and unprecedented but clinically not exactly earth shattering. If it holds up in phase 3, the cost-benefit will need to be carefully weighed.”
Nevertheless, the publicly available data seem to lay a firm foundation for future studies, he said. “It’s unusual to see this kind of clarity in both clinical and biomarker results in a phase 2. There’s a history of large drug companies taking things from phase 2 to phase 3 on data that have been less clear than this, teasing out results from subgroups or using biomarker but not clinical data to make a decision on moving forward.”
The BAN2401 research team staked this commitment in the 2016 paper describing the study methodology. “They wanted to have clear evidence on both biomarker and clinical efficacy to allow them to make a decision [to move into phase 3],” Dr. Fargo said. “I don’t know if they are or not, but I’d be surprised if they don’t, and I think they would be on solid footing.”
BAN2401 selectively binds to amyloid-beta protofibrils – large AB oligomers that are still soluble – and targets them for clearance. It was originally developed by Swedish biopharma company BioArctic; Eisai acquired the molecule in 2007 and entered the Biogen deal in 2014.
The study randomized 856 patients with mild cognitive impairment or early Alzheimer’s dementia to six treatment arms: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. All patients had PET-confirmed amyloid brain pathology, a key baseline requirement; only one other antiamyloid agent (Biogen’s antiamyloid antibody aducanumab) has completed a phase 2 study in a purely amyloid-positive cohort. Before PET imaging, patients with non-Alzheimer’s pathology comprised up to 30% of Alzheimer’s drug studies, which researchers say confounded results and likely contributed to the long string of antiamyloid failures.
The coprimary endpoints were reduction of brain amyloid on PET scan and slowing of progression as measured by the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai. ADCOMS combines measures from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), Clinical Dementia Rating Sum of Boxes (CDR-sb), and the Mini-Mental State Examination (MMSE). In devising ADCOMS, researchers chose individual components of each tool that are most likely to change in very-early-stage disease. The scale was validated retrospectively in 1,160 patients who were included in four datasets. This is the first time it’s been used in an Alzheimer’s study.
The BAN2401 trial employed a Bayesian adaptive randomization, a computer-driven algorithm designed to drive patients to the two most effective doses. Often seen in trials of faster-progressing diseases, like cancer, it is unusual in Alzheimer’s studies, Dr. Fargo said.
“I would say it’s unorthodox, but it doesn’t give me heartburn. It’s an adaptive trial design that’s been considered hard to do in the AD field, because the changes between placebo and treatment groups tend to be very slow. In studies that have a very clear biomarker endpoint, like tumor size for example, that everyone can agree on, you can quickly see which treatment arm is most effective. In general, we haven’t been able to do this in AD because the signal changes so slowly.”
The BAN2401 algorithm assessed outcomes monthly, and reallocated incoming subjects according to the most recent efficacy data. But the 12-month primary endpoint assessment, a widely publicized failure, was “unfortunate,” Dr. Fargo said.
“This study had a built-in 12-month endpoint, at which time the sponsor could declare either futility or early success, and stop it for either one.” If neither was achieved, the study was to continue for 18 months and reassess outcomes. This was the situation Eisai and Biogen encountered in December when they announced that BAN2401 had failed to achieve its clinical and imaging endpoints but that the study would continue as planned. That news generated a large amount of negative press for the companies – which saw stock prices plunge – and contributed to media and consumer confusion about the trial design’s validity, Dr. Fargo said.
The 18-month data released on July 5 also included some information on adverse events. Amyloid-related imaging abnormalities, both edematous and hemorrhagic (ARIA-E and ARIA-H) occurred in an undisclosed number of patients. Dr. Kramer said ARIA occurred in “not more than 10% in any of the treatment arms” and in less than 15% of patients who carried an apolipoprotein E e4 allele. Only a portion of these patients were included in the final analysis, and this may have influenced the results somewhat negatively, Dr. Kramer said. In the first years of the study, before ARIA was understood to be largely subclinical and self-resolving, any patient who developed it was dropped.
“We initially dropped every patient who had ARIA, and this is one of the issues that actually make the observed effect [of BAN2401] probably a little bit conservative. Patients with ARIA are typically responding to amyloid removal, and they could be expected to do better.”
ICD use curbed in hospitals named in federal lawsuit
A 2005 update in Medicare reimbursement policy had a modest effect on the use of implantable cardioverter defibrillators for primary prevention, but it took a whistle-blower and a federal lawsuit to bring the numbers down substantially.
Usage dropped just slightly from 2007 to 2009, after Medicare updated its appropriate use criteria, Nihar R. Desai, MD, MPH, and his colleagues reported in JAMA. From 2010 to 2011, after the Department of Justice suit became public knowledge, the declines were significantly greater: 7.4% in hospitals that eventually settled for a total of $280 million, and 4.7% in hospitals that weren’t named in the suit.
The government launched the suit in 2010, after a whistle-blower used Medicare data to allege that many hospitals weren’t waiting the appropriate amount of time to implant an implantable cardioverter defibrillator (ICD) after a heart attack or coronary revascularization, wrote Dr. Desai of Yale University, New Haven, Conn., and his team. These procedures would have been against the 2005 Centers for Medicare & Medicaid Services National Coverage Determination (NCD), which required delaying implantation for 40 days after a heart attack and 90 days after a revascularization.
Just a year after the suit was filed, an independent investigator concluded that 22.5% of the ICDs implanted from 2006 to 2009 for primary prevention were not evidence based.
Dr. Desai and his coauthors used CMS data to examine changes in the proportion of primary-prevention ICD implantations at hospitals that eventually settled the suit, and those that did not. The study spanned 2007-2015 and comprised 1,809 U.S. hospitals in the National Cardiovascular Data Registry ICD Registry; of these, 452 hospitals that had done 99,591 procedures reached settlements.
After the steeper drops in 2010 and 2011, the number of procedures leveled off. From July 2011 to 2015, the proportions of ICDs not meeting the NCD criteria were similar and stable in both hospital settlement groups, with an annual change of −0.5% for settlement hospitals and −0.4% for nonsettlement hospitals, the team wrote.
Despite the changes, there was “persistent variation” among hospitals, with more than 14% of the primary-prevention ICDs not meeting NCD criteria at some of the worst-performing hospitals.
The decreases weren’t just in Medicare beneficiaries, though. Hospitals were rethinking this indication for ICD use in everyone, although the investigators found no evidence that the changing clinical landscape endangered the health of patients.
“The analyses of secondary prevention ICDs do not suggest that access to necessary procedures was negatively affected by the investigation. … These analyses offer some reassurance, but further research into hospital responses to the investigation could offer additional insights about possible unintended consequences,” the investigators wrote.
The study was sponsored by the Agency for Healthcare Research and Quality. Dr. Desai had no financial disclosures.
SOURCE: Desai NR et al. JAMA. 2018; 320: 63-71.
The federal investigation into inappropriate use of implanted cardioverter defibrillators (ICDs) appeared to be highly effective, both in recovering costs and changing behavior at hospitals.
Even though individuals were not the focus of the investigation, many physicians sensed a new exposure to civil liability, if not criminal penalties, and felt accused of providing substandard care. Did this investigation have the intended effect of improving care?
The numbers suggest it did.
The observed decrease in use raises the question of whether appropriate ICDs were also avoided, a potential unintended consequence of the investigation. The study by Desai et al noted that ICD implantations for secondary prevention remained relatively stable during this period, suggesting that appropriate ICD use likely did not decline substantially.
The investigation also clearly showed the power of a large, financially intimidating legal action.
The mere announcement of the investigation appeared to have a large and immediate influence on prompting hospitals to limit inappropriate ICD implantation for primary prevention. As a form of audit and feedback, the Department of Justice investigation appeared to be highly effective in changing practice. Past studies of audit and feedback show relatively modest effects on changing physician behavior, although these studies did not involve allegations of fraud with financial penalties. Clearly, the reward or penalty attached to the feedback influences clinician behavior with penalties likely more effective in promoting change.
Paul A. Heidenreich, MD, professor of cardiovascular medicine at Stanford (Calif.) University, made these comments in an accompanying editorial (JAMA. 2018; 320:40-2).
The federal investigation into inappropriate use of implanted cardioverter defibrillators (ICDs) appeared to be highly effective, both in recovering costs and changing behavior at hospitals.
Even though individuals were not the focus of the investigation, many physicians sensed a new exposure to civil liability, if not criminal penalties, and felt accused of providing substandard care. Did this investigation have the intended effect of improving care?
The numbers suggest it did.
The observed decrease in use raises the question of whether appropriate ICDs were also avoided, a potential unintended consequence of the investigation. The study by Desai et al noted that ICD implantations for secondary prevention remained relatively stable during this period, suggesting that appropriate ICD use likely did not decline substantially.
The investigation also clearly showed the power of a large, financially intimidating legal action.
The mere announcement of the investigation appeared to have a large and immediate influence on prompting hospitals to limit inappropriate ICD implantation for primary prevention. As a form of audit and feedback, the Department of Justice investigation appeared to be highly effective in changing practice. Past studies of audit and feedback show relatively modest effects on changing physician behavior, although these studies did not involve allegations of fraud with financial penalties. Clearly, the reward or penalty attached to the feedback influences clinician behavior with penalties likely more effective in promoting change.
Paul A. Heidenreich, MD, professor of cardiovascular medicine at Stanford (Calif.) University, made these comments in an accompanying editorial (JAMA. 2018; 320:40-2).
The federal investigation into inappropriate use of implanted cardioverter defibrillators (ICDs) appeared to be highly effective, both in recovering costs and changing behavior at hospitals.
Even though individuals were not the focus of the investigation, many physicians sensed a new exposure to civil liability, if not criminal penalties, and felt accused of providing substandard care. Did this investigation have the intended effect of improving care?
The numbers suggest it did.
The observed decrease in use raises the question of whether appropriate ICDs were also avoided, a potential unintended consequence of the investigation. The study by Desai et al noted that ICD implantations for secondary prevention remained relatively stable during this period, suggesting that appropriate ICD use likely did not decline substantially.
The investigation also clearly showed the power of a large, financially intimidating legal action.
The mere announcement of the investigation appeared to have a large and immediate influence on prompting hospitals to limit inappropriate ICD implantation for primary prevention. As a form of audit and feedback, the Department of Justice investigation appeared to be highly effective in changing practice. Past studies of audit and feedback show relatively modest effects on changing physician behavior, although these studies did not involve allegations of fraud with financial penalties. Clearly, the reward or penalty attached to the feedback influences clinician behavior with penalties likely more effective in promoting change.
Paul A. Heidenreich, MD, professor of cardiovascular medicine at Stanford (Calif.) University, made these comments in an accompanying editorial (JAMA. 2018; 320:40-2).
A 2005 update in Medicare reimbursement policy had a modest effect on the use of implantable cardioverter defibrillators for primary prevention, but it took a whistle-blower and a federal lawsuit to bring the numbers down substantially.
Usage dropped just slightly from 2007 to 2009, after Medicare updated its appropriate use criteria, Nihar R. Desai, MD, MPH, and his colleagues reported in JAMA. From 2010 to 2011, after the Department of Justice suit became public knowledge, the declines were significantly greater: 7.4% in hospitals that eventually settled for a total of $280 million, and 4.7% in hospitals that weren’t named in the suit.
The government launched the suit in 2010, after a whistle-blower used Medicare data to allege that many hospitals weren’t waiting the appropriate amount of time to implant an implantable cardioverter defibrillator (ICD) after a heart attack or coronary revascularization, wrote Dr. Desai of Yale University, New Haven, Conn., and his team. These procedures would have been against the 2005 Centers for Medicare & Medicaid Services National Coverage Determination (NCD), which required delaying implantation for 40 days after a heart attack and 90 days after a revascularization.
Just a year after the suit was filed, an independent investigator concluded that 22.5% of the ICDs implanted from 2006 to 2009 for primary prevention were not evidence based.
Dr. Desai and his coauthors used CMS data to examine changes in the proportion of primary-prevention ICD implantations at hospitals that eventually settled the suit, and those that did not. The study spanned 2007-2015 and comprised 1,809 U.S. hospitals in the National Cardiovascular Data Registry ICD Registry; of these, 452 hospitals that had done 99,591 procedures reached settlements.
After the steeper drops in 2010 and 2011, the number of procedures leveled off. From July 2011 to 2015, the proportions of ICDs not meeting the NCD criteria were similar and stable in both hospital settlement groups, with an annual change of −0.5% for settlement hospitals and −0.4% for nonsettlement hospitals, the team wrote.
Despite the changes, there was “persistent variation” among hospitals, with more than 14% of the primary-prevention ICDs not meeting NCD criteria at some of the worst-performing hospitals.
The decreases weren’t just in Medicare beneficiaries, though. Hospitals were rethinking this indication for ICD use in everyone, although the investigators found no evidence that the changing clinical landscape endangered the health of patients.
“The analyses of secondary prevention ICDs do not suggest that access to necessary procedures was negatively affected by the investigation. … These analyses offer some reassurance, but further research into hospital responses to the investigation could offer additional insights about possible unintended consequences,” the investigators wrote.
The study was sponsored by the Agency for Healthcare Research and Quality. Dr. Desai had no financial disclosures.
SOURCE: Desai NR et al. JAMA. 2018; 320: 63-71.
A 2005 update in Medicare reimbursement policy had a modest effect on the use of implantable cardioverter defibrillators for primary prevention, but it took a whistle-blower and a federal lawsuit to bring the numbers down substantially.
Usage dropped just slightly from 2007 to 2009, after Medicare updated its appropriate use criteria, Nihar R. Desai, MD, MPH, and his colleagues reported in JAMA. From 2010 to 2011, after the Department of Justice suit became public knowledge, the declines were significantly greater: 7.4% in hospitals that eventually settled for a total of $280 million, and 4.7% in hospitals that weren’t named in the suit.
The government launched the suit in 2010, after a whistle-blower used Medicare data to allege that many hospitals weren’t waiting the appropriate amount of time to implant an implantable cardioverter defibrillator (ICD) after a heart attack or coronary revascularization, wrote Dr. Desai of Yale University, New Haven, Conn., and his team. These procedures would have been against the 2005 Centers for Medicare & Medicaid Services National Coverage Determination (NCD), which required delaying implantation for 40 days after a heart attack and 90 days after a revascularization.
Just a year after the suit was filed, an independent investigator concluded that 22.5% of the ICDs implanted from 2006 to 2009 for primary prevention were not evidence based.
Dr. Desai and his coauthors used CMS data to examine changes in the proportion of primary-prevention ICD implantations at hospitals that eventually settled the suit, and those that did not. The study spanned 2007-2015 and comprised 1,809 U.S. hospitals in the National Cardiovascular Data Registry ICD Registry; of these, 452 hospitals that had done 99,591 procedures reached settlements.
After the steeper drops in 2010 and 2011, the number of procedures leveled off. From July 2011 to 2015, the proportions of ICDs not meeting the NCD criteria were similar and stable in both hospital settlement groups, with an annual change of −0.5% for settlement hospitals and −0.4% for nonsettlement hospitals, the team wrote.
Despite the changes, there was “persistent variation” among hospitals, with more than 14% of the primary-prevention ICDs not meeting NCD criteria at some of the worst-performing hospitals.
The decreases weren’t just in Medicare beneficiaries, though. Hospitals were rethinking this indication for ICD use in everyone, although the investigators found no evidence that the changing clinical landscape endangered the health of patients.
“The analyses of secondary prevention ICDs do not suggest that access to necessary procedures was negatively affected by the investigation. … These analyses offer some reassurance, but further research into hospital responses to the investigation could offer additional insights about possible unintended consequences,” the investigators wrote.
The study was sponsored by the Agency for Healthcare Research and Quality. Dr. Desai had no financial disclosures.
SOURCE: Desai NR et al. JAMA. 2018; 320: 63-71.
FROM JAMA
Key clinical point: A federal lawsuit against hospitals changed the practice of using implantable cardioverter defibrillators for primary prevention.
Major finding: In the year after the Department of Justice lawsuit was announced, ICD for primary prevention use dropped 7.4% in hospitals that settled and dropped 4.7% in hospitals that were nonsettlers.
Study details: An analysis of data from the Centers for Medicare & Medicaid Services.
Disclosures: The Agency for Healthcare Research and Quality sponsored the study. Dr. Desai had no financial disclosures.
Source: Desai NR et al. JAMA. 2018; 320:63-71.
HPV testing detects cervical precancers earlier than cytology
Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
SOURCE: Ogilvie GS et al. JAMA. 2018;320:43-52.
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
SOURCE: Ogilvie GS et al. JAMA. 2018;320:43-52.
Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
SOURCE: Ogilvie GS et al. JAMA. 2018;320:43-52.
FROM JAMA
Key clinical point: Compared with a Pap smear, HPV testing detected CIN3+ more often and earlier.
Major finding: Women who had HPV testing were 58% less likely to be CIN3+ 48 months later.
Study details: The prospective randomized trial comprised 19,009 women.
Disclosures: The Canadian Institute of Health Research funded the study, Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
Source: Ogilvie GS et al. JAMA. 2018;320:43-52.
New look at ATLAS suggests rivaroxaban may still have role in ACS
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
FDA reverses warning on LABA-containing asthma medications
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory committee meeting.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
The combination a by 17%, without increasing the risk of asthma-related intubation or death.
An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.
“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.
The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.
In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.
“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.
The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.
Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.
Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.
However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.
The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.
“… Our data provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report 3 of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus,” the committee wrote. “Finally, our combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for asthma treatment.”
Dr. Busse disclosed financial relationships with a number of pharmaceutical companies, including Novartis, but noted that none of them were relevant to this work.
SOURCE: Busse WW et al. N Engl J Med. 2018;78:2497-505.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Combination LABA/inhaled glucocorticoid products appear safe for patients with asthma.
Major finding: The products reduced the risk of an asthma exacerbation by 17%, without increasing the risk of a serious adverse outcome.
Study details: The four randomized studies comprised more than 13,000 patients.
Disclosures: The studies were sponsored by AstraZeneca, GlaxoSmithKline, Merck, and Novartis. Dr. Busse disclosed a financial relationship with Novartis, but said it was not relevant to this work.
Source: Busse WW. N Engl J Med. 2018;78:2497-505.
Elderly patients with psoriasis can benefit from biologics with low rates of adverse events
according to a new retrospective study.
Among 266 older patients, 65% achieved a 75% improvement in Psoriasis Area Severity Index score (PASI 75) after 1 year of therapy; 50% reached a PASI 90, and 40% a PASI 100, Francesca Prignano MD, PhD, and her colleagues reported in the Journal of the European Academy of Dermatology and Venereology. The rate of serious adverse events was less than 10%.
Elderly patients – those aged 65 years and older – are commonly excluded from studies on biologic treatments because they have more medical comorbidities and are thought to be more at risk for serious adverse events, like infections and malignancy, wrote Dr. Prignano of the dermatology unit, University of Florence, Italy, and her colleagues.
As a result, they noted, there is a “lack of information concerning safety and effectiveness of available treatments for psoriasis in the elderly, particularly about new biologic agents. Disease remission should be an objective for both younger patients and older patients, and biologic therapy should be considered a treatment option for all patients.”
To examine both the benefit and risk of biologics in this population, the team reviewed the records of 266 elderly psoriasis patients; everyone had been on a biologic treatment for at least 1 year.
The primary outcome was PASI score at weeks 8, 16, 28, and 52. The secondary outcomes were the rate and types of biologic-associated adverse events.
The study comprised 266 patients (mean age 72 years). Their mean psoriasis duration was 25.7 years. Comorbidities included psoriatic arthritis; hypertension and dyslipidemia; diabetes mellitus; cardiovascular, gastrointestinal and respiratory diseases; osteoporosis; thyroid dysfunction; depression; and cancer.
Adalimumab was the most commonly prescribed biologic (31%), followed by ustekinumab (28.9%), etanercept (20%), and secukinumab (15%). A smaller proportion of patients were taking infliximab, golimumab, or certolizumab pegol.
The mean baseline PASI was 16.5, although the range was wide (4-54). At the time of review, the average biologic treatment duration was 44 months. Almost half of the cohort (128) were on their second biologic, and 20 more had been on three biologics. A few patients were taking concomitant medications, including steroids, cyclosporine, and acitretin.
The mean PASI scores decreased to 3.7 at week 16, 1.6 at week 28, and 1.2 at week 52. The group exhibited a rapid response to biologic treatment. By 16 weeks, about 55% had achieved a PASI 75, about 28% a PASI 90, and about 20% a PASI 100. By 28 weeks, these numbers were about 64%, 45%, and 35%, respectively. At 1 year, they were about 65%, 50%, and 40%, respectively.
The rate of adverse events was 9.4%. There were 25 events in the cohort, the majority of which (48%) were infections; these included four respiratory infections, three urinary tract infections, two cases of mucocutaneous candidiasis, two cases of herpes zoster infection, and one case of erysipelas.
There were four malignancies: three nonmelanoma skin cancers and one vocal cord cancer.
Noting that, to date, their study represented “the broadest experience on the use of biological drugs” for elderly patients with psoriasis, they wrote that while “comorbidities should be taken into consideration when a long-term treatment is proposed, for the higher risk of side effects and drug interactions,” they wrote, noting that none of the 266 patients had a serious infection and the malignancy rate was low (1.5%).
None of the authors had financial disclosures, and the study had no funding source.
SOURCE: Ricceri F et al. J Eur Acad Dermatol Venereol. 2018 Jun 15. doi: 10.1111/jdv.15139.
according to a new retrospective study.
Among 266 older patients, 65% achieved a 75% improvement in Psoriasis Area Severity Index score (PASI 75) after 1 year of therapy; 50% reached a PASI 90, and 40% a PASI 100, Francesca Prignano MD, PhD, and her colleagues reported in the Journal of the European Academy of Dermatology and Venereology. The rate of serious adverse events was less than 10%.
Elderly patients – those aged 65 years and older – are commonly excluded from studies on biologic treatments because they have more medical comorbidities and are thought to be more at risk for serious adverse events, like infections and malignancy, wrote Dr. Prignano of the dermatology unit, University of Florence, Italy, and her colleagues.
As a result, they noted, there is a “lack of information concerning safety and effectiveness of available treatments for psoriasis in the elderly, particularly about new biologic agents. Disease remission should be an objective for both younger patients and older patients, and biologic therapy should be considered a treatment option for all patients.”
To examine both the benefit and risk of biologics in this population, the team reviewed the records of 266 elderly psoriasis patients; everyone had been on a biologic treatment for at least 1 year.
The primary outcome was PASI score at weeks 8, 16, 28, and 52. The secondary outcomes were the rate and types of biologic-associated adverse events.
The study comprised 266 patients (mean age 72 years). Their mean psoriasis duration was 25.7 years. Comorbidities included psoriatic arthritis; hypertension and dyslipidemia; diabetes mellitus; cardiovascular, gastrointestinal and respiratory diseases; osteoporosis; thyroid dysfunction; depression; and cancer.
Adalimumab was the most commonly prescribed biologic (31%), followed by ustekinumab (28.9%), etanercept (20%), and secukinumab (15%). A smaller proportion of patients were taking infliximab, golimumab, or certolizumab pegol.
The mean baseline PASI was 16.5, although the range was wide (4-54). At the time of review, the average biologic treatment duration was 44 months. Almost half of the cohort (128) were on their second biologic, and 20 more had been on three biologics. A few patients were taking concomitant medications, including steroids, cyclosporine, and acitretin.
The mean PASI scores decreased to 3.7 at week 16, 1.6 at week 28, and 1.2 at week 52. The group exhibited a rapid response to biologic treatment. By 16 weeks, about 55% had achieved a PASI 75, about 28% a PASI 90, and about 20% a PASI 100. By 28 weeks, these numbers were about 64%, 45%, and 35%, respectively. At 1 year, they were about 65%, 50%, and 40%, respectively.
The rate of adverse events was 9.4%. There were 25 events in the cohort, the majority of which (48%) were infections; these included four respiratory infections, three urinary tract infections, two cases of mucocutaneous candidiasis, two cases of herpes zoster infection, and one case of erysipelas.
There were four malignancies: three nonmelanoma skin cancers and one vocal cord cancer.
Noting that, to date, their study represented “the broadest experience on the use of biological drugs” for elderly patients with psoriasis, they wrote that while “comorbidities should be taken into consideration when a long-term treatment is proposed, for the higher risk of side effects and drug interactions,” they wrote, noting that none of the 266 patients had a serious infection and the malignancy rate was low (1.5%).
None of the authors had financial disclosures, and the study had no funding source.
SOURCE: Ricceri F et al. J Eur Acad Dermatol Venereol. 2018 Jun 15. doi: 10.1111/jdv.15139.
according to a new retrospective study.
Among 266 older patients, 65% achieved a 75% improvement in Psoriasis Area Severity Index score (PASI 75) after 1 year of therapy; 50% reached a PASI 90, and 40% a PASI 100, Francesca Prignano MD, PhD, and her colleagues reported in the Journal of the European Academy of Dermatology and Venereology. The rate of serious adverse events was less than 10%.
Elderly patients – those aged 65 years and older – are commonly excluded from studies on biologic treatments because they have more medical comorbidities and are thought to be more at risk for serious adverse events, like infections and malignancy, wrote Dr. Prignano of the dermatology unit, University of Florence, Italy, and her colleagues.
As a result, they noted, there is a “lack of information concerning safety and effectiveness of available treatments for psoriasis in the elderly, particularly about new biologic agents. Disease remission should be an objective for both younger patients and older patients, and biologic therapy should be considered a treatment option for all patients.”
To examine both the benefit and risk of biologics in this population, the team reviewed the records of 266 elderly psoriasis patients; everyone had been on a biologic treatment for at least 1 year.
The primary outcome was PASI score at weeks 8, 16, 28, and 52. The secondary outcomes were the rate and types of biologic-associated adverse events.
The study comprised 266 patients (mean age 72 years). Their mean psoriasis duration was 25.7 years. Comorbidities included psoriatic arthritis; hypertension and dyslipidemia; diabetes mellitus; cardiovascular, gastrointestinal and respiratory diseases; osteoporosis; thyroid dysfunction; depression; and cancer.
Adalimumab was the most commonly prescribed biologic (31%), followed by ustekinumab (28.9%), etanercept (20%), and secukinumab (15%). A smaller proportion of patients were taking infliximab, golimumab, or certolizumab pegol.
The mean baseline PASI was 16.5, although the range was wide (4-54). At the time of review, the average biologic treatment duration was 44 months. Almost half of the cohort (128) were on their second biologic, and 20 more had been on three biologics. A few patients were taking concomitant medications, including steroids, cyclosporine, and acitretin.
The mean PASI scores decreased to 3.7 at week 16, 1.6 at week 28, and 1.2 at week 52. The group exhibited a rapid response to biologic treatment. By 16 weeks, about 55% had achieved a PASI 75, about 28% a PASI 90, and about 20% a PASI 100. By 28 weeks, these numbers were about 64%, 45%, and 35%, respectively. At 1 year, they were about 65%, 50%, and 40%, respectively.
The rate of adverse events was 9.4%. There were 25 events in the cohort, the majority of which (48%) were infections; these included four respiratory infections, three urinary tract infections, two cases of mucocutaneous candidiasis, two cases of herpes zoster infection, and one case of erysipelas.
There were four malignancies: three nonmelanoma skin cancers and one vocal cord cancer.
Noting that, to date, their study represented “the broadest experience on the use of biological drugs” for elderly patients with psoriasis, they wrote that while “comorbidities should be taken into consideration when a long-term treatment is proposed, for the higher risk of side effects and drug interactions,” they wrote, noting that none of the 266 patients had a serious infection and the malignancy rate was low (1.5%).
None of the authors had financial disclosures, and the study had no funding source.
SOURCE: Ricceri F et al. J Eur Acad Dermatol Venereol. 2018 Jun 15. doi: 10.1111/jdv.15139.
FROM THE JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
Key clinical point: Patients aged 65 years and older responded well to biologics and had a low rate of serious adverse events.
Major finding: At 1 year, 65% achieved a PASI 75, 50% achieved a reached PASI 90, and 40% achieved a PASI 100, with a 9.4% rate of serious adverse events.
Study details: The retrospective study comprised 266 patients aged 65 years and older treated with biologics for psoriasis.
Disclosures: None of the authors had financial disclosures, and the study had no funding source.
Source: Ricceri F et al. J Eur Acad Dermatol Venereol. 2018. doi: 10.1111/jdv.15139.
Dupilumab reduces exacerbations, cuts glucocorticoid use in moderate to severe asthma
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.
The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.
By week 12, FEV1 it had already increased by 0.32 L, they said.
“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”
Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
Liberty Asthma Quest
This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.
Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.
Both doses outperformed placebo in all endpoints.
Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.
The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.
By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.
Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.
The benefit was already noticeable by the 2-week evaluation, the investigators noted.
Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).
Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
Liberty Asthma Venture
In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.
These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.
Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.
By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.
Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”
In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.
Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.
Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.
The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.
Antidrug antibodies developed in five patients in each group, without clinical effect.
Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Dupilumab allowed asthma patients to decrease glucocorticoids with no risk of asthma exacerbation.
Major finding: Dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%.
Study details: Liberty Asthma Quest comprised 1,902 patients and Liberty Asthma Venture comprised 210. Both were randomized, placebo-controlled trials.
Disclosures: Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.
Sources: Castro M et al. N Engl J Med. 2018;378:2486-96; Rabe KF et al. N Engl J Med. 2018;378:2475-85.
Medicare hospital deaths decline, hospice usage increases
Since 2000, Medicare beneficiaries have become less likely to die in hospitals, and more likely to die in their homes or in community health care facilities.
A review of Medicare records also determined that there was a decline in health care transitions in the final 3 days of life for these patients, Joan M. Teno, MD, and her colleagues wrote in JAMA.
It is not possible to identify a specific reason for the shift, wrote Dr. Teno, professor of medicine at the Oregon Health & Science University, Portland. Between the study years of 2000 and 2015, there were several large efforts to improve care at the end of life.
“Since 2009, programs ranging from ensuring informed patient decision making to enhanced care coordination have had the goal of improving care at the end of life. Specific interventions have included promoting conversations about the goals of care, continued growth of hospice services and palliative care, and the debate and passage of the Affordable Care Act … It is difficult to disentangle efforts such as public education, promotion of advance directives through the Patient Self- Determination Act, increased access to hospice and palliative care services, financial incentives of payment policies, and other secular changes.”
The study mined data from the Centers for Medicare & Medicaid Services, and examined end-of-life outcomes among two Medicare groups: Medicare fee-for-service recipients (1,361,870) during 2009-2015, and Medicare Advantage recipients (871,845), comparing 2011 and 2015. The mean age of both cohorts was 82 years.
Outcomes included site of death and “potentially burdensome transitions,” during the last days of life. These were defined as three or more hospitalizations in the previous 3 months, or two or more hospitalizations for pneumonia, urinary tract infection, dehydration, or sepsis during the last 120 days of life. Prolonged mechanical ventilation also was deemed potentially burdensome.
Among fee-for-service recipients, deaths in acute care hospitals declined from 32.6% to19.8%. Deaths in nursing homes remained steady, at 27.2% and 24.9%. Many of these deaths (42.9%) were preceded by a stay in an ICU. There was a transient increase in end-of-life ICU use, around 2009, but by 2015, the percentage was down to 29%, compared with 65.2% in 2000.
Transitions between a nursing home and hospital in the last 90 days of life were 0.49/person in 2000 and 0.33/person in 2015. Hospitalizations for infection or dehydration fell from 14.6% to12.2%. Hospitalization with prolonged ventilation fell from 3.1% to 2.5%.
Dying in hospice care increased from 21.6% to 50.4%, and people were taking advantage of hospice services longer: the proportion using short-term services (3 days or less) fell from 9.8% to 7.7%.
Among Medicare Advantage recipients, the numbers were somewhat different. More than 50% of recipients entered hospice care in both 2011 and 2015; in both years, 8% had services for more than 3 days. About 27% had ICU care in the last days of life, in both years. Compared to fee-for-service recipients, fewer Medicare Advantage patients were in nursing homes at the time of death, and that number declined from 2011 to 2015 (37.7% to 33.2%).
In each year, about 10% of these patients had a hospitalization for dehydration or infection, and 3% had a stay requiring prolonged mechanical ventilation in each year. The mean number of health care transitions remained steady, at 0.23 and 0.21 per person each year.
Dr. Teno had no financial disclosures.
SOURCE: Teno JM et al. JAMA. 2018 Jun 25. doi: 10.1001/jama.2018.8981.
Since 2000, Medicare beneficiaries have become less likely to die in hospitals, and more likely to die in their homes or in community health care facilities.
A review of Medicare records also determined that there was a decline in health care transitions in the final 3 days of life for these patients, Joan M. Teno, MD, and her colleagues wrote in JAMA.
It is not possible to identify a specific reason for the shift, wrote Dr. Teno, professor of medicine at the Oregon Health & Science University, Portland. Between the study years of 2000 and 2015, there were several large efforts to improve care at the end of life.
“Since 2009, programs ranging from ensuring informed patient decision making to enhanced care coordination have had the goal of improving care at the end of life. Specific interventions have included promoting conversations about the goals of care, continued growth of hospice services and palliative care, and the debate and passage of the Affordable Care Act … It is difficult to disentangle efforts such as public education, promotion of advance directives through the Patient Self- Determination Act, increased access to hospice and palliative care services, financial incentives of payment policies, and other secular changes.”
The study mined data from the Centers for Medicare & Medicaid Services, and examined end-of-life outcomes among two Medicare groups: Medicare fee-for-service recipients (1,361,870) during 2009-2015, and Medicare Advantage recipients (871,845), comparing 2011 and 2015. The mean age of both cohorts was 82 years.
Outcomes included site of death and “potentially burdensome transitions,” during the last days of life. These were defined as three or more hospitalizations in the previous 3 months, or two or more hospitalizations for pneumonia, urinary tract infection, dehydration, or sepsis during the last 120 days of life. Prolonged mechanical ventilation also was deemed potentially burdensome.
Among fee-for-service recipients, deaths in acute care hospitals declined from 32.6% to19.8%. Deaths in nursing homes remained steady, at 27.2% and 24.9%. Many of these deaths (42.9%) were preceded by a stay in an ICU. There was a transient increase in end-of-life ICU use, around 2009, but by 2015, the percentage was down to 29%, compared with 65.2% in 2000.
Transitions between a nursing home and hospital in the last 90 days of life were 0.49/person in 2000 and 0.33/person in 2015. Hospitalizations for infection or dehydration fell from 14.6% to12.2%. Hospitalization with prolonged ventilation fell from 3.1% to 2.5%.
Dying in hospice care increased from 21.6% to 50.4%, and people were taking advantage of hospice services longer: the proportion using short-term services (3 days or less) fell from 9.8% to 7.7%.
Among Medicare Advantage recipients, the numbers were somewhat different. More than 50% of recipients entered hospice care in both 2011 and 2015; in both years, 8% had services for more than 3 days. About 27% had ICU care in the last days of life, in both years. Compared to fee-for-service recipients, fewer Medicare Advantage patients were in nursing homes at the time of death, and that number declined from 2011 to 2015 (37.7% to 33.2%).
In each year, about 10% of these patients had a hospitalization for dehydration or infection, and 3% had a stay requiring prolonged mechanical ventilation in each year. The mean number of health care transitions remained steady, at 0.23 and 0.21 per person each year.
Dr. Teno had no financial disclosures.
SOURCE: Teno JM et al. JAMA. 2018 Jun 25. doi: 10.1001/jama.2018.8981.
Since 2000, Medicare beneficiaries have become less likely to die in hospitals, and more likely to die in their homes or in community health care facilities.
A review of Medicare records also determined that there was a decline in health care transitions in the final 3 days of life for these patients, Joan M. Teno, MD, and her colleagues wrote in JAMA.
It is not possible to identify a specific reason for the shift, wrote Dr. Teno, professor of medicine at the Oregon Health & Science University, Portland. Between the study years of 2000 and 2015, there were several large efforts to improve care at the end of life.
“Since 2009, programs ranging from ensuring informed patient decision making to enhanced care coordination have had the goal of improving care at the end of life. Specific interventions have included promoting conversations about the goals of care, continued growth of hospice services and palliative care, and the debate and passage of the Affordable Care Act … It is difficult to disentangle efforts such as public education, promotion of advance directives through the Patient Self- Determination Act, increased access to hospice and palliative care services, financial incentives of payment policies, and other secular changes.”
The study mined data from the Centers for Medicare & Medicaid Services, and examined end-of-life outcomes among two Medicare groups: Medicare fee-for-service recipients (1,361,870) during 2009-2015, and Medicare Advantage recipients (871,845), comparing 2011 and 2015. The mean age of both cohorts was 82 years.
Outcomes included site of death and “potentially burdensome transitions,” during the last days of life. These were defined as three or more hospitalizations in the previous 3 months, or two or more hospitalizations for pneumonia, urinary tract infection, dehydration, or sepsis during the last 120 days of life. Prolonged mechanical ventilation also was deemed potentially burdensome.
Among fee-for-service recipients, deaths in acute care hospitals declined from 32.6% to19.8%. Deaths in nursing homes remained steady, at 27.2% and 24.9%. Many of these deaths (42.9%) were preceded by a stay in an ICU. There was a transient increase in end-of-life ICU use, around 2009, but by 2015, the percentage was down to 29%, compared with 65.2% in 2000.
Transitions between a nursing home and hospital in the last 90 days of life were 0.49/person in 2000 and 0.33/person in 2015. Hospitalizations for infection or dehydration fell from 14.6% to12.2%. Hospitalization with prolonged ventilation fell from 3.1% to 2.5%.
Dying in hospice care increased from 21.6% to 50.4%, and people were taking advantage of hospice services longer: the proportion using short-term services (3 days or less) fell from 9.8% to 7.7%.
Among Medicare Advantage recipients, the numbers were somewhat different. More than 50% of recipients entered hospice care in both 2011 and 2015; in both years, 8% had services for more than 3 days. About 27% had ICU care in the last days of life, in both years. Compared to fee-for-service recipients, fewer Medicare Advantage patients were in nursing homes at the time of death, and that number declined from 2011 to 2015 (37.7% to 33.2%).
In each year, about 10% of these patients had a hospitalization for dehydration or infection, and 3% had a stay requiring prolonged mechanical ventilation in each year. The mean number of health care transitions remained steady, at 0.23 and 0.21 per person each year.
Dr. Teno had no financial disclosures.
SOURCE: Teno JM et al. JAMA. 2018 Jun 25. doi: 10.1001/jama.2018.8981.
FROM JAMA
Key clinical point: During 2000-2015, Medicare recipients became less likely to die in hospitals.
Major finding:
Study details: The retrospective study comprised more than 2.3 million Medicare recipients.
Disclosures: Dr. Teno had no financial disclosures.
Source: Teno JM et al. JAMA. 2018 Jun 25. doi: 10.1001/jama.2018.8981.
Accidental bowel injury occurs in 2% of hernia repairs
occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.
“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.
The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.
The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.
Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.
Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”
In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).
The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.
“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.
The investigators reported no financial disclosures.
SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003
occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.
“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.
The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.
The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.
Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.
Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”
In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).
The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.
“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.
The investigators reported no financial disclosures.
SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003
occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.
“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.
The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.
The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.
Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.
Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”
In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).
The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.
“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.
The investigators reported no financial disclosures.
SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003
FROM SURGERY
Key clinical point: Accidental bowel injuries during ventral hernia increase risk for longer hospital stays, fistula, sepsis, and readmissions.
Major finding: The overall rate of accidental enterotomy during ventral hernia repair was 2%.
Study details: The database review included 5,916 hernia repair patients.
Disclosures: None of the authors reported any financial disclosures.
Source: Krpata D et al. Surg 2018; doi.org/10.1016/j.surg.2018.04.003