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New hypertension guidelines would add 15.6 million new diagnoses
A new analysis estimates that adopting the 2017 ACC/AHA hypertension guidelines would add 15.6 million Americans to the ranks of the hypertensives, and half of those would be candidates for treatment.
Similar increases would occur in other countries, according to study authors, who analyzed two large datasets from the United States and China.
That happened by resetting the definition of adult hypertension from the long-standing threshold of 140/90 mm Hg to a blood pressure at or above 130/80 mm Hg, meaning more than half of people aged 45-75 years in both countries would be classified as having hypertension, according to the researchers, led by Harlan M. Krumholz, MD, of the Center for Outcomes Research and Evaluation at Yale–New Haven (Conn.) Hospital and the section of cardiovascular medicine at Yale
An additional 7.5 million Americans would be recommended for treatment under the new lower treatment thresholds, with a correspondingly large increase in the Chinese population, according to results published in the BMJ.
The guideline changes are “not firmly rooted in evidence” and could have health policy implications that include strain on public health programs, Dr. Krumholz and his colleagues said in their report on the study.
“The change occurs at a time when both countries have substantial numbers of people who are not aware of having hypertension, and who have hypertension that is not controlled, even according to the previous standards,” they wrote.
The analysis by Dr. Krumholz and his colleagues was based on the two most recent cycles of the U.S. National Health and Nutrition Examination Survey (NHANES), representing 2013-2014 and 2015-2016 periods, as well as the China Health and Retirement Longitudinal Study (CHARLS) in 2011-2012.
Under the new ACC/AHA guidelines, they found, 70.1 million Americans aged 45-65 years would be classified as hypertensive, representing 63% of that age group. That’s a 27% relative increase over the 55.3 million individuals, or 49.7%, with hypertension as defined in the JNC-8 guidelines.
In addition, 15.6 million persons would be classified as eligible for treatment but not receiving it, up from 8.1 million under the JNC-8 guidance.
Previous estimates projected a far greater jump in new hypertension classifications, including one that used data from the National Health and Nutrition Examination Survey, antihypertensive clinical trials, and population-based cohort studies. That study estimated that 31 million people would newly carry the label (JAMA Cardiol. 2018 May 23; doi: 10.1001/jamacardio.2018.1240.)
In the current analysis, in China, 267 million aged 45-65 years (55% of that age group) would be classified with hypertension under the ACC/AHA guidelines, a relative increase of 45% over the JNC-8 guidelines, while the number of candidates for treatment would be 129 million, up from 74.5 million under the earlier guidelines.
Dr. Krumholz noted that the ACC/AHA guideline changes were prompted by results from the SPRINT trial. However, the improvements in outcomes seen in SPRINT, which included patients at high risk for cardiovascular events but without diabetes, have not been observed in individuals at low or intermediate risk, or in those with diabetes, they said.
“Expanding the pool of patients who merit treatment to include those at low risk could potentially render public health programs less efficient and viable,” they wrote in a discussion of health policy implications.
The new guidelines also put millions at risk of the “psychological morbidity” that comes with the label of a chronic disease, and at risk for more adverse events caused by inappropriate use of drug therapy, they added.
Dr. Krumholz reported research agreements from Medtronic and from Johnson and Johnson (Janssen) through Yale University, and a grant from the Food and Drug Administration and Medtronic. He reported other disclosures related to UnitedHealth, the IBM Watson Health Life Sciences Board, Element Science, Aetna, and Hugo, a personal health information platform he founded. First author Rohan Khera, MD, reported support from the National Institutes of Health.
SOURCE: Khera R et al. BMJ. 2018 Jul 11;362:k2357
This article was updated 7/19/18.
This study addressing hypertension guideline changes is unique because it was initially published on a public preprint server.
Preprints are common in some scientific areas, but uncommon in major medical journals. They allow investigators to share research, quickly and openly, for critique and feedback before standard peer review and publication.
In the case of this study, researchers analyzed the public health implications of the anticipated changes to the 2017 ACC/AHA hypertension guidelines in two nationally representative data sets from the United States and China.
The authors quickly finalized their manuscript right after the revised hypertension guidelines were released. They chose the preprint approach because they realized their research would be immediately relevant to the discussion that followed, first author Rohan Khera, MD, recounted on BMJ Blogs.
“The traditional approach of submitting to a medical journal would mean being out of the public eye for several months,” Dr. Khera said in his post. “The preprint platform offered us an excellent opportunity of ensuring early dissemination of our research study in its entirety, while we sought its evaluation by peer reviewers and the refinement by a medical journal.”
The manuscript was submitted via a Web-based system and was publicly available 2 hours later on the same day the guidelines were published. The researchers received comments and suggestions on the preprint, some of which were incorporated into the final manuscript they submitted for peer review.
Then the manuscript went through the usual iterative peer review process; however, the preprint was still available online to guide other investigators and limit duplication of effort, Dr. Khera said in his blog post.
That contrasts with another recent experience in which Dr. Khera and his colleagues performed work that “failed to inform” ongoing policy discussions, and other research efforts, while they waited for eventual publication.
“We hope that more journals will accept the benefits of science that is publicly available while journal editors and peer reviewers carry out their critical role of improving both the quality and the impact of these scientific contributions,” Dr. Khera wrote.
Rohan Khera, MD, a cardiology fellow at the University of Texas (Dallas) Southwestern Medical Center in, wrote about his experience with preprints for BMJ Blogs . Dr. Khera had no conflicts of interest to disclose.
This study addressing hypertension guideline changes is unique because it was initially published on a public preprint server.
Preprints are common in some scientific areas, but uncommon in major medical journals. They allow investigators to share research, quickly and openly, for critique and feedback before standard peer review and publication.
In the case of this study, researchers analyzed the public health implications of the anticipated changes to the 2017 ACC/AHA hypertension guidelines in two nationally representative data sets from the United States and China.
The authors quickly finalized their manuscript right after the revised hypertension guidelines were released. They chose the preprint approach because they realized their research would be immediately relevant to the discussion that followed, first author Rohan Khera, MD, recounted on BMJ Blogs.
“The traditional approach of submitting to a medical journal would mean being out of the public eye for several months,” Dr. Khera said in his post. “The preprint platform offered us an excellent opportunity of ensuring early dissemination of our research study in its entirety, while we sought its evaluation by peer reviewers and the refinement by a medical journal.”
The manuscript was submitted via a Web-based system and was publicly available 2 hours later on the same day the guidelines were published. The researchers received comments and suggestions on the preprint, some of which were incorporated into the final manuscript they submitted for peer review.
Then the manuscript went through the usual iterative peer review process; however, the preprint was still available online to guide other investigators and limit duplication of effort, Dr. Khera said in his blog post.
That contrasts with another recent experience in which Dr. Khera and his colleagues performed work that “failed to inform” ongoing policy discussions, and other research efforts, while they waited for eventual publication.
“We hope that more journals will accept the benefits of science that is publicly available while journal editors and peer reviewers carry out their critical role of improving both the quality and the impact of these scientific contributions,” Dr. Khera wrote.
Rohan Khera, MD, a cardiology fellow at the University of Texas (Dallas) Southwestern Medical Center in, wrote about his experience with preprints for BMJ Blogs . Dr. Khera had no conflicts of interest to disclose.
This study addressing hypertension guideline changes is unique because it was initially published on a public preprint server.
Preprints are common in some scientific areas, but uncommon in major medical journals. They allow investigators to share research, quickly and openly, for critique and feedback before standard peer review and publication.
In the case of this study, researchers analyzed the public health implications of the anticipated changes to the 2017 ACC/AHA hypertension guidelines in two nationally representative data sets from the United States and China.
The authors quickly finalized their manuscript right after the revised hypertension guidelines were released. They chose the preprint approach because they realized their research would be immediately relevant to the discussion that followed, first author Rohan Khera, MD, recounted on BMJ Blogs.
“The traditional approach of submitting to a medical journal would mean being out of the public eye for several months,” Dr. Khera said in his post. “The preprint platform offered us an excellent opportunity of ensuring early dissemination of our research study in its entirety, while we sought its evaluation by peer reviewers and the refinement by a medical journal.”
The manuscript was submitted via a Web-based system and was publicly available 2 hours later on the same day the guidelines were published. The researchers received comments and suggestions on the preprint, some of which were incorporated into the final manuscript they submitted for peer review.
Then the manuscript went through the usual iterative peer review process; however, the preprint was still available online to guide other investigators and limit duplication of effort, Dr. Khera said in his blog post.
That contrasts with another recent experience in which Dr. Khera and his colleagues performed work that “failed to inform” ongoing policy discussions, and other research efforts, while they waited for eventual publication.
“We hope that more journals will accept the benefits of science that is publicly available while journal editors and peer reviewers carry out their critical role of improving both the quality and the impact of these scientific contributions,” Dr. Khera wrote.
Rohan Khera, MD, a cardiology fellow at the University of Texas (Dallas) Southwestern Medical Center in, wrote about his experience with preprints for BMJ Blogs . Dr. Khera had no conflicts of interest to disclose.
A new analysis estimates that adopting the 2017 ACC/AHA hypertension guidelines would add 15.6 million Americans to the ranks of the hypertensives, and half of those would be candidates for treatment.
Similar increases would occur in other countries, according to study authors, who analyzed two large datasets from the United States and China.
That happened by resetting the definition of adult hypertension from the long-standing threshold of 140/90 mm Hg to a blood pressure at or above 130/80 mm Hg, meaning more than half of people aged 45-75 years in both countries would be classified as having hypertension, according to the researchers, led by Harlan M. Krumholz, MD, of the Center for Outcomes Research and Evaluation at Yale–New Haven (Conn.) Hospital and the section of cardiovascular medicine at Yale
An additional 7.5 million Americans would be recommended for treatment under the new lower treatment thresholds, with a correspondingly large increase in the Chinese population, according to results published in the BMJ.
The guideline changes are “not firmly rooted in evidence” and could have health policy implications that include strain on public health programs, Dr. Krumholz and his colleagues said in their report on the study.
“The change occurs at a time when both countries have substantial numbers of people who are not aware of having hypertension, and who have hypertension that is not controlled, even according to the previous standards,” they wrote.
The analysis by Dr. Krumholz and his colleagues was based on the two most recent cycles of the U.S. National Health and Nutrition Examination Survey (NHANES), representing 2013-2014 and 2015-2016 periods, as well as the China Health and Retirement Longitudinal Study (CHARLS) in 2011-2012.
Under the new ACC/AHA guidelines, they found, 70.1 million Americans aged 45-65 years would be classified as hypertensive, representing 63% of that age group. That’s a 27% relative increase over the 55.3 million individuals, or 49.7%, with hypertension as defined in the JNC-8 guidelines.
In addition, 15.6 million persons would be classified as eligible for treatment but not receiving it, up from 8.1 million under the JNC-8 guidance.
Previous estimates projected a far greater jump in new hypertension classifications, including one that used data from the National Health and Nutrition Examination Survey, antihypertensive clinical trials, and population-based cohort studies. That study estimated that 31 million people would newly carry the label (JAMA Cardiol. 2018 May 23; doi: 10.1001/jamacardio.2018.1240.)
In the current analysis, in China, 267 million aged 45-65 years (55% of that age group) would be classified with hypertension under the ACC/AHA guidelines, a relative increase of 45% over the JNC-8 guidelines, while the number of candidates for treatment would be 129 million, up from 74.5 million under the earlier guidelines.
Dr. Krumholz noted that the ACC/AHA guideline changes were prompted by results from the SPRINT trial. However, the improvements in outcomes seen in SPRINT, which included patients at high risk for cardiovascular events but without diabetes, have not been observed in individuals at low or intermediate risk, or in those with diabetes, they said.
“Expanding the pool of patients who merit treatment to include those at low risk could potentially render public health programs less efficient and viable,” they wrote in a discussion of health policy implications.
The new guidelines also put millions at risk of the “psychological morbidity” that comes with the label of a chronic disease, and at risk for more adverse events caused by inappropriate use of drug therapy, they added.
Dr. Krumholz reported research agreements from Medtronic and from Johnson and Johnson (Janssen) through Yale University, and a grant from the Food and Drug Administration and Medtronic. He reported other disclosures related to UnitedHealth, the IBM Watson Health Life Sciences Board, Element Science, Aetna, and Hugo, a personal health information platform he founded. First author Rohan Khera, MD, reported support from the National Institutes of Health.
SOURCE: Khera R et al. BMJ. 2018 Jul 11;362:k2357
This article was updated 7/19/18.
A new analysis estimates that adopting the 2017 ACC/AHA hypertension guidelines would add 15.6 million Americans to the ranks of the hypertensives, and half of those would be candidates for treatment.
Similar increases would occur in other countries, according to study authors, who analyzed two large datasets from the United States and China.
That happened by resetting the definition of adult hypertension from the long-standing threshold of 140/90 mm Hg to a blood pressure at or above 130/80 mm Hg, meaning more than half of people aged 45-75 years in both countries would be classified as having hypertension, according to the researchers, led by Harlan M. Krumholz, MD, of the Center for Outcomes Research and Evaluation at Yale–New Haven (Conn.) Hospital and the section of cardiovascular medicine at Yale
An additional 7.5 million Americans would be recommended for treatment under the new lower treatment thresholds, with a correspondingly large increase in the Chinese population, according to results published in the BMJ.
The guideline changes are “not firmly rooted in evidence” and could have health policy implications that include strain on public health programs, Dr. Krumholz and his colleagues said in their report on the study.
“The change occurs at a time when both countries have substantial numbers of people who are not aware of having hypertension, and who have hypertension that is not controlled, even according to the previous standards,” they wrote.
The analysis by Dr. Krumholz and his colleagues was based on the two most recent cycles of the U.S. National Health and Nutrition Examination Survey (NHANES), representing 2013-2014 and 2015-2016 periods, as well as the China Health and Retirement Longitudinal Study (CHARLS) in 2011-2012.
Under the new ACC/AHA guidelines, they found, 70.1 million Americans aged 45-65 years would be classified as hypertensive, representing 63% of that age group. That’s a 27% relative increase over the 55.3 million individuals, or 49.7%, with hypertension as defined in the JNC-8 guidelines.
In addition, 15.6 million persons would be classified as eligible for treatment but not receiving it, up from 8.1 million under the JNC-8 guidance.
Previous estimates projected a far greater jump in new hypertension classifications, including one that used data from the National Health and Nutrition Examination Survey, antihypertensive clinical trials, and population-based cohort studies. That study estimated that 31 million people would newly carry the label (JAMA Cardiol. 2018 May 23; doi: 10.1001/jamacardio.2018.1240.)
In the current analysis, in China, 267 million aged 45-65 years (55% of that age group) would be classified with hypertension under the ACC/AHA guidelines, a relative increase of 45% over the JNC-8 guidelines, while the number of candidates for treatment would be 129 million, up from 74.5 million under the earlier guidelines.
Dr. Krumholz noted that the ACC/AHA guideline changes were prompted by results from the SPRINT trial. However, the improvements in outcomes seen in SPRINT, which included patients at high risk for cardiovascular events but without diabetes, have not been observed in individuals at low or intermediate risk, or in those with diabetes, they said.
“Expanding the pool of patients who merit treatment to include those at low risk could potentially render public health programs less efficient and viable,” they wrote in a discussion of health policy implications.
The new guidelines also put millions at risk of the “psychological morbidity” that comes with the label of a chronic disease, and at risk for more adverse events caused by inappropriate use of drug therapy, they added.
Dr. Krumholz reported research agreements from Medtronic and from Johnson and Johnson (Janssen) through Yale University, and a grant from the Food and Drug Administration and Medtronic. He reported other disclosures related to UnitedHealth, the IBM Watson Health Life Sciences Board, Element Science, Aetna, and Hugo, a personal health information platform he founded. First author Rohan Khera, MD, reported support from the National Institutes of Health.
SOURCE: Khera R et al. BMJ. 2018 Jul 11;362:k2357
This article was updated 7/19/18.
FROM THE BMJ
Key clinical point: The 2017 ACC/AHA hypertension guidelines could dramatically increase the number of individuals with hypertension and candidates for treatment.
Major finding: The number of individuals with untreated hypertension increased from 8.1 million to 15.6 million.
Study details: A cross-sectional study of adults in nationally representative databases in the United States (NHANES) and China (CHARLS).
Disclosures: Authors reported disclosures related to Medtronic, Johnson and Johnson (Janssen), the Food and Drug Administration, UnitedHealth, the IBM Watson Health Life Sciences Board, Element Science, Aetna, and Hugo.
Source: Khera R et al. BMJ 2018;362:k2357.
Fluoroquinolones can cause fatal hypoglycemia, FDA warns
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Fluoroquinolones have caused at least 67 cases of life-threatening hypoglycemic coma, including 13 deaths and 9 permanent and disabling injuries, according to an internal safety review by the Food and Drug Administration. Most cases (44) were associated with levofloxacin.
The review also found new neuropsychiatric side effects associated with fluoroquinolones, including disturbances in attention, memory impairment, and delirium.
Considering these findings, the agency will strengthen warning labels on all fluoroquinolones, which already warn that the antibiotics may cause hypoglycemia and mental health issues, especially in older people, the FDA said in a press statement.
“Health care professionals should be aware of the potential risk of hypoglycemia, sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin,” the statement said. “Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients and discuss with them how to treat themselves if they have symptoms of hypoglycemia. Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose. Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non–fluoroquinolone antibiotic if possible. Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non–fluoroquinolone antibiotic to complete the patient’s treatment course.”
The statement also warned not to prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients.
The FDA conducted the postmarketing review on all five of the fluoroquinolones (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin). The newest fluoroquinolone, delafloxacin, approved a year ago, was not included in the class review. However, the agency expects that similar adverse events will be associated with delafloxacin and labeling on that drug will include the new warnings.
The agency reviewed cases in the FDA Adverse Event Reporting System, and in published medical literature, during 1987-2017. Most of the incidents (56) were in the system; 11 additional cases were published. Levofloxacin caused most of the incidents (44), followed by ciprofloxacin (12), moxifloxacin (9), and ofloxacin (2). Four of the fluoroquinolones have a labeled drug interaction with sulfonylurea agents, which can cause hypoglycemia.
Some of those who died were getting the antibiotics for complicated infections, including urinary tract and upper respiratory tract infections, and postoperative antibiotic prophylaxis. Others had renal insufficiency – a risk factor for hypoglycemia.
Of the 54 patients who survived, 9 never fully recovered and had permanent disabilities. Four patients remained in a coma for at least 1 month, despite blood sugar normalization. Five experienced some type of neurologic injury.
The new label changes will also fortify the existing warning about mental health side effects, after the review found new reactions that are not listed in the current warning, including the new reports of disturbance in attention, memory impairment, and delirium.
The FDA statement did not include the number of cases found or the associated drugs. Again, the safety review was based on reports in the FAERS database and published medical literature.
“We found that psychiatric adverse reactions were not consistent in the drug labels. The labels of fluoroquinolones currently include many psychiatric adverse reactions in the Warnings and Precautions section, for example, hallucination, psychoses, confusion, depression, anxiety, and paranoia. In an effort to harmonize the psychiatric adverse reactions described in the drug labels across the class of fluoroquinolones, we are requiring that all fluoroquinolones include six psychiatric adverse reactions (disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation) in the Central Nervous System Effects of the Warnings and Precautions section of the labels. Disturbance in attention, memory impairment, and delirium are new adverse reactions to be added to the labels of the entire class of fluoroquinolones. Nervousness, agitation, and disorientation had been previously listed in the fluoroquinolone drug labels and will now be added to the Warnings and Precautions section of each drug label to harmonize labels across the fluoroquinolone drug class. The new label changes will make the psychiatric adverse reactions more prominent and more consistent.”
The FDA has previously warned about other adverse events associated with fluoroquinolones in May 2016, restricting use for certain uncomplicated infections; July 2016, for disabling side effects; August 2013, for peripheral neuropathy, and July 2008, for tendinitis and tendon rupture.
Rebleeding and mortality after lower-GI bleeding in patients taking antiplatelets or anticoagulants
Clinical question: Is there a difference in lower GI rebleeding risk in patients on antiplatelet medications versus those on anticoagulation medications?
Background: It is estimated that 29%-37% of patient with GI bleeds are also on antiplatelet or anticoagulation medications. Minimal research has looked at outcomes for these populations and the comparative risk of rebleeding.
Study design: A retrospective study.
Setting: Multicenter study in the United Kingdom.
Synopsis: The study followed 2,528 patients with lower GI bleeds, 917 of whom were on antiplatelet or anticoagulation medications. Of these, 504 were on single-antiplatelet therapy, 79 on dual-antiplatelet therapy, 232 on warfarin, and 102 on direct-acting oral anticoagulants (DOACs). Patients on single-antiplatelet agents had a threefold increased risk of rebleeding (hazard ratio, 3.57), those on dual-antiplatelet agents had a fivefold increased risk of rebleeding (HR, 5.38), and patients taking warfarin or DOACs had no increased risk of rebleeding.
In addition, the authors concluded that there was no significant difference in rebleeding risk if antiplatelet medications were held for less than 5 days during hospitalization versus if they were continued. The risk of rebleeding with antiplatelet agents is likely caused by the relatively long half-lives of these therapies. In contrast, warfarin and DOACs have available reversal agents, and DOACs have comparatively shorter half-lives.
Bottom line: The risk of rebleeding from a lower-GI bleed is higher in patients on antiplatelet medications than it is in patients on warfarin or DOACs.
Citation: Oakland K et al. Rebleeding and mortality after lower gastrointestinal bleeding in patients taking antiplatelets or anticoagulants. Clin Gastroent Hepatol. 2017 Dec 23. doi: 10.1016/j.cgh.2017.12.032.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Clinical question: Is there a difference in lower GI rebleeding risk in patients on antiplatelet medications versus those on anticoagulation medications?
Background: It is estimated that 29%-37% of patient with GI bleeds are also on antiplatelet or anticoagulation medications. Minimal research has looked at outcomes for these populations and the comparative risk of rebleeding.
Study design: A retrospective study.
Setting: Multicenter study in the United Kingdom.
Synopsis: The study followed 2,528 patients with lower GI bleeds, 917 of whom were on antiplatelet or anticoagulation medications. Of these, 504 were on single-antiplatelet therapy, 79 on dual-antiplatelet therapy, 232 on warfarin, and 102 on direct-acting oral anticoagulants (DOACs). Patients on single-antiplatelet agents had a threefold increased risk of rebleeding (hazard ratio, 3.57), those on dual-antiplatelet agents had a fivefold increased risk of rebleeding (HR, 5.38), and patients taking warfarin or DOACs had no increased risk of rebleeding.
In addition, the authors concluded that there was no significant difference in rebleeding risk if antiplatelet medications were held for less than 5 days during hospitalization versus if they were continued. The risk of rebleeding with antiplatelet agents is likely caused by the relatively long half-lives of these therapies. In contrast, warfarin and DOACs have available reversal agents, and DOACs have comparatively shorter half-lives.
Bottom line: The risk of rebleeding from a lower-GI bleed is higher in patients on antiplatelet medications than it is in patients on warfarin or DOACs.
Citation: Oakland K et al. Rebleeding and mortality after lower gastrointestinal bleeding in patients taking antiplatelets or anticoagulants. Clin Gastroent Hepatol. 2017 Dec 23. doi: 10.1016/j.cgh.2017.12.032.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Clinical question: Is there a difference in lower GI rebleeding risk in patients on antiplatelet medications versus those on anticoagulation medications?
Background: It is estimated that 29%-37% of patient with GI bleeds are also on antiplatelet or anticoagulation medications. Minimal research has looked at outcomes for these populations and the comparative risk of rebleeding.
Study design: A retrospective study.
Setting: Multicenter study in the United Kingdom.
Synopsis: The study followed 2,528 patients with lower GI bleeds, 917 of whom were on antiplatelet or anticoagulation medications. Of these, 504 were on single-antiplatelet therapy, 79 on dual-antiplatelet therapy, 232 on warfarin, and 102 on direct-acting oral anticoagulants (DOACs). Patients on single-antiplatelet agents had a threefold increased risk of rebleeding (hazard ratio, 3.57), those on dual-antiplatelet agents had a fivefold increased risk of rebleeding (HR, 5.38), and patients taking warfarin or DOACs had no increased risk of rebleeding.
In addition, the authors concluded that there was no significant difference in rebleeding risk if antiplatelet medications were held for less than 5 days during hospitalization versus if they were continued. The risk of rebleeding with antiplatelet agents is likely caused by the relatively long half-lives of these therapies. In contrast, warfarin and DOACs have available reversal agents, and DOACs have comparatively shorter half-lives.
Bottom line: The risk of rebleeding from a lower-GI bleed is higher in patients on antiplatelet medications than it is in patients on warfarin or DOACs.
Citation: Oakland K et al. Rebleeding and mortality after lower gastrointestinal bleeding in patients taking antiplatelets or anticoagulants. Clin Gastroent Hepatol. 2017 Dec 23. doi: 10.1016/j.cgh.2017.12.032.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Alteplase, aspirin provide similar functional outcomes after nondisabling stroke
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
FROM JAMA
Key clinical point: Alteplase does not appear to offer benefit over aspirin in terms of functional outcomes after nondisabling acute ischemic stroke.
Major finding: No significant difference was seen in functional outcomes with alteplase vs. aspirin at 90 days (adjusted risk difference, –1.1%).
Study details: The phase 3b PRISMS trial, involving 313 patients.
Disclosures: Genentech sponsored the trial. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment. Dr. Powers reported having no disclosures.
Source: Khatri P et al. JAMA. 2018; 320[2]:156-66.
SHM expresses support for Fairness for High-Skilled Immigrants Act
Without immigrant hospitalists, health care accessibility would decrease tremendously.
The Society of Hospital Medicine recently expressed its support for the Fairness for High-Skilled Immigrants Act (H.R. 392). This legislation will ensure that highly-skilled medical professionals and their families will not be turned away from working in the United States based on per-country limitations.
What inspired the PPC – and more broadly, SHM – to express support for this bill?
SHM and the PPC have always taken pride in assuming a leadership role when it comes to policy issues affecting hospitalists and the patients they serve, ranging from observation status to addressing the opiate epidemic and now, immigration reform. We are one of the first medical societies to support this bill.
What inspired us to take action is that there are country-specific caps when applying for a green card for those immigrants currently in the United States on an H1B visa. In the current green card pool, no country can occupy more than 7% of applications. For more populated countries like India and China, two significant countries of origin for hospitalists practicing in the U.S., this creates a significant backlog. At the moment, the projected wait time for applicants from countries in this situation to receive their green cards could easily exceed 25 years.
What impact would this have on hospital medicine providers and patients?
The number of hospitalists trained in the U.S. who have come on visas from other countries is astounding. By virtue of what we do as hospital medicine providers, we are leaders in health care. We own major QI initiatives across the hospital and oversee health care outcomes that many other providers never become involved with. By stifling the ability of people to enter the country and stay here long-term, it would have a devastating impact on our communities. A large chunk of hospitalist staffing companies employ providers who are international medical graduates who completed their residencies in the U.S. Without them, health care accessibility would decrease tremendously – especially in rural areas like those in which I work.
This is more than just an issue of citizenship – these caps have a major impact on quality of life and morale for those affected by them. The high level of uncertainty surrounding the current process affects large-scale decision-making. For example, people who are waiting to be approved for their green cards often ask questions like, “Should I buy a house?” and “Can I visit my family abroad and still be able to get back into the U.S. without any unwarranted delays or hassles?” This demoralizes quality providers personally, and if they feel this way, I can’t see how it wouldn’t affect their performance professionally as hospital medicine providers.
How have the existing restrictions affected you?
I graduated from medical school in India and came to the U.S..initially as a student and eventually transitioned to an H1B visa. After waiting for many years and having participated in numerous QI initiatives, I was fortunate enough to have my green card petition approved under a higher application category termed “Aliens of Extraordinary Ability” with a lesser wait time. However, by nature of the work that they perform, most hospitalists usually are eligible to apply for their green cards under the “Exceptional Ability” or “Advanced Degree” category, the wait times of which are excruciatingly long, and that is what we at the PPC and at the SHM level are striving to address and correct.
If someone is reading and says, “I want to do more and help advocate,” what can they do?
You don’t have to be a member of the PPC to have an impact on policy. Every member of SHM can contact their local representatives and be informed using SHM’s Grassroots Network. I have even gone so far as to meet and talk with local representatives to help them understand how policy issues affect both me and my patients. It is imperative that we are on the right side of history for those affected by this bill, and all bills affecting our fellow providers in the future.
Without immigrant hospitalists, health care accessibility would decrease tremendously.
Without immigrant hospitalists, health care accessibility would decrease tremendously.
The Society of Hospital Medicine recently expressed its support for the Fairness for High-Skilled Immigrants Act (H.R. 392). This legislation will ensure that highly-skilled medical professionals and their families will not be turned away from working in the United States based on per-country limitations.
What inspired the PPC – and more broadly, SHM – to express support for this bill?
SHM and the PPC have always taken pride in assuming a leadership role when it comes to policy issues affecting hospitalists and the patients they serve, ranging from observation status to addressing the opiate epidemic and now, immigration reform. We are one of the first medical societies to support this bill.
What inspired us to take action is that there are country-specific caps when applying for a green card for those immigrants currently in the United States on an H1B visa. In the current green card pool, no country can occupy more than 7% of applications. For more populated countries like India and China, two significant countries of origin for hospitalists practicing in the U.S., this creates a significant backlog. At the moment, the projected wait time for applicants from countries in this situation to receive their green cards could easily exceed 25 years.
What impact would this have on hospital medicine providers and patients?
The number of hospitalists trained in the U.S. who have come on visas from other countries is astounding. By virtue of what we do as hospital medicine providers, we are leaders in health care. We own major QI initiatives across the hospital and oversee health care outcomes that many other providers never become involved with. By stifling the ability of people to enter the country and stay here long-term, it would have a devastating impact on our communities. A large chunk of hospitalist staffing companies employ providers who are international medical graduates who completed their residencies in the U.S. Without them, health care accessibility would decrease tremendously – especially in rural areas like those in which I work.
This is more than just an issue of citizenship – these caps have a major impact on quality of life and morale for those affected by them. The high level of uncertainty surrounding the current process affects large-scale decision-making. For example, people who are waiting to be approved for their green cards often ask questions like, “Should I buy a house?” and “Can I visit my family abroad and still be able to get back into the U.S. without any unwarranted delays or hassles?” This demoralizes quality providers personally, and if they feel this way, I can’t see how it wouldn’t affect their performance professionally as hospital medicine providers.
How have the existing restrictions affected you?
I graduated from medical school in India and came to the U.S..initially as a student and eventually transitioned to an H1B visa. After waiting for many years and having participated in numerous QI initiatives, I was fortunate enough to have my green card petition approved under a higher application category termed “Aliens of Extraordinary Ability” with a lesser wait time. However, by nature of the work that they perform, most hospitalists usually are eligible to apply for their green cards under the “Exceptional Ability” or “Advanced Degree” category, the wait times of which are excruciatingly long, and that is what we at the PPC and at the SHM level are striving to address and correct.
If someone is reading and says, “I want to do more and help advocate,” what can they do?
You don’t have to be a member of the PPC to have an impact on policy. Every member of SHM can contact their local representatives and be informed using SHM’s Grassroots Network. I have even gone so far as to meet and talk with local representatives to help them understand how policy issues affect both me and my patients. It is imperative that we are on the right side of history for those affected by this bill, and all bills affecting our fellow providers in the future.
The Society of Hospital Medicine recently expressed its support for the Fairness for High-Skilled Immigrants Act (H.R. 392). This legislation will ensure that highly-skilled medical professionals and their families will not be turned away from working in the United States based on per-country limitations.
What inspired the PPC – and more broadly, SHM – to express support for this bill?
SHM and the PPC have always taken pride in assuming a leadership role when it comes to policy issues affecting hospitalists and the patients they serve, ranging from observation status to addressing the opiate epidemic and now, immigration reform. We are one of the first medical societies to support this bill.
What inspired us to take action is that there are country-specific caps when applying for a green card for those immigrants currently in the United States on an H1B visa. In the current green card pool, no country can occupy more than 7% of applications. For more populated countries like India and China, two significant countries of origin for hospitalists practicing in the U.S., this creates a significant backlog. At the moment, the projected wait time for applicants from countries in this situation to receive their green cards could easily exceed 25 years.
What impact would this have on hospital medicine providers and patients?
The number of hospitalists trained in the U.S. who have come on visas from other countries is astounding. By virtue of what we do as hospital medicine providers, we are leaders in health care. We own major QI initiatives across the hospital and oversee health care outcomes that many other providers never become involved with. By stifling the ability of people to enter the country and stay here long-term, it would have a devastating impact on our communities. A large chunk of hospitalist staffing companies employ providers who are international medical graduates who completed their residencies in the U.S. Without them, health care accessibility would decrease tremendously – especially in rural areas like those in which I work.
This is more than just an issue of citizenship – these caps have a major impact on quality of life and morale for those affected by them. The high level of uncertainty surrounding the current process affects large-scale decision-making. For example, people who are waiting to be approved for their green cards often ask questions like, “Should I buy a house?” and “Can I visit my family abroad and still be able to get back into the U.S. without any unwarranted delays or hassles?” This demoralizes quality providers personally, and if they feel this way, I can’t see how it wouldn’t affect their performance professionally as hospital medicine providers.
How have the existing restrictions affected you?
I graduated from medical school in India and came to the U.S..initially as a student and eventually transitioned to an H1B visa. After waiting for many years and having participated in numerous QI initiatives, I was fortunate enough to have my green card petition approved under a higher application category termed “Aliens of Extraordinary Ability” with a lesser wait time. However, by nature of the work that they perform, most hospitalists usually are eligible to apply for their green cards under the “Exceptional Ability” or “Advanced Degree” category, the wait times of which are excruciatingly long, and that is what we at the PPC and at the SHM level are striving to address and correct.
If someone is reading and says, “I want to do more and help advocate,” what can they do?
You don’t have to be a member of the PPC to have an impact on policy. Every member of SHM can contact their local representatives and be informed using SHM’s Grassroots Network. I have even gone so far as to meet and talk with local representatives to help them understand how policy issues affect both me and my patients. It is imperative that we are on the right side of history for those affected by this bill, and all bills affecting our fellow providers in the future.
Long-term follow-up of monoclonal gammopathy of undetermined significance
Clinical question: What is the expected clinical progression of patients with monoclonal gammopathy of undetermined significance (MGUS)?
Study design: Prospective, observational cohort study.
Setting: Single institution in Minnesota.
Synopsis: Investigators identified 1,395 patients with MGUS during 1960-1994, with a median follow-up of 34 years. Progression to multiple myeloma, plasma cell disorders, or lymphoid disorders was noted in 147 patients (11%), which represents a 6.5-times higher risk for these disorders, compared with the age/sex–adjusted control population.
Two risk factors were associated with progression of disease: elevated serum M protein (greater than 1.5 g/dL) and an abnormal serum free light chain ratio. Risk of progression at 20 years in patients with both of these risk factors was 55% in patients with IgM subtypes and 30% in patients with non-IgM subtypes. With a single risk factor, risk of progression at 20 years was 41% and 20%, respectively. With no risk factors the risk of progression at 20 years was 19% and 7%. Overall expected survival was shorter in patients with MGUS versus that in the age/sex–matched control population.
Bottom line: Patients with MGUS have a shorter life expectancy than the general population, and the IgM subtype is associated with a greater risk of progression at 20 years, compared with the non-IgM subtype.
Citation: Kyle RA et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Eng J Med. 2018 Jan 18;378(3):241-9.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Clinical question: What is the expected clinical progression of patients with monoclonal gammopathy of undetermined significance (MGUS)?
Study design: Prospective, observational cohort study.
Setting: Single institution in Minnesota.
Synopsis: Investigators identified 1,395 patients with MGUS during 1960-1994, with a median follow-up of 34 years. Progression to multiple myeloma, plasma cell disorders, or lymphoid disorders was noted in 147 patients (11%), which represents a 6.5-times higher risk for these disorders, compared with the age/sex–adjusted control population.
Two risk factors were associated with progression of disease: elevated serum M protein (greater than 1.5 g/dL) and an abnormal serum free light chain ratio. Risk of progression at 20 years in patients with both of these risk factors was 55% in patients with IgM subtypes and 30% in patients with non-IgM subtypes. With a single risk factor, risk of progression at 20 years was 41% and 20%, respectively. With no risk factors the risk of progression at 20 years was 19% and 7%. Overall expected survival was shorter in patients with MGUS versus that in the age/sex–matched control population.
Bottom line: Patients with MGUS have a shorter life expectancy than the general population, and the IgM subtype is associated with a greater risk of progression at 20 years, compared with the non-IgM subtype.
Citation: Kyle RA et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Eng J Med. 2018 Jan 18;378(3):241-9.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Clinical question: What is the expected clinical progression of patients with monoclonal gammopathy of undetermined significance (MGUS)?
Study design: Prospective, observational cohort study.
Setting: Single institution in Minnesota.
Synopsis: Investigators identified 1,395 patients with MGUS during 1960-1994, with a median follow-up of 34 years. Progression to multiple myeloma, plasma cell disorders, or lymphoid disorders was noted in 147 patients (11%), which represents a 6.5-times higher risk for these disorders, compared with the age/sex–adjusted control population.
Two risk factors were associated with progression of disease: elevated serum M protein (greater than 1.5 g/dL) and an abnormal serum free light chain ratio. Risk of progression at 20 years in patients with both of these risk factors was 55% in patients with IgM subtypes and 30% in patients with non-IgM subtypes. With a single risk factor, risk of progression at 20 years was 41% and 20%, respectively. With no risk factors the risk of progression at 20 years was 19% and 7%. Overall expected survival was shorter in patients with MGUS versus that in the age/sex–matched control population.
Bottom line: Patients with MGUS have a shorter life expectancy than the general population, and the IgM subtype is associated with a greater risk of progression at 20 years, compared with the non-IgM subtype.
Citation: Kyle RA et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Eng J Med. 2018 Jan 18;378(3):241-9.
Dr. Thota is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
More than 16% of ED sepsis patients not admitted to hospital
SAN DIEGO – More than 16% of emergency department sepsis patients are not admitted to the hospital, preliminary results from a large retrospective cohort study found.
“Nothing is really known about this topic,” lead study author Ithan D. Peltan, MD, said in an interview at an international conference of the American Thoracic Society. “In previous research, we’ve been focused on patients with sepsis who are admitted to the hospital. We have never thoroughly recognized that a fair number of patients who meet clinical criteria for sepsis in the emergency department are actually triaged to outpatient management. We don’t really know anything about these patients. What are their clinical characteristics and what are their outcomes like? And what are the factors that are leading them to be discharged from the ED rather than be admitted to the hospital?”
To find out, he and his associates retrospectively reviewed the medical records of 12,002 adult ED patients who met criteria for sepsis at two tertiary hospitals and two community hospitals in Utah between July 2013 and December 2016. They excluded trauma patients, those who left the ED against medical advice, those who were discharged to hospice or who died in the ED, and eligible patients’ repeat ED encounters. Patients transferred to another acute care facility were considered admitted, while transfers to non-acute care such as skilled nursing or psychiatric facilities were classified as discharges. Next, Dr. Peltan and his associates employed inverse probability weights using a propensity score for ED discharge based on age, sex, Charlson score, ED acuity score, initial ED vital signs, white blood cell count, lactate, sequential organ failure assessment (SOFA)score, busyness of the ED, and study hospital to compare 30-day mortality between patients admitted to the hospital versus those discharged from the ED.
Of the 12,002 patients included in the analysis, 10,032 (83.6%) were admitted, while 1,970 (16.4%) were discharged. Compared with admitted patients, discharged patients were younger (a mean of 53 vs. 60 years, respectively; P less than .001); more likely to be female (65% vs. 55%; P less than .001); more likely to be nonwhite or Hispanic (21% vs 17%; P less than .001), and had fewer comorbidities and physiologic derangements. In addition, crude mortality at 30 days was lower in discharged versus admitted patients (1.0% vs. 6.2%, respectively; P less than .001). After the propensity-adjusted analysis, there was no significant difference in 30-day mortality for discharged vs. admitted sepsis patients (adjusted odds ratio 1.0).
“We were worried that discharged ED sepsis patients were being mismanaged and weren’t going to do well as similar patients who were admitted to the hospital,” Dr. Peltan said. “This analysis is still a work in progress, but with that caveat, our findings so far suggest that physicians are making pretty good decisions overall.”
The researchers also found that, among 89 ED physicians who cared for 20 or more eligible patients, some did not discharge any of their sepsis patients, while others discharged 39% of their sepsis patients. “That was surprising,” Dr. Peltan said. “This could mean that some hospital sepsis admissions depend on physician practice style more than the patient’s condition or treatment needs.”
Researchers emphasized that they do not recommend routine outpatient management for individual sepsis patients. “Almost certainly, some of the discharged patients should have been admitted to the hospital.” Dr. Peltan said. “I think there’s still a lot of opportunity to understand who these patients are, understand why there is so much physician variation, and to develop tools to further optimize triage decisions.”
The study was funded in part by the Intermountain Research and Medical Foundation in Salt Lake City. Dr. Peltan reported having no financial disclosures.
SOURCE: Peltan ID et al. ATS 2018, Abstract A5994/702.
SAN DIEGO – More than 16% of emergency department sepsis patients are not admitted to the hospital, preliminary results from a large retrospective cohort study found.
“Nothing is really known about this topic,” lead study author Ithan D. Peltan, MD, said in an interview at an international conference of the American Thoracic Society. “In previous research, we’ve been focused on patients with sepsis who are admitted to the hospital. We have never thoroughly recognized that a fair number of patients who meet clinical criteria for sepsis in the emergency department are actually triaged to outpatient management. We don’t really know anything about these patients. What are their clinical characteristics and what are their outcomes like? And what are the factors that are leading them to be discharged from the ED rather than be admitted to the hospital?”
To find out, he and his associates retrospectively reviewed the medical records of 12,002 adult ED patients who met criteria for sepsis at two tertiary hospitals and two community hospitals in Utah between July 2013 and December 2016. They excluded trauma patients, those who left the ED against medical advice, those who were discharged to hospice or who died in the ED, and eligible patients’ repeat ED encounters. Patients transferred to another acute care facility were considered admitted, while transfers to non-acute care such as skilled nursing or psychiatric facilities were classified as discharges. Next, Dr. Peltan and his associates employed inverse probability weights using a propensity score for ED discharge based on age, sex, Charlson score, ED acuity score, initial ED vital signs, white blood cell count, lactate, sequential organ failure assessment (SOFA)score, busyness of the ED, and study hospital to compare 30-day mortality between patients admitted to the hospital versus those discharged from the ED.
Of the 12,002 patients included in the analysis, 10,032 (83.6%) were admitted, while 1,970 (16.4%) were discharged. Compared with admitted patients, discharged patients were younger (a mean of 53 vs. 60 years, respectively; P less than .001); more likely to be female (65% vs. 55%; P less than .001); more likely to be nonwhite or Hispanic (21% vs 17%; P less than .001), and had fewer comorbidities and physiologic derangements. In addition, crude mortality at 30 days was lower in discharged versus admitted patients (1.0% vs. 6.2%, respectively; P less than .001). After the propensity-adjusted analysis, there was no significant difference in 30-day mortality for discharged vs. admitted sepsis patients (adjusted odds ratio 1.0).
“We were worried that discharged ED sepsis patients were being mismanaged and weren’t going to do well as similar patients who were admitted to the hospital,” Dr. Peltan said. “This analysis is still a work in progress, but with that caveat, our findings so far suggest that physicians are making pretty good decisions overall.”
The researchers also found that, among 89 ED physicians who cared for 20 or more eligible patients, some did not discharge any of their sepsis patients, while others discharged 39% of their sepsis patients. “That was surprising,” Dr. Peltan said. “This could mean that some hospital sepsis admissions depend on physician practice style more than the patient’s condition or treatment needs.”
Researchers emphasized that they do not recommend routine outpatient management for individual sepsis patients. “Almost certainly, some of the discharged patients should have been admitted to the hospital.” Dr. Peltan said. “I think there’s still a lot of opportunity to understand who these patients are, understand why there is so much physician variation, and to develop tools to further optimize triage decisions.”
The study was funded in part by the Intermountain Research and Medical Foundation in Salt Lake City. Dr. Peltan reported having no financial disclosures.
SOURCE: Peltan ID et al. ATS 2018, Abstract A5994/702.
SAN DIEGO – More than 16% of emergency department sepsis patients are not admitted to the hospital, preliminary results from a large retrospective cohort study found.
“Nothing is really known about this topic,” lead study author Ithan D. Peltan, MD, said in an interview at an international conference of the American Thoracic Society. “In previous research, we’ve been focused on patients with sepsis who are admitted to the hospital. We have never thoroughly recognized that a fair number of patients who meet clinical criteria for sepsis in the emergency department are actually triaged to outpatient management. We don’t really know anything about these patients. What are their clinical characteristics and what are their outcomes like? And what are the factors that are leading them to be discharged from the ED rather than be admitted to the hospital?”
To find out, he and his associates retrospectively reviewed the medical records of 12,002 adult ED patients who met criteria for sepsis at two tertiary hospitals and two community hospitals in Utah between July 2013 and December 2016. They excluded trauma patients, those who left the ED against medical advice, those who were discharged to hospice or who died in the ED, and eligible patients’ repeat ED encounters. Patients transferred to another acute care facility were considered admitted, while transfers to non-acute care such as skilled nursing or psychiatric facilities were classified as discharges. Next, Dr. Peltan and his associates employed inverse probability weights using a propensity score for ED discharge based on age, sex, Charlson score, ED acuity score, initial ED vital signs, white blood cell count, lactate, sequential organ failure assessment (SOFA)score, busyness of the ED, and study hospital to compare 30-day mortality between patients admitted to the hospital versus those discharged from the ED.
Of the 12,002 patients included in the analysis, 10,032 (83.6%) were admitted, while 1,970 (16.4%) were discharged. Compared with admitted patients, discharged patients were younger (a mean of 53 vs. 60 years, respectively; P less than .001); more likely to be female (65% vs. 55%; P less than .001); more likely to be nonwhite or Hispanic (21% vs 17%; P less than .001), and had fewer comorbidities and physiologic derangements. In addition, crude mortality at 30 days was lower in discharged versus admitted patients (1.0% vs. 6.2%, respectively; P less than .001). After the propensity-adjusted analysis, there was no significant difference in 30-day mortality for discharged vs. admitted sepsis patients (adjusted odds ratio 1.0).
“We were worried that discharged ED sepsis patients were being mismanaged and weren’t going to do well as similar patients who were admitted to the hospital,” Dr. Peltan said. “This analysis is still a work in progress, but with that caveat, our findings so far suggest that physicians are making pretty good decisions overall.”
The researchers also found that, among 89 ED physicians who cared for 20 or more eligible patients, some did not discharge any of their sepsis patients, while others discharged 39% of their sepsis patients. “That was surprising,” Dr. Peltan said. “This could mean that some hospital sepsis admissions depend on physician practice style more than the patient’s condition or treatment needs.”
Researchers emphasized that they do not recommend routine outpatient management for individual sepsis patients. “Almost certainly, some of the discharged patients should have been admitted to the hospital.” Dr. Peltan said. “I think there’s still a lot of opportunity to understand who these patients are, understand why there is so much physician variation, and to develop tools to further optimize triage decisions.”
The study was funded in part by the Intermountain Research and Medical Foundation in Salt Lake City. Dr. Peltan reported having no financial disclosures.
SOURCE: Peltan ID et al. ATS 2018, Abstract A5994/702.
AT ATS 2018
Key clinical point: More research is needed to optimize triage decisions for ED sepsis patients and to understand possible disparities in ED disposition.
Major finding: Among adult patients who met clinical criteria for sepsis in the emergency department, 16.4% were not admitted to the hospital.
Study details: A retrospective study of 12,002 adult ED patients who met criteria for sepsis at two tertiary hospitals and two community hospitals in Utah.
Disclosures: The study was funded in part by the Intermountain Research and Medical Foundation in Salt Lake City. Dr. Peltan reported having no financial disclosures.
Source: Peltan ID et al. Abstract 5994/702, ATS 2018.
DOACs’ safety affirmed in real-world setting
Direct oral anticoagulants were associated with decreased bleeding risk versus warfarin in a recent retrospective analysis of primary care databases.
Apixaban (Eliquis) was associated with decreased risk of major bleeding events versus warfarin both in patients with atrial fibrillation (AF) and those prescribed anticoagulants for other causes, according to study results.
Rivaroxaban (Xarelto) was associated with a decrease in risk of intracranial bleeding, compared with warfarin in patients without AF, as was dabigatran (Pradaxa), reported Yana Vinogradova, a research statistician in the division of primary care at the University of Nottingham, England, and her coauthors.
An increased risk of all-cause mortality was seen with both rivaroxaban and low-dose apixaban, possibly because more patients died of age-related causes while on these direct oral anticoagulants (DOACs), they reported.
“This large observational study, based on a general population in a primary care setting, provides reassurance about the safety of DOACs as an alternative to warfarin across all new incident users,” Ms. Vinogradova and her colleagues said in the BMJ.
Evidence establishing the noninferiority of DOACs to warfarin comes mostly from controlled trials in AF leaving “residual concerns” about the safety of these newer agents in real world settings, where a broader range of patients may receive them, they added.
Accordingly, they conducted an analysis based on patient data from two U.K. primary care databases that were representative of the national population, according to the researchers.
A total of 196,061 patients were represented in the study, including 103,270 (53%) with AF and 92,791 (47%) who received anticoagulants for other reasons.
A total of 67% of patients received warfarin, though its use declined from 98% in 2011, the beginning of the study period, to 23% in 2016, the end of the study period. Over that same time period, use of rivaroxaban rose from 1% to 42%, and use of apixaban rose from 0% to 31%, while dabigatran use peaked in 2013 at 10%, dropping to 3% by 2016.
Edoxaban was excluded from the study because it was not licensed in the United Kingdom until the end of 2015, investigators said.
For patients with AF, apixaban was linked to a lower major bleeding risk, both versus warfarin (adjusted hazard ratio, 0.66; 95% confidence interval, 0.54-0.79) and versus rivaroxaban, the published data show. Apixaban was associated with a lower risk of intracranial bleed versus warfarin in patients with AF (aHR, 0.40; 95% CI, 0.25-0.64) as was dabigatran (aHR, 0.45; 95% CI, 0.26-0.77).
For patients without AF, apixaban was again associated with a lower risk of major bleeding versus warfarin and versus rivaroxaban, while rivaroxaban was associated with lower intracranial bleeding risk versus warfarin, and apixaban with lower risks for gastrointestinal bleeds.
Compared with apixaban, rivaroxaban and dabigatran were associated with higher risks of certain bleeding events, further analyses show.
Rivaroxaban and lower-dose apixaban were both associated with increased all-cause mortality risk versus warfarin, both in the atrial fibrillation and non-AF groups, Ms. Vinogradova and her coinvestigators noted.
“A greater proportion of the older patients on apixaban and rivaroxaban may have died while still taking anticoagulants but from age-related causes other than ischemic stroke or venous thromboembolism,” they wrote.
Compared with patients on higher doses of DOACs, patients receiving lower doses were older and had more comorbidities and more previous events, they added.
Between DOACs, results of this particular analysis were most favorable for apixaban, according to investigators.
“Our study has shown that the risk of major bleeding is lower in patients taking apixaban regardless of the reason for prescribing,” they wrote. “This was most pronounced for intracranial bleeding in patients with atrial fibrillation and for gastrointestinal bleeding in patients without atrial fibrillation, appearing, in general, to show apixaban to be the safest drug.”
The study was supported by a grant from the National Institute for Health Research. The investigators had no relevant disclosures.
SOURCE: Vinogradova Y et al. BMJ 2018; 362:K2505.
Direct oral anticoagulants were associated with decreased bleeding risk versus warfarin in a recent retrospective analysis of primary care databases.
Apixaban (Eliquis) was associated with decreased risk of major bleeding events versus warfarin both in patients with atrial fibrillation (AF) and those prescribed anticoagulants for other causes, according to study results.
Rivaroxaban (Xarelto) was associated with a decrease in risk of intracranial bleeding, compared with warfarin in patients without AF, as was dabigatran (Pradaxa), reported Yana Vinogradova, a research statistician in the division of primary care at the University of Nottingham, England, and her coauthors.
An increased risk of all-cause mortality was seen with both rivaroxaban and low-dose apixaban, possibly because more patients died of age-related causes while on these direct oral anticoagulants (DOACs), they reported.
“This large observational study, based on a general population in a primary care setting, provides reassurance about the safety of DOACs as an alternative to warfarin across all new incident users,” Ms. Vinogradova and her colleagues said in the BMJ.
Evidence establishing the noninferiority of DOACs to warfarin comes mostly from controlled trials in AF leaving “residual concerns” about the safety of these newer agents in real world settings, where a broader range of patients may receive them, they added.
Accordingly, they conducted an analysis based on patient data from two U.K. primary care databases that were representative of the national population, according to the researchers.
A total of 196,061 patients were represented in the study, including 103,270 (53%) with AF and 92,791 (47%) who received anticoagulants for other reasons.
A total of 67% of patients received warfarin, though its use declined from 98% in 2011, the beginning of the study period, to 23% in 2016, the end of the study period. Over that same time period, use of rivaroxaban rose from 1% to 42%, and use of apixaban rose from 0% to 31%, while dabigatran use peaked in 2013 at 10%, dropping to 3% by 2016.
Edoxaban was excluded from the study because it was not licensed in the United Kingdom until the end of 2015, investigators said.
For patients with AF, apixaban was linked to a lower major bleeding risk, both versus warfarin (adjusted hazard ratio, 0.66; 95% confidence interval, 0.54-0.79) and versus rivaroxaban, the published data show. Apixaban was associated with a lower risk of intracranial bleed versus warfarin in patients with AF (aHR, 0.40; 95% CI, 0.25-0.64) as was dabigatran (aHR, 0.45; 95% CI, 0.26-0.77).
For patients without AF, apixaban was again associated with a lower risk of major bleeding versus warfarin and versus rivaroxaban, while rivaroxaban was associated with lower intracranial bleeding risk versus warfarin, and apixaban with lower risks for gastrointestinal bleeds.
Compared with apixaban, rivaroxaban and dabigatran were associated with higher risks of certain bleeding events, further analyses show.
Rivaroxaban and lower-dose apixaban were both associated with increased all-cause mortality risk versus warfarin, both in the atrial fibrillation and non-AF groups, Ms. Vinogradova and her coinvestigators noted.
“A greater proportion of the older patients on apixaban and rivaroxaban may have died while still taking anticoagulants but from age-related causes other than ischemic stroke or venous thromboembolism,” they wrote.
Compared with patients on higher doses of DOACs, patients receiving lower doses were older and had more comorbidities and more previous events, they added.
Between DOACs, results of this particular analysis were most favorable for apixaban, according to investigators.
“Our study has shown that the risk of major bleeding is lower in patients taking apixaban regardless of the reason for prescribing,” they wrote. “This was most pronounced for intracranial bleeding in patients with atrial fibrillation and for gastrointestinal bleeding in patients without atrial fibrillation, appearing, in general, to show apixaban to be the safest drug.”
The study was supported by a grant from the National Institute for Health Research. The investigators had no relevant disclosures.
SOURCE: Vinogradova Y et al. BMJ 2018; 362:K2505.
Direct oral anticoagulants were associated with decreased bleeding risk versus warfarin in a recent retrospective analysis of primary care databases.
Apixaban (Eliquis) was associated with decreased risk of major bleeding events versus warfarin both in patients with atrial fibrillation (AF) and those prescribed anticoagulants for other causes, according to study results.
Rivaroxaban (Xarelto) was associated with a decrease in risk of intracranial bleeding, compared with warfarin in patients without AF, as was dabigatran (Pradaxa), reported Yana Vinogradova, a research statistician in the division of primary care at the University of Nottingham, England, and her coauthors.
An increased risk of all-cause mortality was seen with both rivaroxaban and low-dose apixaban, possibly because more patients died of age-related causes while on these direct oral anticoagulants (DOACs), they reported.
“This large observational study, based on a general population in a primary care setting, provides reassurance about the safety of DOACs as an alternative to warfarin across all new incident users,” Ms. Vinogradova and her colleagues said in the BMJ.
Evidence establishing the noninferiority of DOACs to warfarin comes mostly from controlled trials in AF leaving “residual concerns” about the safety of these newer agents in real world settings, where a broader range of patients may receive them, they added.
Accordingly, they conducted an analysis based on patient data from two U.K. primary care databases that were representative of the national population, according to the researchers.
A total of 196,061 patients were represented in the study, including 103,270 (53%) with AF and 92,791 (47%) who received anticoagulants for other reasons.
A total of 67% of patients received warfarin, though its use declined from 98% in 2011, the beginning of the study period, to 23% in 2016, the end of the study period. Over that same time period, use of rivaroxaban rose from 1% to 42%, and use of apixaban rose from 0% to 31%, while dabigatran use peaked in 2013 at 10%, dropping to 3% by 2016.
Edoxaban was excluded from the study because it was not licensed in the United Kingdom until the end of 2015, investigators said.
For patients with AF, apixaban was linked to a lower major bleeding risk, both versus warfarin (adjusted hazard ratio, 0.66; 95% confidence interval, 0.54-0.79) and versus rivaroxaban, the published data show. Apixaban was associated with a lower risk of intracranial bleed versus warfarin in patients with AF (aHR, 0.40; 95% CI, 0.25-0.64) as was dabigatran (aHR, 0.45; 95% CI, 0.26-0.77).
For patients without AF, apixaban was again associated with a lower risk of major bleeding versus warfarin and versus rivaroxaban, while rivaroxaban was associated with lower intracranial bleeding risk versus warfarin, and apixaban with lower risks for gastrointestinal bleeds.
Compared with apixaban, rivaroxaban and dabigatran were associated with higher risks of certain bleeding events, further analyses show.
Rivaroxaban and lower-dose apixaban were both associated with increased all-cause mortality risk versus warfarin, both in the atrial fibrillation and non-AF groups, Ms. Vinogradova and her coinvestigators noted.
“A greater proportion of the older patients on apixaban and rivaroxaban may have died while still taking anticoagulants but from age-related causes other than ischemic stroke or venous thromboembolism,” they wrote.
Compared with patients on higher doses of DOACs, patients receiving lower doses were older and had more comorbidities and more previous events, they added.
Between DOACs, results of this particular analysis were most favorable for apixaban, according to investigators.
“Our study has shown that the risk of major bleeding is lower in patients taking apixaban regardless of the reason for prescribing,” they wrote. “This was most pronounced for intracranial bleeding in patients with atrial fibrillation and for gastrointestinal bleeding in patients without atrial fibrillation, appearing, in general, to show apixaban to be the safest drug.”
The study was supported by a grant from the National Institute for Health Research. The investigators had no relevant disclosures.
SOURCE: Vinogradova Y et al. BMJ 2018; 362:K2505.
FROM THE BMJ
Key clinical point: .
Major finding: Apixaban was linked with an adjusted 34% decreased risk of major bleeding in patients with AF and a 40% lower risk in those prescribed anticoagulants for other causes, compared with warfarin.
Study details: A retrospective cohort study representing 196,061 patients from two U.K. primary care databases.
Disclosures: The study was supported by a grant from the National Institute for Health Research. The investigators had no relevant disclosures.
Source: Vinogradova Y et al. BMJ 2018;362:k2505.
ICH: Recent NOAC use associated with lower risk of in-hospital mortality, compared with warfarin
Background: Previous studies comparing NOACs with warfarin have demonstrated a lower incidence of ICH in patients receiving NOACs. Data have been limited, though, regarding ICH with recent anticoagulant use and in-hospital mortality.
Study design: Retrospective cohort study.
Setting: More than 1,600 U.S. hospitals that participate in the Get With The Guidelines–Stroke national registry.
Synopsis: Of 141,311 patients admitted with ICH, 10.6% were receiving warfarin and 3.5% were receiving NOACs prior to hospitalization. Prior use of warfarin or NOACs, compared with no anticoagulant use, was associated with higher in-hospital mortality. However, use of NOACs, compared with use of warfarin, was associated with lower in-hospital mortality risk (adjusted risk difference, –5.7%; adjusted odds ratio, 0.75). Among patients with prior NOAC use, 54% of them were using rivaroxaban.
A limitation to this study is that reversal strategies, such as the use of vitamin K, fresh frozen plasma, or intravenous factor concentrates, were not available in the database. In addition, since rivaroxaban accounted for more than half the NOACs used, it may be difficult to apply the overall findings to all other available NOACs.
Bottom line: In patients admitted for ICH, prior use of NOACs, compared with warfarin, was associated with lower risk of in-hospital mortality.
Citation: Inohara T et al. Association of intracerebral hemorrhage among patients taking non–vitamin K antagonist vs. vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. 2018 Feb 6;319(5):463-73.
Dr. Farkhondehpour is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Background: Previous studies comparing NOACs with warfarin have demonstrated a lower incidence of ICH in patients receiving NOACs. Data have been limited, though, regarding ICH with recent anticoagulant use and in-hospital mortality.
Study design: Retrospective cohort study.
Setting: More than 1,600 U.S. hospitals that participate in the Get With The Guidelines–Stroke national registry.
Synopsis: Of 141,311 patients admitted with ICH, 10.6% were receiving warfarin and 3.5% were receiving NOACs prior to hospitalization. Prior use of warfarin or NOACs, compared with no anticoagulant use, was associated with higher in-hospital mortality. However, use of NOACs, compared with use of warfarin, was associated with lower in-hospital mortality risk (adjusted risk difference, –5.7%; adjusted odds ratio, 0.75). Among patients with prior NOAC use, 54% of them were using rivaroxaban.
A limitation to this study is that reversal strategies, such as the use of vitamin K, fresh frozen plasma, or intravenous factor concentrates, were not available in the database. In addition, since rivaroxaban accounted for more than half the NOACs used, it may be difficult to apply the overall findings to all other available NOACs.
Bottom line: In patients admitted for ICH, prior use of NOACs, compared with warfarin, was associated with lower risk of in-hospital mortality.
Citation: Inohara T et al. Association of intracerebral hemorrhage among patients taking non–vitamin K antagonist vs. vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. 2018 Feb 6;319(5):463-73.
Dr. Farkhondehpour is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Background: Previous studies comparing NOACs with warfarin have demonstrated a lower incidence of ICH in patients receiving NOACs. Data have been limited, though, regarding ICH with recent anticoagulant use and in-hospital mortality.
Study design: Retrospective cohort study.
Setting: More than 1,600 U.S. hospitals that participate in the Get With The Guidelines–Stroke national registry.
Synopsis: Of 141,311 patients admitted with ICH, 10.6% were receiving warfarin and 3.5% were receiving NOACs prior to hospitalization. Prior use of warfarin or NOACs, compared with no anticoagulant use, was associated with higher in-hospital mortality. However, use of NOACs, compared with use of warfarin, was associated with lower in-hospital mortality risk (adjusted risk difference, –5.7%; adjusted odds ratio, 0.75). Among patients with prior NOAC use, 54% of them were using rivaroxaban.
A limitation to this study is that reversal strategies, such as the use of vitamin K, fresh frozen plasma, or intravenous factor concentrates, were not available in the database. In addition, since rivaroxaban accounted for more than half the NOACs used, it may be difficult to apply the overall findings to all other available NOACs.
Bottom line: In patients admitted for ICH, prior use of NOACs, compared with warfarin, was associated with lower risk of in-hospital mortality.
Citation: Inohara T et al. Association of intracerebral hemorrhage among patients taking non–vitamin K antagonist vs. vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. 2018 Feb 6;319(5):463-73.
Dr. Farkhondehpour is a hospitalist at UC San Diego Health and an assistant clinical professor at the University of California, San Diego.
Primary cirrhotic prophylaxis of bacterial peritonitis falls short
WASHINGTON –
The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week®.
Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.
“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.
Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.
The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.
Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”
The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.
The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.
Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.
Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.
Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.
WASHINGTON –
The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week®.
Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.
“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.
Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.
The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.
Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”
The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.
The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.
Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.
Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.
Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.
WASHINGTON –
The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week®.
Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.
“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.
Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.
The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.
Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”
The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.
The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.
Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.
Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.
Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.
REPORTING FROM DDW 2018
Key clinical point: Antibiotic prophylaxis for bacterial peritonitis showed limitations, especially for primary prophylaxis.
Major finding: Mortality was 19% among primary prophylaxis patients and 9% among secondary prophylaxis patients during hospitalization and 30 days following.
Study details: An analysis of data from 308 cirrhotic patients on antibiotic prophylaxis at 14 North American centers.
Disclosures: Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.