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FDA investigates NDMA contamination in metformin
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
Perioperative antirheumatic drug use does not impact postsurgery infection rate in RA patients
ATLANTA – Patients with rheumatoid arthritis were more at risk of postoperative infection because of a high Charlson Comorbidity Index or longer surgery time than because of perioperative use of antirheumatic medications, according to a presentation at the annual meeting of the American College of Rheumatology.
Anna Shmagel, MD, of the University of Minnesota in Minneapolis and colleagues performed a retrospective cohort study of 154 patients with seropositive RA who were in the Fairview Health System between Jan. 2010 and Dec. 2017 and underwent either orthopedic or major organ surgery. The patients were classified based on their use of disease-modifying antirheumatic drugs (DMARDs) and biologics alone or in combination, with patients divided into “no DMARD or biologic,” “DMARD but no biologic” and “biologic with or without DMARD” groups.
The question of whether to discontinue antirheumatic medications before surgery is still controversial, with conflicting evidence across studies, Dr. Shmagel said in her presentation. A study by Giles and colleagues found 10 of 91 patients (11%) RA who underwent an orthopedic surgical procedure developed a postoperative infection, with patients receiving tumor necrosis factor (TNF) inhibitors more likely to develop an infection, compared with patients who were not receiving TNF inhibitors (Arthritis Care Res. 2006. doi: 10.1002/art.21841).
However, other studies have challenged that idea, and a 2018 study from Goodman and colleagues raised the issue of whether patients stopping biologics prior to surgery are at increased risk of flares. Of 120 RA patients in their study who underwent total hip or total knee arthroplasty, 75% of patients flared at 6 weeks after surgery. While patients who halted biologics before surgery were more likely to flare, stopping biologics did not predict flaring after surgery (J Rheumatol. 2018. doi: 10.3899/jrheum.170366).
“It’s not entirely clear whether these theories are related to what we do with antirheumatic medications, but we felt that it was pertinent to further study this question.” Dr. Shmagel said.
Dr. Shmagel and colleagues examined the 30-day infection rate of RA patients postoperatively, with 30-day readmission and 30-day mortality rates as secondary outcomes. Patient-associated factors such as age, gender, race, body mass index, smoking status, Charlson Comorbidity Index, income, and use of corticosteroids were analyzed as covariates in addition to factors involving surgery such as expected surgery time, perioperative antibiotic use, and whether the procedure was elective or emergency surgery.
A majority of the patients in the study across all groups were white women about 63 years old with a body mass index above 30 kg/m2 and almost all undergoing electing surgery compared with emergency surgery. While patients in each group were similar with regard to Charlson Comorbidity Index, expected length of surgery, and percentage of patients undergoing elective surgery, patients in the biologic with or without DMARD group had a significantly lower median income level compared with those in the other two groups (P = .01).
Overall, there were 244 surgeries in 154 patients, with 117 surgeries in the group not receiving biologics or DMARDs, 95 surgeries in the group receiving DMARDs but no biologics, and 32 surgeries in the biologics with or without DMARD group. In the DMARD but no biologics group, most patients were receiving methotrexate (45%) or hydroxychloroquine (44%), while the most common biologics in the biologics with or without DMARD group were infliximab (25%), tocilizumab (19%), abatacept (16%), etanercept (13%), rituximab (9%), and tofacitinib (9%).
There was an 11% overall rate of infection, with a similar rate of infection across all groups (P = .09). While there was a higher rate of surgical site infections among patients in the biologics with or without DMARD group (9%) and a higher percentage of urinary tract infections in the no DMARD and no biologics group (4%), the results were not statistically significant. When the rate of infections was examined by type of surgery, there were no significant differences between infections from musculoskeletal surgery (P = .7) and major organ surgery (P = .8).
The overall 30-day readmission rate was 12%, but there were no statistically significant differences between groups. Although there were five deaths in the study, four deaths were in the group not receiving DMARDs or biologics, and one death was in the biologic with or without DMARD group.
Higher Charlson Comorbidity Index did predict infection risk, with an odds ratio of 1.37 per 1-point increase in the index (95% confidence interval, 1.10-1.70). Length of surgery also increased the risk of infection, with an OR of 1.16 per 15-minute increase in surgery time (95% CI, 1.09-1.23).
Dr. Shmagel noted that the retrospective nature of the study and the midwestern cohort may mean the results are not generalizable to other populations and that larger randomized trials should be considered. “Certainly, a larger study with more events would be needed,” she said.
This study was funded by the University of Minnesota. Dr. Shmagel reported no relevant conflicts of interest.
SOURCE: Kerski M et al. Arthritis Rheumatol. 2019;71 (suppl 10), Abstract 1805.
ATLANTA – Patients with rheumatoid arthritis were more at risk of postoperative infection because of a high Charlson Comorbidity Index or longer surgery time than because of perioperative use of antirheumatic medications, according to a presentation at the annual meeting of the American College of Rheumatology.
Anna Shmagel, MD, of the University of Minnesota in Minneapolis and colleagues performed a retrospective cohort study of 154 patients with seropositive RA who were in the Fairview Health System between Jan. 2010 and Dec. 2017 and underwent either orthopedic or major organ surgery. The patients were classified based on their use of disease-modifying antirheumatic drugs (DMARDs) and biologics alone or in combination, with patients divided into “no DMARD or biologic,” “DMARD but no biologic” and “biologic with or without DMARD” groups.
The question of whether to discontinue antirheumatic medications before surgery is still controversial, with conflicting evidence across studies, Dr. Shmagel said in her presentation. A study by Giles and colleagues found 10 of 91 patients (11%) RA who underwent an orthopedic surgical procedure developed a postoperative infection, with patients receiving tumor necrosis factor (TNF) inhibitors more likely to develop an infection, compared with patients who were not receiving TNF inhibitors (Arthritis Care Res. 2006. doi: 10.1002/art.21841).
However, other studies have challenged that idea, and a 2018 study from Goodman and colleagues raised the issue of whether patients stopping biologics prior to surgery are at increased risk of flares. Of 120 RA patients in their study who underwent total hip or total knee arthroplasty, 75% of patients flared at 6 weeks after surgery. While patients who halted biologics before surgery were more likely to flare, stopping biologics did not predict flaring after surgery (J Rheumatol. 2018. doi: 10.3899/jrheum.170366).
“It’s not entirely clear whether these theories are related to what we do with antirheumatic medications, but we felt that it was pertinent to further study this question.” Dr. Shmagel said.
Dr. Shmagel and colleagues examined the 30-day infection rate of RA patients postoperatively, with 30-day readmission and 30-day mortality rates as secondary outcomes. Patient-associated factors such as age, gender, race, body mass index, smoking status, Charlson Comorbidity Index, income, and use of corticosteroids were analyzed as covariates in addition to factors involving surgery such as expected surgery time, perioperative antibiotic use, and whether the procedure was elective or emergency surgery.
A majority of the patients in the study across all groups were white women about 63 years old with a body mass index above 30 kg/m2 and almost all undergoing electing surgery compared with emergency surgery. While patients in each group were similar with regard to Charlson Comorbidity Index, expected length of surgery, and percentage of patients undergoing elective surgery, patients in the biologic with or without DMARD group had a significantly lower median income level compared with those in the other two groups (P = .01).
Overall, there were 244 surgeries in 154 patients, with 117 surgeries in the group not receiving biologics or DMARDs, 95 surgeries in the group receiving DMARDs but no biologics, and 32 surgeries in the biologics with or without DMARD group. In the DMARD but no biologics group, most patients were receiving methotrexate (45%) or hydroxychloroquine (44%), while the most common biologics in the biologics with or without DMARD group were infliximab (25%), tocilizumab (19%), abatacept (16%), etanercept (13%), rituximab (9%), and tofacitinib (9%).
There was an 11% overall rate of infection, with a similar rate of infection across all groups (P = .09). While there was a higher rate of surgical site infections among patients in the biologics with or without DMARD group (9%) and a higher percentage of urinary tract infections in the no DMARD and no biologics group (4%), the results were not statistically significant. When the rate of infections was examined by type of surgery, there were no significant differences between infections from musculoskeletal surgery (P = .7) and major organ surgery (P = .8).
The overall 30-day readmission rate was 12%, but there were no statistically significant differences between groups. Although there were five deaths in the study, four deaths were in the group not receiving DMARDs or biologics, and one death was in the biologic with or without DMARD group.
Higher Charlson Comorbidity Index did predict infection risk, with an odds ratio of 1.37 per 1-point increase in the index (95% confidence interval, 1.10-1.70). Length of surgery also increased the risk of infection, with an OR of 1.16 per 15-minute increase in surgery time (95% CI, 1.09-1.23).
Dr. Shmagel noted that the retrospective nature of the study and the midwestern cohort may mean the results are not generalizable to other populations and that larger randomized trials should be considered. “Certainly, a larger study with more events would be needed,” she said.
This study was funded by the University of Minnesota. Dr. Shmagel reported no relevant conflicts of interest.
SOURCE: Kerski M et al. Arthritis Rheumatol. 2019;71 (suppl 10), Abstract 1805.
ATLANTA – Patients with rheumatoid arthritis were more at risk of postoperative infection because of a high Charlson Comorbidity Index or longer surgery time than because of perioperative use of antirheumatic medications, according to a presentation at the annual meeting of the American College of Rheumatology.
Anna Shmagel, MD, of the University of Minnesota in Minneapolis and colleagues performed a retrospective cohort study of 154 patients with seropositive RA who were in the Fairview Health System between Jan. 2010 and Dec. 2017 and underwent either orthopedic or major organ surgery. The patients were classified based on their use of disease-modifying antirheumatic drugs (DMARDs) and biologics alone or in combination, with patients divided into “no DMARD or biologic,” “DMARD but no biologic” and “biologic with or without DMARD” groups.
The question of whether to discontinue antirheumatic medications before surgery is still controversial, with conflicting evidence across studies, Dr. Shmagel said in her presentation. A study by Giles and colleagues found 10 of 91 patients (11%) RA who underwent an orthopedic surgical procedure developed a postoperative infection, with patients receiving tumor necrosis factor (TNF) inhibitors more likely to develop an infection, compared with patients who were not receiving TNF inhibitors (Arthritis Care Res. 2006. doi: 10.1002/art.21841).
However, other studies have challenged that idea, and a 2018 study from Goodman and colleagues raised the issue of whether patients stopping biologics prior to surgery are at increased risk of flares. Of 120 RA patients in their study who underwent total hip or total knee arthroplasty, 75% of patients flared at 6 weeks after surgery. While patients who halted biologics before surgery were more likely to flare, stopping biologics did not predict flaring after surgery (J Rheumatol. 2018. doi: 10.3899/jrheum.170366).
“It’s not entirely clear whether these theories are related to what we do with antirheumatic medications, but we felt that it was pertinent to further study this question.” Dr. Shmagel said.
Dr. Shmagel and colleagues examined the 30-day infection rate of RA patients postoperatively, with 30-day readmission and 30-day mortality rates as secondary outcomes. Patient-associated factors such as age, gender, race, body mass index, smoking status, Charlson Comorbidity Index, income, and use of corticosteroids were analyzed as covariates in addition to factors involving surgery such as expected surgery time, perioperative antibiotic use, and whether the procedure was elective or emergency surgery.
A majority of the patients in the study across all groups were white women about 63 years old with a body mass index above 30 kg/m2 and almost all undergoing electing surgery compared with emergency surgery. While patients in each group were similar with regard to Charlson Comorbidity Index, expected length of surgery, and percentage of patients undergoing elective surgery, patients in the biologic with or without DMARD group had a significantly lower median income level compared with those in the other two groups (P = .01).
Overall, there were 244 surgeries in 154 patients, with 117 surgeries in the group not receiving biologics or DMARDs, 95 surgeries in the group receiving DMARDs but no biologics, and 32 surgeries in the biologics with or without DMARD group. In the DMARD but no biologics group, most patients were receiving methotrexate (45%) or hydroxychloroquine (44%), while the most common biologics in the biologics with or without DMARD group were infliximab (25%), tocilizumab (19%), abatacept (16%), etanercept (13%), rituximab (9%), and tofacitinib (9%).
There was an 11% overall rate of infection, with a similar rate of infection across all groups (P = .09). While there was a higher rate of surgical site infections among patients in the biologics with or without DMARD group (9%) and a higher percentage of urinary tract infections in the no DMARD and no biologics group (4%), the results were not statistically significant. When the rate of infections was examined by type of surgery, there were no significant differences between infections from musculoskeletal surgery (P = .7) and major organ surgery (P = .8).
The overall 30-day readmission rate was 12%, but there were no statistically significant differences between groups. Although there were five deaths in the study, four deaths were in the group not receiving DMARDs or biologics, and one death was in the biologic with or without DMARD group.
Higher Charlson Comorbidity Index did predict infection risk, with an odds ratio of 1.37 per 1-point increase in the index (95% confidence interval, 1.10-1.70). Length of surgery also increased the risk of infection, with an OR of 1.16 per 15-minute increase in surgery time (95% CI, 1.09-1.23).
Dr. Shmagel noted that the retrospective nature of the study and the midwestern cohort may mean the results are not generalizable to other populations and that larger randomized trials should be considered. “Certainly, a larger study with more events would be needed,” she said.
This study was funded by the University of Minnesota. Dr. Shmagel reported no relevant conflicts of interest.
SOURCE: Kerski M et al. Arthritis Rheumatol. 2019;71 (suppl 10), Abstract 1805.
REPORTING FROM ACR 2019
New heart failure trial data presage guideline revisions
PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.
The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.
U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).
Expanding the heart failure group for sacubitril/valsartan
Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”
That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).
Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.
Bringing SGLT2 inhibitors into heart failure management
Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.
The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.
Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.
And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.
Dr. Yancy had no relevant disclosures.
PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.
The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.
U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).
Expanding the heart failure group for sacubitril/valsartan
Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”
That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).
Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.
Bringing SGLT2 inhibitors into heart failure management
Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.
The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.
Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.
And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.
Dr. Yancy had no relevant disclosures.
PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.
The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.
U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).
Expanding the heart failure group for sacubitril/valsartan
Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”
That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).
Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.
Bringing SGLT2 inhibitors into heart failure management
Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.
The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.
Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.
And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.
Dr. Yancy had no relevant disclosures.
EXPERT ANALYSIS FROM AHA 2019
A triple-antibiotic cure for Crohn’s disease?
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
REPORTING FROM ACG 2019
A patient-centered approach to tapering opioids
Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.5 (See “Tapering and harm-reduction strategies have failed.”6-14)
SIDEBAR
Tapering and harm-reduction strategies have failed
Efforts to address the rising number of overdose events that involve opioids began in earnest in 2010. In a 2011 Government Accountability Office report to Congress, the Drug Enforcement Agency reported that “the number of regulatory investigations (of medical providers who prescribed opioids) tripled between fiscal years 2009- 2010.”6
How has it gone since 2010? High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.7,8 Just the opposite: The 19,000 overdose deaths recorded in 2010 involving any opioid increased to 49,068 by 2017, the National Institute on Drug Abuse reports.9 The increase in opioid overdose deaths is fueled by a recent 9-fold increase in consumption of the synthetic opioid fentanyl: “The rate of drug overdose deaths involving synthetic opioids other than methadone … increased on average by 8% per year from 1999 through 2013 and by 71% per year from 2013 through 2017.”10
These and other statistics document only a modest rise in deaths that involve prescription opioids: from 15,000 in 2010 to 19,000 in 2016.9,10 Since 2010, the crisis of opioid overdose deaths burns hotter, and the pattern of opioid use has shifted from prescription drugs to much deadlier illicit drugs, such as heroin.
Interventions have not been successful overall. Results of research focused on the impact of opioid tapering and harm-reduction strategies implemented this decade are likewise discouraging. In 2018, the US Department of Veterans Affairs reported that opioid discontinuation was not associated with a reduction in overdose but was associated with an increase in suicide.11,12 Von Korff and colleagues, in a 2017 report, concluded that “Long-term implementation of opioid dose and risk reduction initiatives [in Washington state] was not associated with lower rates of prescription opioid use disorder among prevalent [chronic opioid therapy] patients.”13
Evidence suggests that efforts to address the opioid crisis of the past decade have had an effect that is the opposite of what was intended. The federal government recognized this in April 2019 in a Drug Safety Communication: “The US Food and Drug Administration (FDA) has received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide.”14
In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.
Why Americans obtain prescription opioids
There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:
1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:
- In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
- In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.15
- Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.13
- In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.16
There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.17-20
It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.21
2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”22 In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,23 and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”
Continue to: Psychological trauma...
Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.24
To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”22 requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”25
We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”26
3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.27 The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.13
4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.28
Continue to: Why we taper opioid analgesics
Why we taper opioid analgesics
Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.
Misunderstanding can lead to inappropriate tapering
We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, addiction or OUD).29
Physical dependence is “a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”30 Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.
Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition27), comprises primarily 3 behavioral criteria:
- Loss of control of the medication, with compulsive use
- Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
- Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.29 A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.31 As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”32
Assessment should focus on why the patient is taking an opioid
A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.
Continue to: During assessment...
During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.
We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.
If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.
SIDEBAR
2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain
#1 Should I provide the patient with a prescription for an opioid for a few days, while I await more information?a
Yes. Writing a prescription is a reasonable decision if all of the following apply:
- You do not have significant suspicion of diversion (based on a clinical interview).
- You do not suspect an active addiction disorder, based on the score of the 10-question Drug Abuse Screening Test (DAST-10) and on a clinical interview. (DAST-10 is available at: https://cde.drugabuse.gov/instrument/e9053390-ee9c-9140-e040-bb89ad433d69.)
- The patient is likely to experience withdrawal symptoms if you don’t provide the medication immediately.
- The patient’s pain and function are likely to be impaired if you do not provide the medication.
- The patient does not display altered mental status during the visit (eg, drowsy, slurred speech).
No. If writing a prescription for an opioid for a few days does not seem to be a reasonable decision because the criteria above are not met, but withdrawal symptoms are likely, you can prescribe medication to mitigate symptoms or refer the patient for treatment of withdrawal.
#2 I’ve decided to provide the patient with a prescription for an opioid. For how many days should I write it?
The usual practice, for a patient whose case is familiar to you, is to prescribe a 1-month supply.
However, if any 1 of the following criteria is met, prescribing a 1-month supply is unsafe under most circumstances:
- An unstable social or living environment places the patient at risk by possessing a supply of opioids (based on a clinical interview).
- You suspect an unstable or severe behavioral health condition or a mental health diagnosis (based on a clinical interview or on the patient record from outside your practice).
- The patient scores as “high risk” on the Opioid Risk Tool (ORT; www.drugabuse.gov/sites/default/files/files/OpioidRiskTool.pdf), Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R; www.ncbi.nlm.nih.gov/pmc/articles/PMC4706778/), or a similar opioid risk assessment tool.
When 1 or more of these exclusionary criteria are met, you have 3 options:
- Prescribe an opioid for a brief duration and see the patient often.
- Do not prescribe an opioid; instead, refer the patient as necessary for treatment of withdrawal.
- Refer the patient for treatment of the underlying behavioral health condition.
a Additional information might include findings from consultants you’ve engaged regarding the patient’s diagnosis; a response to your call from a past prescriber; urine drug screen results; and results of a prescription monitoring program check.
Considering a taper? Take this 5-step approach
Once it appears that tapering an opioid is indicated, we propose that you take the following steps:
- Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
- Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE33). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
- Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
- Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).34 This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
- Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.8-11
Shifting to a patient-centered approach
The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach35 that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. 36
Continue to: To underscore the case...
To underscore the case for shifting to a patient-centered approach35 we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”
SIDEBAR
How a patient-centered approach to tapering opioids looks in practice
Five hypothetical cases illustrate what might happen when a practice shifts from an addiction-centered, dosage-centered approach to one that places the individual at the center of care.
CASE #1: Brett F
Mr. F appears to use medication responsibly; benefits functionally from an opioid; has tolerable adverse effects; does not have significant psychosocial risk factors (based on the score of the Opioid Risk Tool [ORT] or the Screener and Opioid Assessment for Patients with Pain–Revised [SOAPP-R]); and is engaged in effective self-management. Most of Mr. F’s pain is thought to have a nociceptive or neuropathic source.
Mr F could reasonably contemplate continuing current opioid treatment.
Action: If the daily morphine milligram equivalent (MME) dosage is high, Mr. F should be referred to a pain medicine specialist. We recommend a periodic (at least annually) empiric trial of dosage reduction to see whether he is indeed best served by the current dosage.
CASE #2: Brett F (version 2.0)
Envision Mr. F having the same profile in all respects except that he is not engaged in effective self-management.
Optimal treatment of chronic pain often requires supplemental modalities beyond opioids.
Action: Physical therapy; an individualized, ongoing exercise regimen; interventional procedures; weight loss (if the patient is obese); smoking cessation; and improving coping skills for anxiety and depression without pharmacotherapy might not only temporarily alleviate the pain but, over time, improve Mr. F’s physical condition.
If Mr. F is not willing to do more than take the prescribed opioids, nothing is likely to change: Over time, his condition is likely to deteriorate. A patient like Mr. F can be harmed if opioids continue to be prescribed for him long-term.
Further action: If Mr. F won’t engage in broadening the approach to treating his pain, the opioid medication should be tapered, in his long-term best interest. A carrot-and-stick approach can facilitate Mr. F’s involvement in his care.
CASE #3: Clark S
Mr. S has a significant psychosocial component driving his pain: depression.a
Prescribing opioids without addressing the root cause of trauma is not in the patient’s best interest.
Action: Because of Mr. S’s depression, refer him to a behavioral health provider. If you determine that he is emotionally stable, wait until he is engaged in trauma treatment to begin the taper. If he appears unstable (eg, crying in the office, recent psychological stressors, recent impulsive behaviors, poor insight) consider (1) urgent behavioral health referral and (2) prescribing only enough opioid medication (ie, at close intervals) to prevent withdrawal and panic. Consider whether a psychotropic medication might be of benefit (eg, a serotonin–norepinephrine reuptake inhibitor or selective serotonin reuptake inhibitor).
Further action: Harm-reduction steps, such as close monitoring and, perhaps, a change to a buprenorphine product, is indicated, especially when the patient is overwhelmed by recent psychosocial stressors. Harm-reduction treatment is available through Medication-Assisted Therapy (MAT) programs; however, patients often run into difficulty obtaining access to these programs because regulations and laws restrict MAT to patients who have a diagnosis of opioid use disorder (OUD) and because some health plans and pharmacy benefit managers require prior authorization.
CASE #4: Gloria B
Ms. B isn’t managing her medications responsibly—although you don’t suspect OUD.
When a patient has shown the inability to manage opioid medication responsibly, you should delve into the reason to determine your next step.
Action: Evaluate Ms. B for a cognitive disorder or a thought disorder. Alternatively, as in the case of Mr. S, a psychosocial component might underlie her pain; in that case, the same recommendations can be made for her. In addition, you can propose that she identify a responsible person to dispense her medication.
CASE #5: Nicole L
You suspect that Ms. L, who is taking opioid medication to alleviate pain, also has a substance use disorder.
Action: Implement harm-reduction early for Ms. L: Obtain addiction medicine consultation and implement behavioral health strategies for addiction treatment.
A key characteristic of a substance use disorder is loss of control over use of the substance. A patient like Ms. L—who is in pain and who has an active OUD—cannot be expected to manage her opioid use responsibly.
Further action: We recommend that Ms. L be referred to an addiction specialist for MAT. Evidence of the harmreduction benefit of MAT is sufficient to strongly recommend it. Continue any other treatment modalities for pain that Ms. L has been using, such as non-opioid medication, physical therapy, alternative treatments, and behavioral therapy, or begin such treatments as appropriate.
a Depression is not the only psychosocial component that can underlie pain. Others include anxiety, posttraumatic stress disorder, and grief.
An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to
- support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
- continue the effort to identify and treat OUD,
- develop best-practice responses to screening, and
- make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.
We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.
CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].
1. Centers for Disease Control and Prevention. Pocket guide: tapering for chronic pain. https://www.cdc.gov/drugoverdose/pdf/clinical_pocket_guide_tapering-a.pdf. Accessed November 25, 2019.
2. Kral LA, Jackson K, Uritsky TJ. A practical guide to tapering opioids. Ment Health Clin. 2015;5:102-108.
3. Murphy L, Babaei-Rad R, Buna D, et al. Guidance on opioid tapering in the context of chronic pain: evidence, practical advice and frequently asked questions. Can Pharm J (Ott). 2018;151:114-120.
4. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2005;90:828-842.
5. Davis M. Prescription opioid use among adults with mental health disorders in the United States. J Am Board Fam Med. 2017;30:407-417.
6. US Government Accountability Office. Report to Congressional Requestors. Prescription drug control: DEA has enhanced efforts to combat diversion, but could better assess and report program results. August 2011. www.gao.gov/assets/520/511464.pdf. Accessed November 25, 2019.
7. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. Annual surveillance report of drug-related risks and outcomes. United States, 2017. www.cdc.gov/drugoverdose/pdf/pubs/2017-cdc-drug-surveillance-report.pdf. Accessed November 25, 2019.
8. Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999-2016, NCHS Data Brief No. 294. December 21, 2017. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/products/databriefs/db294.htm. Accessed November 25, 2019.
9. Overdose death rates. Bethesda, MD: National Institute on Drug Abuse. January 2019. www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates. Accessed November 25, 2019.
10. Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999-2017. NCHS Data Brief No. 329. November 2018. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/data/databriefs/db329-h.pdf . Accessed November 25, 2019.
11. Manhapra A, Kertesz S, Oliva A, et al. VA data about Rx opioids and overdose and suicide: clinical implications. Presented at the 2018 National Rx Drug Abuse and Heroin Summit, Atlanta Georgia, April 4, 2018.
12. Demidenko M, Dobscha SK, Morasco BJ, et al. Suicidal ideation and suicidal self-directed violence following clinician-initiated prescription opioid discontinuation among long-term opioid users. Gen Hosp Psychiatry. 2017;47:29-35.
13. Von Korff M, Walker RL, Saunders K, et al. Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives. Int J Drug Policy. 2017;46:90-98.
14. United States Food and Drug Administration. FDA Drug Safety Communication: FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. April 9, 2019. www.fda.gov/Drugs/DrugSafety/ucm635038.htm. Accessed November 25, 2019.
15. Becker W, Sullivan LE, Tetrault JM, et al. Non-medical use, abuse and dependence on prescription opioids among U.S. adults: psychiatric, medical and substance use correlates. Drug Alcohol Depend. 2008;94:38-47.
16. Yovell Y, Bar G, Mashiah M, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491-498.
17. Pradhan AA, Befort K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32:581-590.
18. Sugiyama A, Yamada M, Saitoh A, et al. Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats. Psychopharmacology (Berl). 2018;235:2947-2955.
19. Richards EM, Mathews DC, Luckenbaugh DA, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology (Berl). 2016;233:1119-1130.
20. Yang PP, Yeh GC, Yeh TK, et al. Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res. 2016;111:867-876.
21. America’s mental health 2018. Stamford, CT: Cohen Veterans Network. October 10, 2018. https://www.cohenveteransnetwork.org/wp-content/uploads/2018/10/Research-Summary-10-10-2018.pdf. Accessed November 25, 2019.
22. Classification of Chronic Pain, Second Edition (Revised). Washington, DC: International Association for the Study of Pain. Updated 2012. www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673. Accessed November 25, 2019.
23. Davis B, Vanderah TW. A new paradigm for pain? J Fam Pract. 2016 65:598-605.
24. Defrin R, Ginzburg K, Solomon Z, et al. Quantitative testing of pain perception in subjects with PTSD—implications for the mechanism of the coexistence between PTSD and chronic pain. Pain. 2008;138:450-459.
25. Foa EB, Gillihan SJ, Bryant RA. Challenges and successes in dissemination of evidence-based treatments for posttraumatic stress: lessons learned from prolonged exposure therapy for PTSD. Psychol Science Public Interest. 2013;14:65-111.
26. Miele D, O’Brien EJ. Underdiagnosis of posttraumatic stress disorder in at risk youth. J Trauma Stress. 2010;23:591-598.
27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edition. Washington, DC: American Psychiatric Publishing; 2013:541.
28. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372:241-248.
29. Schuchat A, Houry D, Guy GP Jr. New data on opioid use and prescribing in the United States. JAMA. 2017;318:425-426.
30. American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Definitions related to the use of opioids for the treatment of pain. 2001. www.naabt.org/documents/APS_consensus_document.pdf. Accessed November 25, 2019.
31. Fishbain DA, Cole B, Lewis J, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9:444-459.
32. Volkow ND, McClellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253-1263.
33. Treede RD, Rief W, Barke A. A classification of chronic pain for ICD-11. Pain. 2015;156:1003-1007.
34. Screening, brief intervention, and referral to treatment (SBIRT). Rockville, MD: Substance Abuse and Mental Health Services Administration. www.samhsa.gov/sbirt. Accessed November 25, 2019.
35. Schneider JP, Davis B. How well do you know your patient? Pract Pain Manag. 2017;17(2). www.practicalpainmanagement.com/resources/practice-management/how-well-do-you-know-your-patient. Accessed November 25, 2019.
36. Schneider JP. A patient-centered approach to the opioid overdose crisis. J Miss State Med Assoc. 2018;59:232-233.
Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.5 (See “Tapering and harm-reduction strategies have failed.”6-14)
SIDEBAR
Tapering and harm-reduction strategies have failed
Efforts to address the rising number of overdose events that involve opioids began in earnest in 2010. In a 2011 Government Accountability Office report to Congress, the Drug Enforcement Agency reported that “the number of regulatory investigations (of medical providers who prescribed opioids) tripled between fiscal years 2009- 2010.”6
How has it gone since 2010? High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.7,8 Just the opposite: The 19,000 overdose deaths recorded in 2010 involving any opioid increased to 49,068 by 2017, the National Institute on Drug Abuse reports.9 The increase in opioid overdose deaths is fueled by a recent 9-fold increase in consumption of the synthetic opioid fentanyl: “The rate of drug overdose deaths involving synthetic opioids other than methadone … increased on average by 8% per year from 1999 through 2013 and by 71% per year from 2013 through 2017.”10
These and other statistics document only a modest rise in deaths that involve prescription opioids: from 15,000 in 2010 to 19,000 in 2016.9,10 Since 2010, the crisis of opioid overdose deaths burns hotter, and the pattern of opioid use has shifted from prescription drugs to much deadlier illicit drugs, such as heroin.
Interventions have not been successful overall. Results of research focused on the impact of opioid tapering and harm-reduction strategies implemented this decade are likewise discouraging. In 2018, the US Department of Veterans Affairs reported that opioid discontinuation was not associated with a reduction in overdose but was associated with an increase in suicide.11,12 Von Korff and colleagues, in a 2017 report, concluded that “Long-term implementation of opioid dose and risk reduction initiatives [in Washington state] was not associated with lower rates of prescription opioid use disorder among prevalent [chronic opioid therapy] patients.”13
Evidence suggests that efforts to address the opioid crisis of the past decade have had an effect that is the opposite of what was intended. The federal government recognized this in April 2019 in a Drug Safety Communication: “The US Food and Drug Administration (FDA) has received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide.”14
In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.
Why Americans obtain prescription opioids
There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:
1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:
- In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
- In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.15
- Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.13
- In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.16
There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.17-20
It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.21
2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”22 In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,23 and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”
Continue to: Psychological trauma...
Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.24
To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”22 requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”25
We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”26
3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.27 The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.13
4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.28
Continue to: Why we taper opioid analgesics
Why we taper opioid analgesics
Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.
Misunderstanding can lead to inappropriate tapering
We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, addiction or OUD).29
Physical dependence is “a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”30 Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.
Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition27), comprises primarily 3 behavioral criteria:
- Loss of control of the medication, with compulsive use
- Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
- Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.29 A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.31 As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”32
Assessment should focus on why the patient is taking an opioid
A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.
Continue to: During assessment...
During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.
We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.
If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.
SIDEBAR
2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain
#1 Should I provide the patient with a prescription for an opioid for a few days, while I await more information?a
Yes. Writing a prescription is a reasonable decision if all of the following apply:
- You do not have significant suspicion of diversion (based on a clinical interview).
- You do not suspect an active addiction disorder, based on the score of the 10-question Drug Abuse Screening Test (DAST-10) and on a clinical interview. (DAST-10 is available at: https://cde.drugabuse.gov/instrument/e9053390-ee9c-9140-e040-bb89ad433d69.)
- The patient is likely to experience withdrawal symptoms if you don’t provide the medication immediately.
- The patient’s pain and function are likely to be impaired if you do not provide the medication.
- The patient does not display altered mental status during the visit (eg, drowsy, slurred speech).
No. If writing a prescription for an opioid for a few days does not seem to be a reasonable decision because the criteria above are not met, but withdrawal symptoms are likely, you can prescribe medication to mitigate symptoms or refer the patient for treatment of withdrawal.
#2 I’ve decided to provide the patient with a prescription for an opioid. For how many days should I write it?
The usual practice, for a patient whose case is familiar to you, is to prescribe a 1-month supply.
However, if any 1 of the following criteria is met, prescribing a 1-month supply is unsafe under most circumstances:
- An unstable social or living environment places the patient at risk by possessing a supply of opioids (based on a clinical interview).
- You suspect an unstable or severe behavioral health condition or a mental health diagnosis (based on a clinical interview or on the patient record from outside your practice).
- The patient scores as “high risk” on the Opioid Risk Tool (ORT; www.drugabuse.gov/sites/default/files/files/OpioidRiskTool.pdf), Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R; www.ncbi.nlm.nih.gov/pmc/articles/PMC4706778/), or a similar opioid risk assessment tool.
When 1 or more of these exclusionary criteria are met, you have 3 options:
- Prescribe an opioid for a brief duration and see the patient often.
- Do not prescribe an opioid; instead, refer the patient as necessary for treatment of withdrawal.
- Refer the patient for treatment of the underlying behavioral health condition.
a Additional information might include findings from consultants you’ve engaged regarding the patient’s diagnosis; a response to your call from a past prescriber; urine drug screen results; and results of a prescription monitoring program check.
Considering a taper? Take this 5-step approach
Once it appears that tapering an opioid is indicated, we propose that you take the following steps:
- Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
- Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE33). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
- Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
- Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).34 This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
- Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.8-11
Shifting to a patient-centered approach
The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach35 that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. 36
Continue to: To underscore the case...
To underscore the case for shifting to a patient-centered approach35 we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”
SIDEBAR
How a patient-centered approach to tapering opioids looks in practice
Five hypothetical cases illustrate what might happen when a practice shifts from an addiction-centered, dosage-centered approach to one that places the individual at the center of care.
CASE #1: Brett F
Mr. F appears to use medication responsibly; benefits functionally from an opioid; has tolerable adverse effects; does not have significant psychosocial risk factors (based on the score of the Opioid Risk Tool [ORT] or the Screener and Opioid Assessment for Patients with Pain–Revised [SOAPP-R]); and is engaged in effective self-management. Most of Mr. F’s pain is thought to have a nociceptive or neuropathic source.
Mr F could reasonably contemplate continuing current opioid treatment.
Action: If the daily morphine milligram equivalent (MME) dosage is high, Mr. F should be referred to a pain medicine specialist. We recommend a periodic (at least annually) empiric trial of dosage reduction to see whether he is indeed best served by the current dosage.
CASE #2: Brett F (version 2.0)
Envision Mr. F having the same profile in all respects except that he is not engaged in effective self-management.
Optimal treatment of chronic pain often requires supplemental modalities beyond opioids.
Action: Physical therapy; an individualized, ongoing exercise regimen; interventional procedures; weight loss (if the patient is obese); smoking cessation; and improving coping skills for anxiety and depression without pharmacotherapy might not only temporarily alleviate the pain but, over time, improve Mr. F’s physical condition.
If Mr. F is not willing to do more than take the prescribed opioids, nothing is likely to change: Over time, his condition is likely to deteriorate. A patient like Mr. F can be harmed if opioids continue to be prescribed for him long-term.
Further action: If Mr. F won’t engage in broadening the approach to treating his pain, the opioid medication should be tapered, in his long-term best interest. A carrot-and-stick approach can facilitate Mr. F’s involvement in his care.
CASE #3: Clark S
Mr. S has a significant psychosocial component driving his pain: depression.a
Prescribing opioids without addressing the root cause of trauma is not in the patient’s best interest.
Action: Because of Mr. S’s depression, refer him to a behavioral health provider. If you determine that he is emotionally stable, wait until he is engaged in trauma treatment to begin the taper. If he appears unstable (eg, crying in the office, recent psychological stressors, recent impulsive behaviors, poor insight) consider (1) urgent behavioral health referral and (2) prescribing only enough opioid medication (ie, at close intervals) to prevent withdrawal and panic. Consider whether a psychotropic medication might be of benefit (eg, a serotonin–norepinephrine reuptake inhibitor or selective serotonin reuptake inhibitor).
Further action: Harm-reduction steps, such as close monitoring and, perhaps, a change to a buprenorphine product, is indicated, especially when the patient is overwhelmed by recent psychosocial stressors. Harm-reduction treatment is available through Medication-Assisted Therapy (MAT) programs; however, patients often run into difficulty obtaining access to these programs because regulations and laws restrict MAT to patients who have a diagnosis of opioid use disorder (OUD) and because some health plans and pharmacy benefit managers require prior authorization.
CASE #4: Gloria B
Ms. B isn’t managing her medications responsibly—although you don’t suspect OUD.
When a patient has shown the inability to manage opioid medication responsibly, you should delve into the reason to determine your next step.
Action: Evaluate Ms. B for a cognitive disorder or a thought disorder. Alternatively, as in the case of Mr. S, a psychosocial component might underlie her pain; in that case, the same recommendations can be made for her. In addition, you can propose that she identify a responsible person to dispense her medication.
CASE #5: Nicole L
You suspect that Ms. L, who is taking opioid medication to alleviate pain, also has a substance use disorder.
Action: Implement harm-reduction early for Ms. L: Obtain addiction medicine consultation and implement behavioral health strategies for addiction treatment.
A key characteristic of a substance use disorder is loss of control over use of the substance. A patient like Ms. L—who is in pain and who has an active OUD—cannot be expected to manage her opioid use responsibly.
Further action: We recommend that Ms. L be referred to an addiction specialist for MAT. Evidence of the harmreduction benefit of MAT is sufficient to strongly recommend it. Continue any other treatment modalities for pain that Ms. L has been using, such as non-opioid medication, physical therapy, alternative treatments, and behavioral therapy, or begin such treatments as appropriate.
a Depression is not the only psychosocial component that can underlie pain. Others include anxiety, posttraumatic stress disorder, and grief.
An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to
- support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
- continue the effort to identify and treat OUD,
- develop best-practice responses to screening, and
- make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.
We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.
CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].
Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.5 (See “Tapering and harm-reduction strategies have failed.”6-14)
SIDEBAR
Tapering and harm-reduction strategies have failed
Efforts to address the rising number of overdose events that involve opioids began in earnest in 2010. In a 2011 Government Accountability Office report to Congress, the Drug Enforcement Agency reported that “the number of regulatory investigations (of medical providers who prescribed opioids) tripled between fiscal years 2009- 2010.”6
How has it gone since 2010? High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.7,8 Just the opposite: The 19,000 overdose deaths recorded in 2010 involving any opioid increased to 49,068 by 2017, the National Institute on Drug Abuse reports.9 The increase in opioid overdose deaths is fueled by a recent 9-fold increase in consumption of the synthetic opioid fentanyl: “The rate of drug overdose deaths involving synthetic opioids other than methadone … increased on average by 8% per year from 1999 through 2013 and by 71% per year from 2013 through 2017.”10
These and other statistics document only a modest rise in deaths that involve prescription opioids: from 15,000 in 2010 to 19,000 in 2016.9,10 Since 2010, the crisis of opioid overdose deaths burns hotter, and the pattern of opioid use has shifted from prescription drugs to much deadlier illicit drugs, such as heroin.
Interventions have not been successful overall. Results of research focused on the impact of opioid tapering and harm-reduction strategies implemented this decade are likewise discouraging. In 2018, the US Department of Veterans Affairs reported that opioid discontinuation was not associated with a reduction in overdose but was associated with an increase in suicide.11,12 Von Korff and colleagues, in a 2017 report, concluded that “Long-term implementation of opioid dose and risk reduction initiatives [in Washington state] was not associated with lower rates of prescription opioid use disorder among prevalent [chronic opioid therapy] patients.”13
Evidence suggests that efforts to address the opioid crisis of the past decade have had an effect that is the opposite of what was intended. The federal government recognized this in April 2019 in a Drug Safety Communication: “The US Food and Drug Administration (FDA) has received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide.”14
In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.
Why Americans obtain prescription opioids
There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:
1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:
- In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
- In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.15
- Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.13
- In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.16
There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.17-20
It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.21
2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”22 In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,23 and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”
Continue to: Psychological trauma...
Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.24
To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”22 requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”25
We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”26
3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.27 The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.13
4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.28
Continue to: Why we taper opioid analgesics
Why we taper opioid analgesics
Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.
Misunderstanding can lead to inappropriate tapering
We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, addiction or OUD).29
Physical dependence is “a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”30 Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.
Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition27), comprises primarily 3 behavioral criteria:
- Loss of control of the medication, with compulsive use
- Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
- Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.29 A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.31 As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”32
Assessment should focus on why the patient is taking an opioid
A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.
Continue to: During assessment...
During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.
We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.
If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.
SIDEBAR
2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain
#1 Should I provide the patient with a prescription for an opioid for a few days, while I await more information?a
Yes. Writing a prescription is a reasonable decision if all of the following apply:
- You do not have significant suspicion of diversion (based on a clinical interview).
- You do not suspect an active addiction disorder, based on the score of the 10-question Drug Abuse Screening Test (DAST-10) and on a clinical interview. (DAST-10 is available at: https://cde.drugabuse.gov/instrument/e9053390-ee9c-9140-e040-bb89ad433d69.)
- The patient is likely to experience withdrawal symptoms if you don’t provide the medication immediately.
- The patient’s pain and function are likely to be impaired if you do not provide the medication.
- The patient does not display altered mental status during the visit (eg, drowsy, slurred speech).
No. If writing a prescription for an opioid for a few days does not seem to be a reasonable decision because the criteria above are not met, but withdrawal symptoms are likely, you can prescribe medication to mitigate symptoms or refer the patient for treatment of withdrawal.
#2 I’ve decided to provide the patient with a prescription for an opioid. For how many days should I write it?
The usual practice, for a patient whose case is familiar to you, is to prescribe a 1-month supply.
However, if any 1 of the following criteria is met, prescribing a 1-month supply is unsafe under most circumstances:
- An unstable social or living environment places the patient at risk by possessing a supply of opioids (based on a clinical interview).
- You suspect an unstable or severe behavioral health condition or a mental health diagnosis (based on a clinical interview or on the patient record from outside your practice).
- The patient scores as “high risk” on the Opioid Risk Tool (ORT; www.drugabuse.gov/sites/default/files/files/OpioidRiskTool.pdf), Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R; www.ncbi.nlm.nih.gov/pmc/articles/PMC4706778/), or a similar opioid risk assessment tool.
When 1 or more of these exclusionary criteria are met, you have 3 options:
- Prescribe an opioid for a brief duration and see the patient often.
- Do not prescribe an opioid; instead, refer the patient as necessary for treatment of withdrawal.
- Refer the patient for treatment of the underlying behavioral health condition.
a Additional information might include findings from consultants you’ve engaged regarding the patient’s diagnosis; a response to your call from a past prescriber; urine drug screen results; and results of a prescription monitoring program check.
Considering a taper? Take this 5-step approach
Once it appears that tapering an opioid is indicated, we propose that you take the following steps:
- Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
- Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE33). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
- Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
- Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).34 This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
- Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.8-11
Shifting to a patient-centered approach
The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach35 that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. 36
Continue to: To underscore the case...
To underscore the case for shifting to a patient-centered approach35 we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”
SIDEBAR
How a patient-centered approach to tapering opioids looks in practice
Five hypothetical cases illustrate what might happen when a practice shifts from an addiction-centered, dosage-centered approach to one that places the individual at the center of care.
CASE #1: Brett F
Mr. F appears to use medication responsibly; benefits functionally from an opioid; has tolerable adverse effects; does not have significant psychosocial risk factors (based on the score of the Opioid Risk Tool [ORT] or the Screener and Opioid Assessment for Patients with Pain–Revised [SOAPP-R]); and is engaged in effective self-management. Most of Mr. F’s pain is thought to have a nociceptive or neuropathic source.
Mr F could reasonably contemplate continuing current opioid treatment.
Action: If the daily morphine milligram equivalent (MME) dosage is high, Mr. F should be referred to a pain medicine specialist. We recommend a periodic (at least annually) empiric trial of dosage reduction to see whether he is indeed best served by the current dosage.
CASE #2: Brett F (version 2.0)
Envision Mr. F having the same profile in all respects except that he is not engaged in effective self-management.
Optimal treatment of chronic pain often requires supplemental modalities beyond opioids.
Action: Physical therapy; an individualized, ongoing exercise regimen; interventional procedures; weight loss (if the patient is obese); smoking cessation; and improving coping skills for anxiety and depression without pharmacotherapy might not only temporarily alleviate the pain but, over time, improve Mr. F’s physical condition.
If Mr. F is not willing to do more than take the prescribed opioids, nothing is likely to change: Over time, his condition is likely to deteriorate. A patient like Mr. F can be harmed if opioids continue to be prescribed for him long-term.
Further action: If Mr. F won’t engage in broadening the approach to treating his pain, the opioid medication should be tapered, in his long-term best interest. A carrot-and-stick approach can facilitate Mr. F’s involvement in his care.
CASE #3: Clark S
Mr. S has a significant psychosocial component driving his pain: depression.a
Prescribing opioids without addressing the root cause of trauma is not in the patient’s best interest.
Action: Because of Mr. S’s depression, refer him to a behavioral health provider. If you determine that he is emotionally stable, wait until he is engaged in trauma treatment to begin the taper. If he appears unstable (eg, crying in the office, recent psychological stressors, recent impulsive behaviors, poor insight) consider (1) urgent behavioral health referral and (2) prescribing only enough opioid medication (ie, at close intervals) to prevent withdrawal and panic. Consider whether a psychotropic medication might be of benefit (eg, a serotonin–norepinephrine reuptake inhibitor or selective serotonin reuptake inhibitor).
Further action: Harm-reduction steps, such as close monitoring and, perhaps, a change to a buprenorphine product, is indicated, especially when the patient is overwhelmed by recent psychosocial stressors. Harm-reduction treatment is available through Medication-Assisted Therapy (MAT) programs; however, patients often run into difficulty obtaining access to these programs because regulations and laws restrict MAT to patients who have a diagnosis of opioid use disorder (OUD) and because some health plans and pharmacy benefit managers require prior authorization.
CASE #4: Gloria B
Ms. B isn’t managing her medications responsibly—although you don’t suspect OUD.
When a patient has shown the inability to manage opioid medication responsibly, you should delve into the reason to determine your next step.
Action: Evaluate Ms. B for a cognitive disorder or a thought disorder. Alternatively, as in the case of Mr. S, a psychosocial component might underlie her pain; in that case, the same recommendations can be made for her. In addition, you can propose that she identify a responsible person to dispense her medication.
CASE #5: Nicole L
You suspect that Ms. L, who is taking opioid medication to alleviate pain, also has a substance use disorder.
Action: Implement harm-reduction early for Ms. L: Obtain addiction medicine consultation and implement behavioral health strategies for addiction treatment.
A key characteristic of a substance use disorder is loss of control over use of the substance. A patient like Ms. L—who is in pain and who has an active OUD—cannot be expected to manage her opioid use responsibly.
Further action: We recommend that Ms. L be referred to an addiction specialist for MAT. Evidence of the harmreduction benefit of MAT is sufficient to strongly recommend it. Continue any other treatment modalities for pain that Ms. L has been using, such as non-opioid medication, physical therapy, alternative treatments, and behavioral therapy, or begin such treatments as appropriate.
a Depression is not the only psychosocial component that can underlie pain. Others include anxiety, posttraumatic stress disorder, and grief.
An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to
- support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
- continue the effort to identify and treat OUD,
- develop best-practice responses to screening, and
- make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.
We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.
CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].
1. Centers for Disease Control and Prevention. Pocket guide: tapering for chronic pain. https://www.cdc.gov/drugoverdose/pdf/clinical_pocket_guide_tapering-a.pdf. Accessed November 25, 2019.
2. Kral LA, Jackson K, Uritsky TJ. A practical guide to tapering opioids. Ment Health Clin. 2015;5:102-108.
3. Murphy L, Babaei-Rad R, Buna D, et al. Guidance on opioid tapering in the context of chronic pain: evidence, practical advice and frequently asked questions. Can Pharm J (Ott). 2018;151:114-120.
4. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2005;90:828-842.
5. Davis M. Prescription opioid use among adults with mental health disorders in the United States. J Am Board Fam Med. 2017;30:407-417.
6. US Government Accountability Office. Report to Congressional Requestors. Prescription drug control: DEA has enhanced efforts to combat diversion, but could better assess and report program results. August 2011. www.gao.gov/assets/520/511464.pdf. Accessed November 25, 2019.
7. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. Annual surveillance report of drug-related risks and outcomes. United States, 2017. www.cdc.gov/drugoverdose/pdf/pubs/2017-cdc-drug-surveillance-report.pdf. Accessed November 25, 2019.
8. Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999-2016, NCHS Data Brief No. 294. December 21, 2017. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/products/databriefs/db294.htm. Accessed November 25, 2019.
9. Overdose death rates. Bethesda, MD: National Institute on Drug Abuse. January 2019. www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates. Accessed November 25, 2019.
10. Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999-2017. NCHS Data Brief No. 329. November 2018. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/data/databriefs/db329-h.pdf . Accessed November 25, 2019.
11. Manhapra A, Kertesz S, Oliva A, et al. VA data about Rx opioids and overdose and suicide: clinical implications. Presented at the 2018 National Rx Drug Abuse and Heroin Summit, Atlanta Georgia, April 4, 2018.
12. Demidenko M, Dobscha SK, Morasco BJ, et al. Suicidal ideation and suicidal self-directed violence following clinician-initiated prescription opioid discontinuation among long-term opioid users. Gen Hosp Psychiatry. 2017;47:29-35.
13. Von Korff M, Walker RL, Saunders K, et al. Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives. Int J Drug Policy. 2017;46:90-98.
14. United States Food and Drug Administration. FDA Drug Safety Communication: FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. April 9, 2019. www.fda.gov/Drugs/DrugSafety/ucm635038.htm. Accessed November 25, 2019.
15. Becker W, Sullivan LE, Tetrault JM, et al. Non-medical use, abuse and dependence on prescription opioids among U.S. adults: psychiatric, medical and substance use correlates. Drug Alcohol Depend. 2008;94:38-47.
16. Yovell Y, Bar G, Mashiah M, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491-498.
17. Pradhan AA, Befort K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32:581-590.
18. Sugiyama A, Yamada M, Saitoh A, et al. Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats. Psychopharmacology (Berl). 2018;235:2947-2955.
19. Richards EM, Mathews DC, Luckenbaugh DA, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology (Berl). 2016;233:1119-1130.
20. Yang PP, Yeh GC, Yeh TK, et al. Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res. 2016;111:867-876.
21. America’s mental health 2018. Stamford, CT: Cohen Veterans Network. October 10, 2018. https://www.cohenveteransnetwork.org/wp-content/uploads/2018/10/Research-Summary-10-10-2018.pdf. Accessed November 25, 2019.
22. Classification of Chronic Pain, Second Edition (Revised). Washington, DC: International Association for the Study of Pain. Updated 2012. www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673. Accessed November 25, 2019.
23. Davis B, Vanderah TW. A new paradigm for pain? J Fam Pract. 2016 65:598-605.
24. Defrin R, Ginzburg K, Solomon Z, et al. Quantitative testing of pain perception in subjects with PTSD—implications for the mechanism of the coexistence between PTSD and chronic pain. Pain. 2008;138:450-459.
25. Foa EB, Gillihan SJ, Bryant RA. Challenges and successes in dissemination of evidence-based treatments for posttraumatic stress: lessons learned from prolonged exposure therapy for PTSD. Psychol Science Public Interest. 2013;14:65-111.
26. Miele D, O’Brien EJ. Underdiagnosis of posttraumatic stress disorder in at risk youth. J Trauma Stress. 2010;23:591-598.
27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edition. Washington, DC: American Psychiatric Publishing; 2013:541.
28. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372:241-248.
29. Schuchat A, Houry D, Guy GP Jr. New data on opioid use and prescribing in the United States. JAMA. 2017;318:425-426.
30. American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Definitions related to the use of opioids for the treatment of pain. 2001. www.naabt.org/documents/APS_consensus_document.pdf. Accessed November 25, 2019.
31. Fishbain DA, Cole B, Lewis J, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9:444-459.
32. Volkow ND, McClellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253-1263.
33. Treede RD, Rief W, Barke A. A classification of chronic pain for ICD-11. Pain. 2015;156:1003-1007.
34. Screening, brief intervention, and referral to treatment (SBIRT). Rockville, MD: Substance Abuse and Mental Health Services Administration. www.samhsa.gov/sbirt. Accessed November 25, 2019.
35. Schneider JP, Davis B. How well do you know your patient? Pract Pain Manag. 2017;17(2). www.practicalpainmanagement.com/resources/practice-management/how-well-do-you-know-your-patient. Accessed November 25, 2019.
36. Schneider JP. A patient-centered approach to the opioid overdose crisis. J Miss State Med Assoc. 2018;59:232-233.
1. Centers for Disease Control and Prevention. Pocket guide: tapering for chronic pain. https://www.cdc.gov/drugoverdose/pdf/clinical_pocket_guide_tapering-a.pdf. Accessed November 25, 2019.
2. Kral LA, Jackson K, Uritsky TJ. A practical guide to tapering opioids. Ment Health Clin. 2015;5:102-108.
3. Murphy L, Babaei-Rad R, Buna D, et al. Guidance on opioid tapering in the context of chronic pain: evidence, practical advice and frequently asked questions. Can Pharm J (Ott). 2018;151:114-120.
4. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2005;90:828-842.
5. Davis M. Prescription opioid use among adults with mental health disorders in the United States. J Am Board Fam Med. 2017;30:407-417.
6. US Government Accountability Office. Report to Congressional Requestors. Prescription drug control: DEA has enhanced efforts to combat diversion, but could better assess and report program results. August 2011. www.gao.gov/assets/520/511464.pdf. Accessed November 25, 2019.
7. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. Annual surveillance report of drug-related risks and outcomes. United States, 2017. www.cdc.gov/drugoverdose/pdf/pubs/2017-cdc-drug-surveillance-report.pdf. Accessed November 25, 2019.
8. Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999-2016, NCHS Data Brief No. 294. December 21, 2017. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/products/databriefs/db294.htm. Accessed November 25, 2019.
9. Overdose death rates. Bethesda, MD: National Institute on Drug Abuse. January 2019. www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates. Accessed November 25, 2019.
10. Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999-2017. NCHS Data Brief No. 329. November 2018. Hyattsville, MD: National Center for Health Statistics. www.cdc.gov/nchs/data/databriefs/db329-h.pdf . Accessed November 25, 2019.
11. Manhapra A, Kertesz S, Oliva A, et al. VA data about Rx opioids and overdose and suicide: clinical implications. Presented at the 2018 National Rx Drug Abuse and Heroin Summit, Atlanta Georgia, April 4, 2018.
12. Demidenko M, Dobscha SK, Morasco BJ, et al. Suicidal ideation and suicidal self-directed violence following clinician-initiated prescription opioid discontinuation among long-term opioid users. Gen Hosp Psychiatry. 2017;47:29-35.
13. Von Korff M, Walker RL, Saunders K, et al. Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives. Int J Drug Policy. 2017;46:90-98.
14. United States Food and Drug Administration. FDA Drug Safety Communication: FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. April 9, 2019. www.fda.gov/Drugs/DrugSafety/ucm635038.htm. Accessed November 25, 2019.
15. Becker W, Sullivan LE, Tetrault JM, et al. Non-medical use, abuse and dependence on prescription opioids among U.S. adults: psychiatric, medical and substance use correlates. Drug Alcohol Depend. 2008;94:38-47.
16. Yovell Y, Bar G, Mashiah M, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491-498.
17. Pradhan AA, Befort K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32:581-590.
18. Sugiyama A, Yamada M, Saitoh A, et al. Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats. Psychopharmacology (Berl). 2018;235:2947-2955.
19. Richards EM, Mathews DC, Luckenbaugh DA, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology (Berl). 2016;233:1119-1130.
20. Yang PP, Yeh GC, Yeh TK, et al. Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res. 2016;111:867-876.
21. America’s mental health 2018. Stamford, CT: Cohen Veterans Network. October 10, 2018. https://www.cohenveteransnetwork.org/wp-content/uploads/2018/10/Research-Summary-10-10-2018.pdf. Accessed November 25, 2019.
22. Classification of Chronic Pain, Second Edition (Revised). Washington, DC: International Association for the Study of Pain. Updated 2012. www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673. Accessed November 25, 2019.
23. Davis B, Vanderah TW. A new paradigm for pain? J Fam Pract. 2016 65:598-605.
24. Defrin R, Ginzburg K, Solomon Z, et al. Quantitative testing of pain perception in subjects with PTSD—implications for the mechanism of the coexistence between PTSD and chronic pain. Pain. 2008;138:450-459.
25. Foa EB, Gillihan SJ, Bryant RA. Challenges and successes in dissemination of evidence-based treatments for posttraumatic stress: lessons learned from prolonged exposure therapy for PTSD. Psychol Science Public Interest. 2013;14:65-111.
26. Miele D, O’Brien EJ. Underdiagnosis of posttraumatic stress disorder in at risk youth. J Trauma Stress. 2010;23:591-598.
27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edition. Washington, DC: American Psychiatric Publishing; 2013:541.
28. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372:241-248.
29. Schuchat A, Houry D, Guy GP Jr. New data on opioid use and prescribing in the United States. JAMA. 2017;318:425-426.
30. American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Definitions related to the use of opioids for the treatment of pain. 2001. www.naabt.org/documents/APS_consensus_document.pdf. Accessed November 25, 2019.
31. Fishbain DA, Cole B, Lewis J, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9:444-459.
32. Volkow ND, McClellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253-1263.
33. Treede RD, Rief W, Barke A. A classification of chronic pain for ICD-11. Pain. 2015;156:1003-1007.
34. Screening, brief intervention, and referral to treatment (SBIRT). Rockville, MD: Substance Abuse and Mental Health Services Administration. www.samhsa.gov/sbirt. Accessed November 25, 2019.
35. Schneider JP, Davis B. How well do you know your patient? Pract Pain Manag. 2017;17(2). www.practicalpainmanagement.com/resources/practice-management/how-well-do-you-know-your-patient. Accessed November 25, 2019.
36. Schneider JP. A patient-centered approach to the opioid overdose crisis. J Miss State Med Assoc. 2018;59:232-233.
PRACTICE RECOMMENDATIONS
› Screen for developmental and adult trauma, for current trauma symptoms, and for opioid use disorder before tapering an opioid. B
› Refer the patient for in-depth behavioral health evaluation when screening identifies risk of behavioral problems, to identify psychological, behavioral, emotional, cognitive, and social factors pertinent to the prevention, treatment, or management of physical health problems, such as chronic pain. A
› Refer the patient for addiction medicine treatment, either within your practice or to an outside consultant, when screening for opioid use disorder indicates that the patient is at risk. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
When guideline treatment of asthma fails, consider a macrolide antibiotic
In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.3
This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.
3 cases to consider
CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.
Outcome. Mr. D has remained free of symptoms of asthma for more than 20 years.
CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.
Outcome. Casey was able to resume normal physical activities, including competitive swimming.
CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.
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Continue to: Outcome...
Outcome. Ms. S’s symptoms resolved completely within months.
Evidence of benefit of macrolides in asthma
These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma
SIDEBAR
Macrolides for Asthma: Registry of Clinical Experience
More information is needed about the “real world” effectiveness of antibiotic treatment for severe refractory and new-onset asthma. If you are a prescribing clinician who cares for patients with asthma and you are considering prescribing antibiotics for asthma, you are invited to document your outcomes by entering prospective, de-identified patient data into a human subjects committee-approved online registry. To gain access to the registry, and for more information, contact the author at [email protected] or visit https://www.fammed.wisc.edu/wren/resources/macrolides-for-asthma/ .
Meta-analysis. Reiter et al4 performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV1) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.
Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and procedures.”
Cochrane meta-analysis. Kew et al5 performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported
- no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
- significant effects of macrolides for asthma symptoms and FEV1.
Continue to: Two within-study subgroup...
Two within-study subgroup analyses showed a possible benefit of macrolides for non-eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al5 noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.
Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.
Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.6 Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.2 Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.2
Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials7,8 that were not included in the cited meta-analyses, along with other evidence,2 point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.
Clinical trial in adults. Gibson et al7 conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.9
Continue to: Azithromycin reduced the frequency...
Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).
There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.
Other evidence10 indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).
Pediatric clinical trial. Stokholm et al8 performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.
Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).
Continue to: No differences between...
No differences between the randomized groups were observed in clinical adverse effects.
Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little12 or no13 short-term benefit; however, these negative findings have been hypothesized to be the result of selection bias.14
Other evidence is worth examining
Other studies not included in the meta-analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.
Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)15 is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.
However, many eligible subjects, whom the principal investigator believed were ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose16 (OL cohort only, Level 2 study: controlled, nonrandomized, nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.
Continue to: The less severely...
The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.
Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”15
Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).17 Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.
Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).
These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.17 Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.
Continue to: Physicians should also note...
Physicians should also note the landmark trial of azithromycin in severe, smoking-associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).18
Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.19 A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.
Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.
Tx recommendations: When to consider azithromycin
Randomized7 and nonrandomized15 evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).
It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.11 Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).10
Continue to: Do biomarkers predict response?
Do biomarkers predict response?
Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended20 but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.
So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma21) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.3 The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.22 Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this recommendation).
Acute bronchitis and asthma-onset associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.23 However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.23 Several other matters are worth noting:
- C pneumoniae-specific IgA23 and IgE24 are promising biomarkers that deserve further investigation.
- M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.21,25
- Noneosinophilic severe asthma is another potential predictive characteristic.26 The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial7 reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.
Potential for harm withlong-term macrolide use?
Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 127,28 and discussed below).29
Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.30 In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.31,32 The major clinical “side effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.31,32
Continue to: Antibiotic resistance
Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens33; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.34 There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.33
In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.35 In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.8,36
Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.
Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in every 4000 administrations.27 Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.37 There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population38,39 or when azithromycin is coadministered with a LABA.3
Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).32 In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32
Continue to: Physicians who prescribe...
Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.
Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.40 Nevertheless:
- Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
- Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of azithromycin.
- The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.40
Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.2 A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.41 Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.41
Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.44
What about cost?
Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS15—costs about as much as 1 ICS and LABA combination inhaler. Using published results,15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.
Continue to: Recommendations to reflect on for your practice
Recommendations to reflect on for your practice
Table 27,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients
- whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
- who have new-onset asthma.
Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.
*Data available from the author upon request. See “Correspondence,” at end of article.
CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].
1. Hahn DL. Role of Chlamydia pneumoniae as an inducer of asthma. In: Friedman H, Yamamoto Y, Bendinelli M, eds. Chlamydia Pneumoniae: Infection and Disease. New York: Kluwer Academic/Plenum Publishers; 2004:239-262.
2. Webley WC, Hahn DL. Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respir Res. 2017;18:98.
3. Wong EH, Porter JD, Edwards MR, et al. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014;2:657-670.
4. Reiter J, Demirel N, Mendy A, et al. Macrolides for the long-term management of asthma—a meta-analysis of randomized clinical trials. Allergy. 2013;68:1040-1049.
5. Kew KM, Undela K, Kotortsi I, et al. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015(9):CD002997.
6. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax. 2007;62:219-223.
7. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
8. Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4:19-26.
9. Korn S, Both J, Jung M, et al. Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. Ann Allergy Asthma Immunol. 2011;107:474-479.
10. Hahn DL. A Cure for Asthma? What Your Doctor Isn’t Telling You—and Why. Durham, North Carolina: Peoples Pharmacy Press; 2013.
11. Hahn DL. Acute asthmatic bronchitis: a new twist to an old problem. J Fam Pract. 1994;39:431-435.
12. Johnston SL, Blasi F, Black PN, et al; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354:1589-1600.
13. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA Randomized Clinical Trial. JAMA Intern Med. 2016;176:1630-1637.
14. Brusselle GG, Van Braeckel E. AZALEA trial highlights antibiotic overuse in acute asthma attacks. JAMA Intern Med. 2016;176:1637-1638.
15. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycinAsthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.
16. Hahn DL. An unanticipated effect of clinical trial registration. BMJ.com. November 2, 2007. https://www.bmj.com/rapid-response/2011/11/01/unanticipated-effect-clinical-trial-registration. Accessed November 2, 2019.
17. Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract. 1995;41:345-351.
18. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
19. Hahn DL, McDonald R. Can acute Chlamydia pneumoniae infection initiate chronic asthma? Ann Allergy Asthma Immunol. 1998;81:339-344.
20. Rollins DR, Beuther DA, Martin RJ. Update on infection and antibiotics in asthma. Curr Allergy Asthma Rep. 2010;10:67-73.
21. Martin RJ, Kraft M, Chu HW, et al. A link between chronic asthma and chronic infection. J Allergy Clin Immunol. 2001;107:595-601.
22. Hahn DL, Plane MB, Mahdi OS, et al. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006;1:e11.
23. Hahn DL, Peeling RW, Dillon E, et al. Serologic markers for Chlamydia pneumoniae in asthma. Ann Allergy Asthma Immunol. 2000;84: 227-233.
24. Hahn DL, Schure A, Patel K, et al. Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. PLoS One. 2012;7:e35945.
25. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782-1788.
26. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
27. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890.
28. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006;332:22-27.
29. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373.
30. Jackson LA, Stewart DK, Wang SP, et al. Safety and effect on antiChlamydia pneumoniae antibody titres of a 1 month course of daily azithromycin in adults with coronary artery disease. J Antimicrob Chemother. 1999;44:411-414.
31. O’Connor CM, Dunne MW, Pfeffer MA, et al; Investigators in the WIZARD Study. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290:1459-1466.
32. Grayston JT, Kronmal RA, Jackson LA, et al; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352:1637-1645.
33. Skalet AH, Cevallos V, Ayele B, et al. Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial. PLoS Med. 2010;7:e1000377.
34. Seppälä H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med. 1997;337:441-446.
35. Keenan JD, Emerson PM, Gaynor BD, et al. Adult mortality in a randomized trial of mass azithromycin for trachoma. JAMA Intern Med. 2013;173:821-833.
36. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314:2034-2044.
37. Wang MT, Liou JT, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. 2018;178:229-238.
38. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368:1704-1712.
39. Khosropour CM, Capizzi JD, Schafer SD, et al. Lack of association between azithromycin and death from cardiovascular causes. N Engl J Med. 2014;370:1961-1962.
40. Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles Drug Subst Excip Relat Methodol. 2014;39:1-40.
41. Huang YJ, Nelson CE, Brodie EL, et al; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011;127:372-381.e1-3.
42. Bisgaard H, Hermansen MN, Bønnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ. 2010;341:c4978.
43. Teo SM, Mok D, Pham K, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015;17:704-715.
44. Wei S, Mortensen MS, Stokholm J, et al. Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: a double-blind, randomized, placebo-controlled trial. EBioMedicine. 2018;38:265-272.
45. Peters SP, Kunselman SJ, Icitovic N, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. New Engl J Med. 2010;363:1715-1726.
In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.3
This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.
3 cases to consider
CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.
Outcome. Mr. D has remained free of symptoms of asthma for more than 20 years.
CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.
Outcome. Casey was able to resume normal physical activities, including competitive swimming.
CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.
[polldaddy:10475438]
Continue to: Outcome...
Outcome. Ms. S’s symptoms resolved completely within months.
Evidence of benefit of macrolides in asthma
These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma
SIDEBAR
Macrolides for Asthma: Registry of Clinical Experience
More information is needed about the “real world” effectiveness of antibiotic treatment for severe refractory and new-onset asthma. If you are a prescribing clinician who cares for patients with asthma and you are considering prescribing antibiotics for asthma, you are invited to document your outcomes by entering prospective, de-identified patient data into a human subjects committee-approved online registry. To gain access to the registry, and for more information, contact the author at [email protected] or visit https://www.fammed.wisc.edu/wren/resources/macrolides-for-asthma/ .
Meta-analysis. Reiter et al4 performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV1) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.
Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and procedures.”
Cochrane meta-analysis. Kew et al5 performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported
- no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
- significant effects of macrolides for asthma symptoms and FEV1.
Continue to: Two within-study subgroup...
Two within-study subgroup analyses showed a possible benefit of macrolides for non-eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al5 noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.
Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.
Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.6 Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.2 Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.2
Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials7,8 that were not included in the cited meta-analyses, along with other evidence,2 point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.
Clinical trial in adults. Gibson et al7 conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.9
Continue to: Azithromycin reduced the frequency...
Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).
There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.
Other evidence10 indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).
Pediatric clinical trial. Stokholm et al8 performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.
Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).
Continue to: No differences between...
No differences between the randomized groups were observed in clinical adverse effects.
Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little12 or no13 short-term benefit; however, these negative findings have been hypothesized to be the result of selection bias.14
Other evidence is worth examining
Other studies not included in the meta-analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.
Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)15 is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.
However, many eligible subjects, whom the principal investigator believed were ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose16 (OL cohort only, Level 2 study: controlled, nonrandomized, nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.
Continue to: The less severely...
The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.
Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”15
Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).17 Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.
Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).
These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.17 Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.
Continue to: Physicians should also note...
Physicians should also note the landmark trial of azithromycin in severe, smoking-associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).18
Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.19 A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.
Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.
Tx recommendations: When to consider azithromycin
Randomized7 and nonrandomized15 evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).
It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.11 Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).10
Continue to: Do biomarkers predict response?
Do biomarkers predict response?
Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended20 but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.
So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma21) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.3 The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.22 Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this recommendation).
Acute bronchitis and asthma-onset associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.23 However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.23 Several other matters are worth noting:
- C pneumoniae-specific IgA23 and IgE24 are promising biomarkers that deserve further investigation.
- M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.21,25
- Noneosinophilic severe asthma is another potential predictive characteristic.26 The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial7 reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.
Potential for harm withlong-term macrolide use?
Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 127,28 and discussed below).29
Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.30 In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.31,32 The major clinical “side effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.31,32
Continue to: Antibiotic resistance
Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens33; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.34 There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.33
In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.35 In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.8,36
Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.
Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in every 4000 administrations.27 Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.37 There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population38,39 or when azithromycin is coadministered with a LABA.3
Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).32 In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32
Continue to: Physicians who prescribe...
Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.
Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.40 Nevertheless:
- Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
- Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of azithromycin.
- The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.40
Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.2 A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.41 Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.41
Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.44
What about cost?
Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS15—costs about as much as 1 ICS and LABA combination inhaler. Using published results,15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.
Continue to: Recommendations to reflect on for your practice
Recommendations to reflect on for your practice
Table 27,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients
- whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
- who have new-onset asthma.
Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.
*Data available from the author upon request. See “Correspondence,” at end of article.
CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].
In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.3
This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.
3 cases to consider
CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.
Outcome. Mr. D has remained free of symptoms of asthma for more than 20 years.
CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.
Outcome. Casey was able to resume normal physical activities, including competitive swimming.
CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.
[polldaddy:10475438]
Continue to: Outcome...
Outcome. Ms. S’s symptoms resolved completely within months.
Evidence of benefit of macrolides in asthma
These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma
SIDEBAR
Macrolides for Asthma: Registry of Clinical Experience
More information is needed about the “real world” effectiveness of antibiotic treatment for severe refractory and new-onset asthma. If you are a prescribing clinician who cares for patients with asthma and you are considering prescribing antibiotics for asthma, you are invited to document your outcomes by entering prospective, de-identified patient data into a human subjects committee-approved online registry. To gain access to the registry, and for more information, contact the author at [email protected] or visit https://www.fammed.wisc.edu/wren/resources/macrolides-for-asthma/ .
Meta-analysis. Reiter et al4 performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV1) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.
Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and procedures.”
Cochrane meta-analysis. Kew et al5 performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported
- no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
- significant effects of macrolides for asthma symptoms and FEV1.
Continue to: Two within-study subgroup...
Two within-study subgroup analyses showed a possible benefit of macrolides for non-eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al5 noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.
Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.
Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.6 Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.2 Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.2
Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials7,8 that were not included in the cited meta-analyses, along with other evidence,2 point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.
Clinical trial in adults. Gibson et al7 conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.9
Continue to: Azithromycin reduced the frequency...
Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).
There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.
Other evidence10 indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).
Pediatric clinical trial. Stokholm et al8 performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.
Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).
Continue to: No differences between...
No differences between the randomized groups were observed in clinical adverse effects.
Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little12 or no13 short-term benefit; however, these negative findings have been hypothesized to be the result of selection bias.14
Other evidence is worth examining
Other studies not included in the meta-analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.
Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)15 is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.
However, many eligible subjects, whom the principal investigator believed were ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose16 (OL cohort only, Level 2 study: controlled, nonrandomized, nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.
Continue to: The less severely...
The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.
Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”15
Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).17 Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.
Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).
These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.17 Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.
Continue to: Physicians should also note...
Physicians should also note the landmark trial of azithromycin in severe, smoking-associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).18
Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.19 A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.
Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.
Tx recommendations: When to consider azithromycin
Randomized7 and nonrandomized15 evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).
It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.11 Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).10
Continue to: Do biomarkers predict response?
Do biomarkers predict response?
Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended20 but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.
So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma21) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.3 The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.22 Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this recommendation).
Acute bronchitis and asthma-onset associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.23 However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.23 Several other matters are worth noting:
- C pneumoniae-specific IgA23 and IgE24 are promising biomarkers that deserve further investigation.
- M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.21,25
- Noneosinophilic severe asthma is another potential predictive characteristic.26 The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial7 reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.
Potential for harm withlong-term macrolide use?
Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 127,28 and discussed below).29
Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.30 In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.31,32 The major clinical “side effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.31,32
Continue to: Antibiotic resistance
Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens33; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.34 There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.33
In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.35 In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.8,36
Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.
Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in every 4000 administrations.27 Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.37 There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population38,39 or when azithromycin is coadministered with a LABA.3
Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).32 In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32
Continue to: Physicians who prescribe...
Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.
Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.40 Nevertheless:
- Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
- Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of azithromycin.
- The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.40
Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.2 A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.41 Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.41
Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.44
What about cost?
Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS15—costs about as much as 1 ICS and LABA combination inhaler. Using published results,15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.
Continue to: Recommendations to reflect on for your practice
Recommendations to reflect on for your practice
Table 27,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients
- whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
- who have new-onset asthma.
Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.
*Data available from the author upon request. See “Correspondence,” at end of article.
CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].
1. Hahn DL. Role of Chlamydia pneumoniae as an inducer of asthma. In: Friedman H, Yamamoto Y, Bendinelli M, eds. Chlamydia Pneumoniae: Infection and Disease. New York: Kluwer Academic/Plenum Publishers; 2004:239-262.
2. Webley WC, Hahn DL. Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respir Res. 2017;18:98.
3. Wong EH, Porter JD, Edwards MR, et al. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014;2:657-670.
4. Reiter J, Demirel N, Mendy A, et al. Macrolides for the long-term management of asthma—a meta-analysis of randomized clinical trials. Allergy. 2013;68:1040-1049.
5. Kew KM, Undela K, Kotortsi I, et al. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015(9):CD002997.
6. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax. 2007;62:219-223.
7. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
8. Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4:19-26.
9. Korn S, Both J, Jung M, et al. Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. Ann Allergy Asthma Immunol. 2011;107:474-479.
10. Hahn DL. A Cure for Asthma? What Your Doctor Isn’t Telling You—and Why. Durham, North Carolina: Peoples Pharmacy Press; 2013.
11. Hahn DL. Acute asthmatic bronchitis: a new twist to an old problem. J Fam Pract. 1994;39:431-435.
12. Johnston SL, Blasi F, Black PN, et al; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354:1589-1600.
13. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA Randomized Clinical Trial. JAMA Intern Med. 2016;176:1630-1637.
14. Brusselle GG, Van Braeckel E. AZALEA trial highlights antibiotic overuse in acute asthma attacks. JAMA Intern Med. 2016;176:1637-1638.
15. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycinAsthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.
16. Hahn DL. An unanticipated effect of clinical trial registration. BMJ.com. November 2, 2007. https://www.bmj.com/rapid-response/2011/11/01/unanticipated-effect-clinical-trial-registration. Accessed November 2, 2019.
17. Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract. 1995;41:345-351.
18. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
19. Hahn DL, McDonald R. Can acute Chlamydia pneumoniae infection initiate chronic asthma? Ann Allergy Asthma Immunol. 1998;81:339-344.
20. Rollins DR, Beuther DA, Martin RJ. Update on infection and antibiotics in asthma. Curr Allergy Asthma Rep. 2010;10:67-73.
21. Martin RJ, Kraft M, Chu HW, et al. A link between chronic asthma and chronic infection. J Allergy Clin Immunol. 2001;107:595-601.
22. Hahn DL, Plane MB, Mahdi OS, et al. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006;1:e11.
23. Hahn DL, Peeling RW, Dillon E, et al. Serologic markers for Chlamydia pneumoniae in asthma. Ann Allergy Asthma Immunol. 2000;84: 227-233.
24. Hahn DL, Schure A, Patel K, et al. Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. PLoS One. 2012;7:e35945.
25. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782-1788.
26. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
27. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890.
28. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006;332:22-27.
29. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373.
30. Jackson LA, Stewart DK, Wang SP, et al. Safety and effect on antiChlamydia pneumoniae antibody titres of a 1 month course of daily azithromycin in adults with coronary artery disease. J Antimicrob Chemother. 1999;44:411-414.
31. O’Connor CM, Dunne MW, Pfeffer MA, et al; Investigators in the WIZARD Study. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290:1459-1466.
32. Grayston JT, Kronmal RA, Jackson LA, et al; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352:1637-1645.
33. Skalet AH, Cevallos V, Ayele B, et al. Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial. PLoS Med. 2010;7:e1000377.
34. Seppälä H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med. 1997;337:441-446.
35. Keenan JD, Emerson PM, Gaynor BD, et al. Adult mortality in a randomized trial of mass azithromycin for trachoma. JAMA Intern Med. 2013;173:821-833.
36. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314:2034-2044.
37. Wang MT, Liou JT, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. 2018;178:229-238.
38. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368:1704-1712.
39. Khosropour CM, Capizzi JD, Schafer SD, et al. Lack of association between azithromycin and death from cardiovascular causes. N Engl J Med. 2014;370:1961-1962.
40. Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles Drug Subst Excip Relat Methodol. 2014;39:1-40.
41. Huang YJ, Nelson CE, Brodie EL, et al; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011;127:372-381.e1-3.
42. Bisgaard H, Hermansen MN, Bønnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ. 2010;341:c4978.
43. Teo SM, Mok D, Pham K, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015;17:704-715.
44. Wei S, Mortensen MS, Stokholm J, et al. Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: a double-blind, randomized, placebo-controlled trial. EBioMedicine. 2018;38:265-272.
45. Peters SP, Kunselman SJ, Icitovic N, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. New Engl J Med. 2010;363:1715-1726.
1. Hahn DL. Role of Chlamydia pneumoniae as an inducer of asthma. In: Friedman H, Yamamoto Y, Bendinelli M, eds. Chlamydia Pneumoniae: Infection and Disease. New York: Kluwer Academic/Plenum Publishers; 2004:239-262.
2. Webley WC, Hahn DL. Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respir Res. 2017;18:98.
3. Wong EH, Porter JD, Edwards MR, et al. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014;2:657-670.
4. Reiter J, Demirel N, Mendy A, et al. Macrolides for the long-term management of asthma—a meta-analysis of randomized clinical trials. Allergy. 2013;68:1040-1049.
5. Kew KM, Undela K, Kotortsi I, et al. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015(9):CD002997.
6. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax. 2007;62:219-223.
7. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
8. Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4:19-26.
9. Korn S, Both J, Jung M, et al. Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. Ann Allergy Asthma Immunol. 2011;107:474-479.
10. Hahn DL. A Cure for Asthma? What Your Doctor Isn’t Telling You—and Why. Durham, North Carolina: Peoples Pharmacy Press; 2013.
11. Hahn DL. Acute asthmatic bronchitis: a new twist to an old problem. J Fam Pract. 1994;39:431-435.
12. Johnston SL, Blasi F, Black PN, et al; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354:1589-1600.
13. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA Randomized Clinical Trial. JAMA Intern Med. 2016;176:1630-1637.
14. Brusselle GG, Van Braeckel E. AZALEA trial highlights antibiotic overuse in acute asthma attacks. JAMA Intern Med. 2016;176:1637-1638.
15. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycinAsthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.
16. Hahn DL. An unanticipated effect of clinical trial registration. BMJ.com. November 2, 2007. https://www.bmj.com/rapid-response/2011/11/01/unanticipated-effect-clinical-trial-registration. Accessed November 2, 2019.
17. Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract. 1995;41:345-351.
18. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
19. Hahn DL, McDonald R. Can acute Chlamydia pneumoniae infection initiate chronic asthma? Ann Allergy Asthma Immunol. 1998;81:339-344.
20. Rollins DR, Beuther DA, Martin RJ. Update on infection and antibiotics in asthma. Curr Allergy Asthma Rep. 2010;10:67-73.
21. Martin RJ, Kraft M, Chu HW, et al. A link between chronic asthma and chronic infection. J Allergy Clin Immunol. 2001;107:595-601.
22. Hahn DL, Plane MB, Mahdi OS, et al. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006;1:e11.
23. Hahn DL, Peeling RW, Dillon E, et al. Serologic markers for Chlamydia pneumoniae in asthma. Ann Allergy Asthma Immunol. 2000;84: 227-233.
24. Hahn DL, Schure A, Patel K, et al. Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. PLoS One. 2012;7:e35945.
25. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782-1788.
26. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
27. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890.
28. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006;332:22-27.
29. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373.
30. Jackson LA, Stewart DK, Wang SP, et al. Safety and effect on antiChlamydia pneumoniae antibody titres of a 1 month course of daily azithromycin in adults with coronary artery disease. J Antimicrob Chemother. 1999;44:411-414.
31. O’Connor CM, Dunne MW, Pfeffer MA, et al; Investigators in the WIZARD Study. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290:1459-1466.
32. Grayston JT, Kronmal RA, Jackson LA, et al; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352:1637-1645.
33. Skalet AH, Cevallos V, Ayele B, et al. Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial. PLoS Med. 2010;7:e1000377.
34. Seppälä H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med. 1997;337:441-446.
35. Keenan JD, Emerson PM, Gaynor BD, et al. Adult mortality in a randomized trial of mass azithromycin for trachoma. JAMA Intern Med. 2013;173:821-833.
36. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314:2034-2044.
37. Wang MT, Liou JT, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. 2018;178:229-238.
38. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368:1704-1712.
39. Khosropour CM, Capizzi JD, Schafer SD, et al. Lack of association between azithromycin and death from cardiovascular causes. N Engl J Med. 2014;370:1961-1962.
40. Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles Drug Subst Excip Relat Methodol. 2014;39:1-40.
41. Huang YJ, Nelson CE, Brodie EL, et al; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011;127:372-381.e1-3.
42. Bisgaard H, Hermansen MN, Bønnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ. 2010;341:c4978.
43. Teo SM, Mok D, Pham K, et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe. 2015;17:704-715.
44. Wei S, Mortensen MS, Stokholm J, et al. Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: a double-blind, randomized, placebo-controlled trial. EBioMedicine. 2018;38:265-272.
45. Peters SP, Kunselman SJ, Icitovic N, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. New Engl J Med. 2010;363:1715-1726.
PRACTICE RECOMMENDATIONS
› Consider a trial of azithromycin for patients who have poorly controlled persistent asthma and are not responding to guideline treatment with the combination of an inhaled corticosteroid and either a long-acting bronchodilator or long-acting muscarinic antagonist. B
› Consider a trial of azithromycin in addition to first-line guideline therapy for patients who have new-onset asthma. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Aspirin plus a DOAC may do more harm than good in some
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
REPORTING FROM ASH 2019
Patient-reported outcomes support first-line pembrolizumab for NSCLC
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
FDA expands use of Toujeo to childhood type 1 diabetes
The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.
The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).
Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.
In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.
The primary endpoint was noninferior reduction in A1c after 26 weeks.
The study met its primary endpoint, confirming a noninferior reduction in A1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).
Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.
No unexpected safety concerns were reported based on the established profiles of both products, the company said.
In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.
For more diabetes and endocrinology news, follow us on Twitter and Facebook.
This story first appeared on Medscape.com.
The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.
The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).
Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.
In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.
The primary endpoint was noninferior reduction in A1c after 26 weeks.
The study met its primary endpoint, confirming a noninferior reduction in A1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).
Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.
No unexpected safety concerns were reported based on the established profiles of both products, the company said.
In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.
For more diabetes and endocrinology news, follow us on Twitter and Facebook.
This story first appeared on Medscape.com.
The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.
The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).
Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.
In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.
The primary endpoint was noninferior reduction in A1c after 26 weeks.
The study met its primary endpoint, confirming a noninferior reduction in A1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).
Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.
No unexpected safety concerns were reported based on the established profiles of both products, the company said.
In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.
For more diabetes and endocrinology news, follow us on Twitter and Facebook.
This story first appeared on Medscape.com.
Cardioprotective Effect of Metformin in Patients with Decreased Renal Function
Study Overview
Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.
Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.
Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.
Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/m
Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.
Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.
For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).
Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.
Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.
Commentary
There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).1 Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.2 Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m2, although patients already taking metformin can continue with caution in that setting.1,3
There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.4
In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m2. The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.
Applications for Clinical Practice
The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.
–Ka Ming Gordon Ngai, MD, MPH
1. Geiss LS, Kirtland K, Lin J, et al. Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012. PLoS One. 2017;12:e0173428.
2. Good CB, Pogach LM. Should metformin be first-line therapy for patients with type 2 diabetes and chronic kidney disease? JAMA Intern Med. 2018;178:911-912.
3. US Food and Drug Administration. FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf. Accessed September 30, 2019.
4. Wexler DJ. Sulfonylureas and cardiovascular safety the final verdict? JAMA. 2019;322:1147-1149.
Study Overview
Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.
Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.
Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.
Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/m
Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.
Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.
For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).
Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.
Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.
Commentary
There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).1 Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.2 Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m2, although patients already taking metformin can continue with caution in that setting.1,3
There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.4
In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m2. The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.
Applications for Clinical Practice
The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.
–Ka Ming Gordon Ngai, MD, MPH
Study Overview
Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.
Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.
Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.
Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/m
Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.
Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.
For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).
Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.
Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.
Commentary
There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).1 Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.2 Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m2, although patients already taking metformin can continue with caution in that setting.1,3
There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.4
In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m2. The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.
Applications for Clinical Practice
The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.
–Ka Ming Gordon Ngai, MD, MPH
1. Geiss LS, Kirtland K, Lin J, et al. Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012. PLoS One. 2017;12:e0173428.
2. Good CB, Pogach LM. Should metformin be first-line therapy for patients with type 2 diabetes and chronic kidney disease? JAMA Intern Med. 2018;178:911-912.
3. US Food and Drug Administration. FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf. Accessed September 30, 2019.
4. Wexler DJ. Sulfonylureas and cardiovascular safety the final verdict? JAMA. 2019;322:1147-1149.
1. Geiss LS, Kirtland K, Lin J, et al. Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012. PLoS One. 2017;12:e0173428.
2. Good CB, Pogach LM. Should metformin be first-line therapy for patients with type 2 diabetes and chronic kidney disease? JAMA Intern Med. 2018;178:911-912.
3. US Food and Drug Administration. FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf. Accessed September 30, 2019.
4. Wexler DJ. Sulfonylureas and cardiovascular safety the final verdict? JAMA. 2019;322:1147-1149.