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Daily polypill lowers BP, cholesterol in underserved population
A daily polypill regimen improved cardiovascular risk factors in a socioeconomically vulnerable minority population, in a randomized controlled trial.
Patients at a federally qualified community health center in Alabama who received treatment with a combination pill for 1 year had greater reductions in systolic blood pressure and LDL cholesterol than did patients who received usual care, according to results published online on Sept. 19 in the New England Journal of Medicine.
“The simplicity and low cost of the polypill regimen make this approach attractive” when barriers such as lack of income, underinsurance, and difficulty attending clinic visits are common, said first author Daniel Muñoz, MD, of Vanderbilt University in Nashville, and coinvestigators. The investigators obtained the pills at a cost of $26 per month per participant.
People with low socioeconomic status and those who are nonwhite have high cardiovascular mortality, and the southeastern United States and rural areas have disproportionately high levels of cardiovascular disease burden, according to the investigators. The rates at which people with low socioeconomic status receive treatment for hypertension and hypercholesterolemia – leading cardiovascular disease risk factors – “are strikingly low,” Dr. Muñoz and colleagues said.
To assess the effectiveness of a polypill-based strategy in an underserved population with low socioeconomic status, the researchers conducted the randomized trial.
They enrolled 303 adults without cardiovascular disease, and 148 of the patients were randomized to receive the polypill, which contained generic versions of atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). The remaining 155 patients received usual care. All participants scheduled 2-month and 12-month follow-up visits.
The participants had an average age of 56 years, 60% were women, and more than 95% were black. More than 70% had an annual household income of less than $15,000. Baseline characteristics of the treatment groups did not significantly differ.
At baseline, the average BP was 140/83 mm Hg, and the average LDL cholesterol level was 113 mg/dL.
In all, 91% of the participants completed the 12-month trial visit. Average systolic BP decreased by 9 mm Hg in the group that received the polypill, compared with 2 mm Hg in the group that received usual care. Average LDL cholesterol level decreased by 15 mg/dL in the polypill group, versus 4 mg/dL in the usual-care group.
Changes in other medications
Clinicians discontinued or reduced doses of other antihypertensive or lipid-lowering medications in 44% of the patients in the polypill group and none in the usual-care group. Clinicians escalated therapy in 2% of the participants in the polypill group and in 10% of the usual-care group.
Side effects in participants who received the polypill included a 1% incidence of myalgias and a 1% incidence of hypotension or light-headedness. Liver function test results were normal.
Five serious adverse events that occurred during the trial – two in the polypill group and three in the usual-care group – were judged to be unrelated to the trial by a data and safety monitoring board.
The authors noted that limitations of the trial include its open-label design and that it was conducted at a single center.
“It is important to emphasize that use of the polypill does not preclude individualized, add-on therapies for residual elevations in blood-pressure or cholesterol levels, as judged by a patient’s physician,” said Dr. Muñoz and colleagues. “We recognize that a ‘one size fits all’ approach to cardiovascular disease prevention runs counter to current trends in precision medicine, in which clinical, genomic, and lifestyle factors are used for the development of individualized treatment strategies. Although the precision approach has clear virtues, a broader approach may benefit patients who face barriers to accessing the full advantages of precision medicine.”
The study was supported by grants from the American Heart Association Strategically Focused Prevention Research Network and the National Institutes of Health. One author disclosed personal fees from Novartis outside the study.
SOURCE: Muñoz D et al. N Engl J Med. 2019 Sep 18;381(12):1114-23. doi: 10.1056/NEJMoa1815359.
A daily polypill regimen improved cardiovascular risk factors in a socioeconomically vulnerable minority population, in a randomized controlled trial.
Patients at a federally qualified community health center in Alabama who received treatment with a combination pill for 1 year had greater reductions in systolic blood pressure and LDL cholesterol than did patients who received usual care, according to results published online on Sept. 19 in the New England Journal of Medicine.
“The simplicity and low cost of the polypill regimen make this approach attractive” when barriers such as lack of income, underinsurance, and difficulty attending clinic visits are common, said first author Daniel Muñoz, MD, of Vanderbilt University in Nashville, and coinvestigators. The investigators obtained the pills at a cost of $26 per month per participant.
People with low socioeconomic status and those who are nonwhite have high cardiovascular mortality, and the southeastern United States and rural areas have disproportionately high levels of cardiovascular disease burden, according to the investigators. The rates at which people with low socioeconomic status receive treatment for hypertension and hypercholesterolemia – leading cardiovascular disease risk factors – “are strikingly low,” Dr. Muñoz and colleagues said.
To assess the effectiveness of a polypill-based strategy in an underserved population with low socioeconomic status, the researchers conducted the randomized trial.
They enrolled 303 adults without cardiovascular disease, and 148 of the patients were randomized to receive the polypill, which contained generic versions of atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). The remaining 155 patients received usual care. All participants scheduled 2-month and 12-month follow-up visits.
The participants had an average age of 56 years, 60% were women, and more than 95% were black. More than 70% had an annual household income of less than $15,000. Baseline characteristics of the treatment groups did not significantly differ.
At baseline, the average BP was 140/83 mm Hg, and the average LDL cholesterol level was 113 mg/dL.
In all, 91% of the participants completed the 12-month trial visit. Average systolic BP decreased by 9 mm Hg in the group that received the polypill, compared with 2 mm Hg in the group that received usual care. Average LDL cholesterol level decreased by 15 mg/dL in the polypill group, versus 4 mg/dL in the usual-care group.
Changes in other medications
Clinicians discontinued or reduced doses of other antihypertensive or lipid-lowering medications in 44% of the patients in the polypill group and none in the usual-care group. Clinicians escalated therapy in 2% of the participants in the polypill group and in 10% of the usual-care group.
Side effects in participants who received the polypill included a 1% incidence of myalgias and a 1% incidence of hypotension or light-headedness. Liver function test results were normal.
Five serious adverse events that occurred during the trial – two in the polypill group and three in the usual-care group – were judged to be unrelated to the trial by a data and safety monitoring board.
The authors noted that limitations of the trial include its open-label design and that it was conducted at a single center.
“It is important to emphasize that use of the polypill does not preclude individualized, add-on therapies for residual elevations in blood-pressure or cholesterol levels, as judged by a patient’s physician,” said Dr. Muñoz and colleagues. “We recognize that a ‘one size fits all’ approach to cardiovascular disease prevention runs counter to current trends in precision medicine, in which clinical, genomic, and lifestyle factors are used for the development of individualized treatment strategies. Although the precision approach has clear virtues, a broader approach may benefit patients who face barriers to accessing the full advantages of precision medicine.”
The study was supported by grants from the American Heart Association Strategically Focused Prevention Research Network and the National Institutes of Health. One author disclosed personal fees from Novartis outside the study.
SOURCE: Muñoz D et al. N Engl J Med. 2019 Sep 18;381(12):1114-23. doi: 10.1056/NEJMoa1815359.
A daily polypill regimen improved cardiovascular risk factors in a socioeconomically vulnerable minority population, in a randomized controlled trial.
Patients at a federally qualified community health center in Alabama who received treatment with a combination pill for 1 year had greater reductions in systolic blood pressure and LDL cholesterol than did patients who received usual care, according to results published online on Sept. 19 in the New England Journal of Medicine.
“The simplicity and low cost of the polypill regimen make this approach attractive” when barriers such as lack of income, underinsurance, and difficulty attending clinic visits are common, said first author Daniel Muñoz, MD, of Vanderbilt University in Nashville, and coinvestigators. The investigators obtained the pills at a cost of $26 per month per participant.
People with low socioeconomic status and those who are nonwhite have high cardiovascular mortality, and the southeastern United States and rural areas have disproportionately high levels of cardiovascular disease burden, according to the investigators. The rates at which people with low socioeconomic status receive treatment for hypertension and hypercholesterolemia – leading cardiovascular disease risk factors – “are strikingly low,” Dr. Muñoz and colleagues said.
To assess the effectiveness of a polypill-based strategy in an underserved population with low socioeconomic status, the researchers conducted the randomized trial.
They enrolled 303 adults without cardiovascular disease, and 148 of the patients were randomized to receive the polypill, which contained generic versions of atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). The remaining 155 patients received usual care. All participants scheduled 2-month and 12-month follow-up visits.
The participants had an average age of 56 years, 60% were women, and more than 95% were black. More than 70% had an annual household income of less than $15,000. Baseline characteristics of the treatment groups did not significantly differ.
At baseline, the average BP was 140/83 mm Hg, and the average LDL cholesterol level was 113 mg/dL.
In all, 91% of the participants completed the 12-month trial visit. Average systolic BP decreased by 9 mm Hg in the group that received the polypill, compared with 2 mm Hg in the group that received usual care. Average LDL cholesterol level decreased by 15 mg/dL in the polypill group, versus 4 mg/dL in the usual-care group.
Changes in other medications
Clinicians discontinued or reduced doses of other antihypertensive or lipid-lowering medications in 44% of the patients in the polypill group and none in the usual-care group. Clinicians escalated therapy in 2% of the participants in the polypill group and in 10% of the usual-care group.
Side effects in participants who received the polypill included a 1% incidence of myalgias and a 1% incidence of hypotension or light-headedness. Liver function test results were normal.
Five serious adverse events that occurred during the trial – two in the polypill group and three in the usual-care group – were judged to be unrelated to the trial by a data and safety monitoring board.
The authors noted that limitations of the trial include its open-label design and that it was conducted at a single center.
“It is important to emphasize that use of the polypill does not preclude individualized, add-on therapies for residual elevations in blood-pressure or cholesterol levels, as judged by a patient’s physician,” said Dr. Muñoz and colleagues. “We recognize that a ‘one size fits all’ approach to cardiovascular disease prevention runs counter to current trends in precision medicine, in which clinical, genomic, and lifestyle factors are used for the development of individualized treatment strategies. Although the precision approach has clear virtues, a broader approach may benefit patients who face barriers to accessing the full advantages of precision medicine.”
The study was supported by grants from the American Heart Association Strategically Focused Prevention Research Network and the National Institutes of Health. One author disclosed personal fees from Novartis outside the study.
SOURCE: Muñoz D et al. N Engl J Med. 2019 Sep 18;381(12):1114-23. doi: 10.1056/NEJMoa1815359.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A daily polypill regimen may improve cardiovascular disease prevention in underserved populations.
Major finding: Mean LDL cholesterol levels decreased by 15 mg/dL in the polypill group, vs. 4 mg/dL in the usual-care group.
Study details: An open-label, randomized trial that enrolled 303 adults without cardiovascular disease at a federally qualified community health center in Alabama.
Disclosures: The study was supported by grants from the American Heart Association Strategically Focused Prevention Research Network and the National Institutes of Health. One author disclosed personal fees from Novartis outside the study.
Source: Muñoz D et al. N Engl J Med. 2019;381(12):1114-23. doi: 10.1056/NEJMoa1815359.
European cholesterol guidelines push LDL targets below 55 mg/dL
PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*
The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.
“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.
While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.
“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.
The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.
“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.
However, other experts see an important difference in the risk faced by patients who reach the ESC’s recommended treatment goals and those who fall just short.
“It’s hard to lower an LDL-cholesterol that is already relatively low. People who are close to their cholesterol target need the most intensified treatment” to reach their goal, said Rory Collins, F.Med.Sci., professor of epidemiology at Oxford University. He was not on the ESC guidelines panel.
“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.
The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.
The ESC also broke new ground by advocating an aggressive path toward achieving these LDL-cholesterol goals by elevating the newest and most potent class of approved LDL-cholesterol-lowering drugs, the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, to a top-tier, class I recommendation (“is recommended”) for secondary prevention in very-high-risk patients not reaching their goal LDL-cholesterol level on a maximally tolerated statin plus ezetimibe. This recommendation to unequivocally add a PCSK9 inhibitor for this patient population contrasts with the 2018 AHA/ACC guideline that deemed adding a PCSK9 inhibitor a IIa recommendation (“is reasonable”).
A similar uptick in treatment aggressiveness appeared in the ESC’s recommendations for managing very-high-risk patients in a primary prevention setting, including those without familial hypercholesterolemia. For these people, the ESC panel, which worked in concert with the European Atherosclerosis Society, pegged adding a PCSK9 inhibitor as a IIb (“may be considered”) recommendation when these very-high-risk people fail to reach their LDL-cholesterol target on a maximally tolerated statin and ezetimibe. Once again, this opening to use a PCSK9 inhibitor contrasted with the 2018 U.S. guideline, which never mentioned an option of adding a PCSK9 inhibitor for primary prevention except when someone also has familial hypercholesterolemia and starts treatment with an LDL level of at least 190 mg/dL (a IIb recommendation). The new European guidelines proposed using a PCSK9 inhibitor as a second-line option to consider when needed for people whose very high risk derives primarily from older age and other factors such as smoking or hypertension that give them at least a 10% 10-year risk for cardiovascular death as estimated with the European-oriented SCORE risk calculator tables.
Updated SCORE risk designations appear in the new ESC dyslipidemia guidelines, and they show, for example, that in lower-risk European countries (mostly Western European nations) virtually all men who are at least 70 years old would fall into the very-high-risk category that makes them potential candidates for treatment with a PCSK9 inhibitor regardless of any other risk they may or may not have. In higher-risk (mostly Eastern European) countries this designation kicks in for most men once they reach the age of 65.
Several Congress attendees who came to a discussion session on the guidelines voiced concerns that the new revision will lead to substantially increased use of the these drugs and hence will significantly boost medical costs, because these drugs today are priced at about $6,000 annually to treat one patient. In response, members of the guideline-writing panel defended their decision as unavoidable given what’s been reported on the clinical impact of PCSK9 inhibitors when lowering LDL cholesterol and cutting atherosclerotic cardiovascular disease events.
“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.
Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.
Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.
“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”
“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.
Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.
This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.
The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”
Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.
*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.
SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.
The new ESC dyslipidemia guidelines recently presented at the society’s annual congress are a welcome addition to the lipid disorder treatment guidelines available to clinicians. These guidelines follow the groundbreaking recommendation in 2017 by AACE in their updated guidelines that introduced an LDL goal of <55 mg/dL in “extreme risk” patients. The ESC guidelines now also recommend an LDL goal of <55 mg/dL in “very-high-risk” patients but go further by also requiring a 50% reduction in LDL. Furthermore, they have established an LDL goal of <40 mg/dL in patients who experienced a second vascular event in the past 2 years while on maximally tolerated statin dose.
The ESC very-high-risk category shares many features with AACE’s extreme-risk category but is broader in that it includes patients without a clinical event who display unequivocal evidence of arteriosclerotic cardiovascular disease (ASCVD) on imaging and patients with severe chronic kidney disease (GFR <30 mL/min ) without known ASCVD. There are substantial differences between the ESC and AHA-ACC 2018 guidelines in the very-high-risk category. The AHA very-high-risk is directed toward secondary prevention only and requires two major ASCVD events or one major and at least two high-risk conditions. Moreover, elements of both major ASCVD events and high-risk conditions as well as the very-high-risk eligibility requirements could mean that some patients, who would clearly be classified by both ESC and AACE as candidates for an LDL goal of <55, may not qualify for threshold consideration for maximal LDL lowering below 70 mg/dL including the use of PCSK9 inhibitors. Relative to this point, the AHA-ACC guidelines do not classify past CABG or PCI as a major ASCVD event, nor is a TIA considered a major event or a high-risk condition.
For LDL, “lower is better” is supported by years of statin clinical trial evidence, along with the robust findings in the 2010 Cholesterol Trialists Collaboration. The goal of <55 mg/dL is supported by the IMPROVE-IT, FOURIER, and ODYSSEY trials. The ESC guidelines appropriately take this body of evidence and applies it to an aggressive treatment platform that, like AACE, sets clinically useful LDL goals for clinicians and patients. It takes early, aggressive LDL-lowering treatment to stay ahead of atherosclerotic plaque development in patients who are at very high or extreme risk. Following AACE’s lead, the ESC guidelines are the newest tool available to clinicians addressing this issue with the promise of further decreasing CVD events and extending lives.
Dr. Jellinger is a member of the editorial advisory board for Clinical Endocrinology News. He is professor of clinical medicine on the voluntary faculty at the University of Miami Miller School of Medicine and a practicing endocrinologist at The Center for Diabetes & Endocrine Care in Hollywood, Fla. He is past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology and was chair of the writing committee for the 2017 AACE-ACE lipid guidelines.
The new ESC dyslipidemia guidelines recently presented at the society’s annual congress are a welcome addition to the lipid disorder treatment guidelines available to clinicians. These guidelines follow the groundbreaking recommendation in 2017 by AACE in their updated guidelines that introduced an LDL goal of <55 mg/dL in “extreme risk” patients. The ESC guidelines now also recommend an LDL goal of <55 mg/dL in “very-high-risk” patients but go further by also requiring a 50% reduction in LDL. Furthermore, they have established an LDL goal of <40 mg/dL in patients who experienced a second vascular event in the past 2 years while on maximally tolerated statin dose.
The ESC very-high-risk category shares many features with AACE’s extreme-risk category but is broader in that it includes patients without a clinical event who display unequivocal evidence of arteriosclerotic cardiovascular disease (ASCVD) on imaging and patients with severe chronic kidney disease (GFR <30 mL/min ) without known ASCVD. There are substantial differences between the ESC and AHA-ACC 2018 guidelines in the very-high-risk category. The AHA very-high-risk is directed toward secondary prevention only and requires two major ASCVD events or one major and at least two high-risk conditions. Moreover, elements of both major ASCVD events and high-risk conditions as well as the very-high-risk eligibility requirements could mean that some patients, who would clearly be classified by both ESC and AACE as candidates for an LDL goal of <55, may not qualify for threshold consideration for maximal LDL lowering below 70 mg/dL including the use of PCSK9 inhibitors. Relative to this point, the AHA-ACC guidelines do not classify past CABG or PCI as a major ASCVD event, nor is a TIA considered a major event or a high-risk condition.
For LDL, “lower is better” is supported by years of statin clinical trial evidence, along with the robust findings in the 2010 Cholesterol Trialists Collaboration. The goal of <55 mg/dL is supported by the IMPROVE-IT, FOURIER, and ODYSSEY trials. The ESC guidelines appropriately take this body of evidence and applies it to an aggressive treatment platform that, like AACE, sets clinically useful LDL goals for clinicians and patients. It takes early, aggressive LDL-lowering treatment to stay ahead of atherosclerotic plaque development in patients who are at very high or extreme risk. Following AACE’s lead, the ESC guidelines are the newest tool available to clinicians addressing this issue with the promise of further decreasing CVD events and extending lives.
Dr. Jellinger is a member of the editorial advisory board for Clinical Endocrinology News. He is professor of clinical medicine on the voluntary faculty at the University of Miami Miller School of Medicine and a practicing endocrinologist at The Center for Diabetes & Endocrine Care in Hollywood, Fla. He is past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology and was chair of the writing committee for the 2017 AACE-ACE lipid guidelines.
The new ESC dyslipidemia guidelines recently presented at the society’s annual congress are a welcome addition to the lipid disorder treatment guidelines available to clinicians. These guidelines follow the groundbreaking recommendation in 2017 by AACE in their updated guidelines that introduced an LDL goal of <55 mg/dL in “extreme risk” patients. The ESC guidelines now also recommend an LDL goal of <55 mg/dL in “very-high-risk” patients but go further by also requiring a 50% reduction in LDL. Furthermore, they have established an LDL goal of <40 mg/dL in patients who experienced a second vascular event in the past 2 years while on maximally tolerated statin dose.
The ESC very-high-risk category shares many features with AACE’s extreme-risk category but is broader in that it includes patients without a clinical event who display unequivocal evidence of arteriosclerotic cardiovascular disease (ASCVD) on imaging and patients with severe chronic kidney disease (GFR <30 mL/min ) without known ASCVD. There are substantial differences between the ESC and AHA-ACC 2018 guidelines in the very-high-risk category. The AHA very-high-risk is directed toward secondary prevention only and requires two major ASCVD events or one major and at least two high-risk conditions. Moreover, elements of both major ASCVD events and high-risk conditions as well as the very-high-risk eligibility requirements could mean that some patients, who would clearly be classified by both ESC and AACE as candidates for an LDL goal of <55, may not qualify for threshold consideration for maximal LDL lowering below 70 mg/dL including the use of PCSK9 inhibitors. Relative to this point, the AHA-ACC guidelines do not classify past CABG or PCI as a major ASCVD event, nor is a TIA considered a major event or a high-risk condition.
For LDL, “lower is better” is supported by years of statin clinical trial evidence, along with the robust findings in the 2010 Cholesterol Trialists Collaboration. The goal of <55 mg/dL is supported by the IMPROVE-IT, FOURIER, and ODYSSEY trials. The ESC guidelines appropriately take this body of evidence and applies it to an aggressive treatment platform that, like AACE, sets clinically useful LDL goals for clinicians and patients. It takes early, aggressive LDL-lowering treatment to stay ahead of atherosclerotic plaque development in patients who are at very high or extreme risk. Following AACE’s lead, the ESC guidelines are the newest tool available to clinicians addressing this issue with the promise of further decreasing CVD events and extending lives.
Dr. Jellinger is a member of the editorial advisory board for Clinical Endocrinology News. He is professor of clinical medicine on the voluntary faculty at the University of Miami Miller School of Medicine and a practicing endocrinologist at The Center for Diabetes & Endocrine Care in Hollywood, Fla. He is past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology and was chair of the writing committee for the 2017 AACE-ACE lipid guidelines.
PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*
The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.
“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.
While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.
“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.
The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.
“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.
However, other experts see an important difference in the risk faced by patients who reach the ESC’s recommended treatment goals and those who fall just short.
“It’s hard to lower an LDL-cholesterol that is already relatively low. People who are close to their cholesterol target need the most intensified treatment” to reach their goal, said Rory Collins, F.Med.Sci., professor of epidemiology at Oxford University. He was not on the ESC guidelines panel.
“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.
The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.
The ESC also broke new ground by advocating an aggressive path toward achieving these LDL-cholesterol goals by elevating the newest and most potent class of approved LDL-cholesterol-lowering drugs, the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, to a top-tier, class I recommendation (“is recommended”) for secondary prevention in very-high-risk patients not reaching their goal LDL-cholesterol level on a maximally tolerated statin plus ezetimibe. This recommendation to unequivocally add a PCSK9 inhibitor for this patient population contrasts with the 2018 AHA/ACC guideline that deemed adding a PCSK9 inhibitor a IIa recommendation (“is reasonable”).
A similar uptick in treatment aggressiveness appeared in the ESC’s recommendations for managing very-high-risk patients in a primary prevention setting, including those without familial hypercholesterolemia. For these people, the ESC panel, which worked in concert with the European Atherosclerosis Society, pegged adding a PCSK9 inhibitor as a IIb (“may be considered”) recommendation when these very-high-risk people fail to reach their LDL-cholesterol target on a maximally tolerated statin and ezetimibe. Once again, this opening to use a PCSK9 inhibitor contrasted with the 2018 U.S. guideline, which never mentioned an option of adding a PCSK9 inhibitor for primary prevention except when someone also has familial hypercholesterolemia and starts treatment with an LDL level of at least 190 mg/dL (a IIb recommendation). The new European guidelines proposed using a PCSK9 inhibitor as a second-line option to consider when needed for people whose very high risk derives primarily from older age and other factors such as smoking or hypertension that give them at least a 10% 10-year risk for cardiovascular death as estimated with the European-oriented SCORE risk calculator tables.
Updated SCORE risk designations appear in the new ESC dyslipidemia guidelines, and they show, for example, that in lower-risk European countries (mostly Western European nations) virtually all men who are at least 70 years old would fall into the very-high-risk category that makes them potential candidates for treatment with a PCSK9 inhibitor regardless of any other risk they may or may not have. In higher-risk (mostly Eastern European) countries this designation kicks in for most men once they reach the age of 65.
Several Congress attendees who came to a discussion session on the guidelines voiced concerns that the new revision will lead to substantially increased use of the these drugs and hence will significantly boost medical costs, because these drugs today are priced at about $6,000 annually to treat one patient. In response, members of the guideline-writing panel defended their decision as unavoidable given what’s been reported on the clinical impact of PCSK9 inhibitors when lowering LDL cholesterol and cutting atherosclerotic cardiovascular disease events.
“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.
Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.
Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.
“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”
“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.
Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.
This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.
The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”
Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.
*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.
SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.
PARIS – The 2019 dyslipidemia management guidelines from the European Society of Cardiology set an LDL cholesterol target for very-high-risk people of less than 55 mg/dL (as well as at least a 50% cut from baseline), a class I recommendation. This marks the first time a cardiology society has either recommended a target goal for this measure below 70 mg/dL or endorsed treating patients to still-lower cholesterol once their level was already under 70 mg/dL.*
The guidelines went further by suggesting consideration of an even lower treatment target for LDL-cholesterol in very-high-risk, secondary prevention patients who have already had at least two atherosclerotic cardiovascular disease events during the past 2 years, a setting that could justify an LDL-cholesterol goal of less than 40 mg/dL (along with a cut from baseline of at least 50%), a class IIb recommendation that denotes a “may be considered,” endorsement.
“In all the trials, lower was better. There was no lower level of LDL cholesterol that’s been studied that was not better” for patient outcomes, Colin Baigent, BMBCH, said while presenting the new guideline at the annual congress of the European Society of Cardiology (ESC). “It’s very clear” that the full treatment benefit from lowering LDL-cholesterol extends to getting very-high risk patients below these levels, said Dr. Baigent, professor of cardiology at Oxford (England) University and one of three chairs of the ESC’s dyslipidemia guideline-writing panel.
While this change was seen as a notably aggressive goal and too fixed on a specific number by at least one author of the 2018 American Heart Association/American College of Cardiology cholesterol management guideline (J Am Coll Cardiol. 2019 Jun;73[24]:e285-e350), it was embraced by another U.S. expert not involved in writing the most recent U.S. recommendations.
“A goal for LDL-cholesterol of less than 55 mg/dL is reasonable; it’s well documented” by trial evidence “and I support it,” said Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado in Aurora. Dr. Eckel added that he “also supports” an LDL-cholesterol of less than 40 mg/dL in very-high-risk patients with a history of multiple events or with multiple residual risk factors, and he said he has applied this lower LDL-cholesterol goal in his practice for selected patients. But Dr. Eckel acknowledged in an interview that the evidence for it was less clear-cut than was the evidence behind a goal of less than 55 mg/dL. He also supported the concept of including a treatment goal in U.S. lipid recommendations, which in recent versions has been missing. “I fall back on a cholesterol goal for practical purposes” of making the success of cholesterol-lowering treatment easier to track.
The new ESC goal was characterized as “arbitrary” by Neil J. Stone, MD, vice-chair of the panel that wrote the 2018 AHA/ACC guideline, which relied on treating secondary-prevention patients at high risk to an LDL-cholesterol at least 50% less than before treatment, and recommended continued intensification for patients whose LDL-cholesterol level remained at or above 70 mg/dL.
“If the patient is at 58 mg/dL I’m not sure anyone can tell me what the difference is,” compared with reaching less than 55 mg/dL, Dr. Stone said in an interview. “I worry about focusing on a number and not on the concept that people at the very highest risk deserve the most intensive treatment; the Europeans agree, but they have a different way of looking at it. Despite this difference in approach, the new ESC guidelines and the 2018 U.S. guideline “are more similar than different,” stressed Dr. Stone, professor of medicine and preventive medicine at Northwestern University, Chicago.
However, other experts see an important difference in the risk faced by patients who reach the ESC’s recommended treatment goals and those who fall just short.
“It’s hard to lower an LDL-cholesterol that is already relatively low. People who are close to their cholesterol target need the most intensified treatment” to reach their goal, said Rory Collins, F.Med.Sci., professor of epidemiology at Oxford University. He was not on the ESC guidelines panel.
“It’s a mind shift that clinicians need to be most aggressive in treating patients with the highest risk” even when their LDL-cholesterol is low but not yet at the target level, Dr. Collins said during a discussion session at the congress.
The new ESC guidelines is about “both getting the LDL-cholesterol down to a certain level and also about achieving a big [at least 50%] change” from baseline. “I think the ESC guidelines make that crystal clear,” said Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, and the sole American to participate in the ESC guidelines-writing panel.
The ESC also broke new ground by advocating an aggressive path toward achieving these LDL-cholesterol goals by elevating the newest and most potent class of approved LDL-cholesterol-lowering drugs, the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, to a top-tier, class I recommendation (“is recommended”) for secondary prevention in very-high-risk patients not reaching their goal LDL-cholesterol level on a maximally tolerated statin plus ezetimibe. This recommendation to unequivocally add a PCSK9 inhibitor for this patient population contrasts with the 2018 AHA/ACC guideline that deemed adding a PCSK9 inhibitor a IIa recommendation (“is reasonable”).
A similar uptick in treatment aggressiveness appeared in the ESC’s recommendations for managing very-high-risk patients in a primary prevention setting, including those without familial hypercholesterolemia. For these people, the ESC panel, which worked in concert with the European Atherosclerosis Society, pegged adding a PCSK9 inhibitor as a IIb (“may be considered”) recommendation when these very-high-risk people fail to reach their LDL-cholesterol target on a maximally tolerated statin and ezetimibe. Once again, this opening to use a PCSK9 inhibitor contrasted with the 2018 U.S. guideline, which never mentioned an option of adding a PCSK9 inhibitor for primary prevention except when someone also has familial hypercholesterolemia and starts treatment with an LDL level of at least 190 mg/dL (a IIb recommendation). The new European guidelines proposed using a PCSK9 inhibitor as a second-line option to consider when needed for people whose very high risk derives primarily from older age and other factors such as smoking or hypertension that give them at least a 10% 10-year risk for cardiovascular death as estimated with the European-oriented SCORE risk calculator tables.
Updated SCORE risk designations appear in the new ESC dyslipidemia guidelines, and they show, for example, that in lower-risk European countries (mostly Western European nations) virtually all men who are at least 70 years old would fall into the very-high-risk category that makes them potential candidates for treatment with a PCSK9 inhibitor regardless of any other risk they may or may not have. In higher-risk (mostly Eastern European) countries this designation kicks in for most men once they reach the age of 65.
Several Congress attendees who came to a discussion session on the guidelines voiced concerns that the new revision will lead to substantially increased use of the these drugs and hence will significantly boost medical costs, because these drugs today are priced at about $6,000 annually to treat one patient. In response, members of the guideline-writing panel defended their decision as unavoidable given what’s been reported on the clinical impact of PCSK9 inhibitors when lowering LDL cholesterol and cutting atherosclerotic cardiovascular disease events.
“I commend the [ESC] guideline for focusing on the science and on what is best for patients. The U.S. guidelines conflated the science and the cost, and the recommendations got watered down by cost considerations,” said Dr. Sabatine, who has led several studies of PCSK9 inhibitors.
Dr. Baigent added that the panel “deliberated long and hard on cost, but we felt that we had to focus on the evidence. The cost will shift” in the future, he predicted.
Other U.S. physicians highlighted the need to take drug cost into account when writing public health policy documents such as lipid-management guidelines and questioned whether this more liberal use of PCSK9 inhibitors was justified.
“I think that in the absence of familial hypercholesterolemia you need to waffle around the edges to justify a PCSK9 inhibitor,” said Dr. Eckel. “The cost of PCSK9 inhibitors has come down, but at $6,000 per year you can’t ignore their cost.”
“In the U.S. we need to be mindful of the cost of treatment,” said Dr. Stone. “The ESC guidelines are probably more aggressive” than the 2018 U.S. guideline. “They use PCSK9 inhibitors perhaps more than we do; we [in the United States] prefer generic ezetimibe. A lot has to do with the definitions of risk. The European guidelines have a lot of risk definitions that differ” from the U.S. guideline, he said.
Members of the ESC guidelines panel acknowledged that the SCORE risk-assessment charts could overestimate risk in older people who need primary prevention treatment, as well as underestimate the risk in younger adults.
This inherent age bias in the SCORE risk tables make it “extremely important to contextualize” a person’s risk “by considering other risk factors,” advised Brian A. Ference, MD, an interventional cardiologist and professor at Cambridge (England) University who was a member of the ESC guidelines writing group.
The new ESC guidelines say that risk categorization “must be interpreted in light of the clinician’s knowledge and experience, and of the patient’s pretest likelihood” of cardiovascular disease.”
Dr. Baigent has received research funding from Boehringer Ingelheim, Novartis, and Pfizer. Dr. Eckel has been an expert witness on behalf of Sanofi/Regeneron. Dr. Sabatine and Dr. Ference have received honoraria and research funding from several companies including those that market lipid-lowering drugs. Dr. Stone and Dr. Collins had no disclosures.
*Correction, 9/20/19: A previous version of this article incorrectly stated that the ESC guidelines were the first by a medical society to recommend the lower cholesterol goals. The American Association of Clinical Endocrinologists included targets below 55 mg/dL in their 2017 dyslipidemia management guidelines.
SOURCE: Mach F et al. Eur Heart J. 2019 Aug 31. doi: 10.1093/eurheartj/ehz455.
REPORTING FROM THE ESC CONGRESS 2019
Hospital-acquired C. diff. tied to four ‘high-risk’ antibiotic classes
The use of four antibiotic classes designated “high risk” was found to be an independent predictor of hospital-acquired Clostridioides difficile (CDI), based upon an analysis of microbiologic and pharmacy data from 171 hospitals in the United States.
The high-risk antibiotic classes were second-, third-, and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and lincosamides, according to a report by Ying P. Tabak, PhD, of Becton Dickinson in Franklin Lakes, N.J., and colleagues published in Infection Control & Hospital Epidemiology.
Of the 171 study sites studied, 66 (39%) were teaching hospitals and 105 (61%) were nonteaching hospitals. The high-risk antibiotics most frequently used were cephalosporins (47.9%), fluoroquinolones (31.6%), carbapenems (13.0%), and lincosamides (7.6%). The sites were distributed across various regions of the United States. The hospital-level antibiotic use was measured as days of therapy (DOT) per 1,000 days present (DP).
The study was not able to determine specific links to individual antibiotic classes but to the use of high-risk antibiotics as a whole, except for cephalosporins, which were significantly correlated with hospital-acquired CDI (r = 0.23; P less than .01).
The overall correlation of high-risk antibiotic use and hospital-acquired CDI was 0.22 (P = .003). Higher correlation was observed in teaching hospitals (r = 0.38; P = .002) versus nonteaching hospitals (r = 0.19; P = .055), according to the researchers. The authors attributed this to the possibility of teaching hospitals dealing with more elderly and sicker patients.
After adjusting for significant confounders, the use of high-risk antibiotics was still independently associated with significant risk for hospital-acquired CDI. “For every 100-day increase of DOT per 1,000 DP in high-risk antibiotic use, there was a 12% increase in [hospital-acquired] CDI (RR, 1.12; 95% [confidence interval], 1.04-1.21; P = .002),” according to the authors. This translated to four additional hospital-acquired CDI cases with every 100 DOT increase per 1,000 DP.
“Using a large and current dataset, we found an independent impact of hospital-level high-risk antibiotic use on [hospital-acquired] CDI even after adjusting for confounding factors such as community CDI pressure, proportion of patients aged 65 years or older, average length of stay, and hospital teaching status,” the researchers concluded.
Funding was provided by Nabriva Therapeutics, an antibiotic development company. Four of the authors are full-time employees of Becton Dickinson, which sells diagnostics for infectious diseases, including CDI, and one author was an employee of Nabriva Therapeutics.
SOURCE: Tabak YP et al. Infect Control Hosp Epidemiol. 2019 Sep 16. doi: 10.1017/ice.2019.236.
The use of four antibiotic classes designated “high risk” was found to be an independent predictor of hospital-acquired Clostridioides difficile (CDI), based upon an analysis of microbiologic and pharmacy data from 171 hospitals in the United States.
The high-risk antibiotic classes were second-, third-, and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and lincosamides, according to a report by Ying P. Tabak, PhD, of Becton Dickinson in Franklin Lakes, N.J., and colleagues published in Infection Control & Hospital Epidemiology.
Of the 171 study sites studied, 66 (39%) were teaching hospitals and 105 (61%) were nonteaching hospitals. The high-risk antibiotics most frequently used were cephalosporins (47.9%), fluoroquinolones (31.6%), carbapenems (13.0%), and lincosamides (7.6%). The sites were distributed across various regions of the United States. The hospital-level antibiotic use was measured as days of therapy (DOT) per 1,000 days present (DP).
The study was not able to determine specific links to individual antibiotic classes but to the use of high-risk antibiotics as a whole, except for cephalosporins, which were significantly correlated with hospital-acquired CDI (r = 0.23; P less than .01).
The overall correlation of high-risk antibiotic use and hospital-acquired CDI was 0.22 (P = .003). Higher correlation was observed in teaching hospitals (r = 0.38; P = .002) versus nonteaching hospitals (r = 0.19; P = .055), according to the researchers. The authors attributed this to the possibility of teaching hospitals dealing with more elderly and sicker patients.
After adjusting for significant confounders, the use of high-risk antibiotics was still independently associated with significant risk for hospital-acquired CDI. “For every 100-day increase of DOT per 1,000 DP in high-risk antibiotic use, there was a 12% increase in [hospital-acquired] CDI (RR, 1.12; 95% [confidence interval], 1.04-1.21; P = .002),” according to the authors. This translated to four additional hospital-acquired CDI cases with every 100 DOT increase per 1,000 DP.
“Using a large and current dataset, we found an independent impact of hospital-level high-risk antibiotic use on [hospital-acquired] CDI even after adjusting for confounding factors such as community CDI pressure, proportion of patients aged 65 years or older, average length of stay, and hospital teaching status,” the researchers concluded.
Funding was provided by Nabriva Therapeutics, an antibiotic development company. Four of the authors are full-time employees of Becton Dickinson, which sells diagnostics for infectious diseases, including CDI, and one author was an employee of Nabriva Therapeutics.
SOURCE: Tabak YP et al. Infect Control Hosp Epidemiol. 2019 Sep 16. doi: 10.1017/ice.2019.236.
The use of four antibiotic classes designated “high risk” was found to be an independent predictor of hospital-acquired Clostridioides difficile (CDI), based upon an analysis of microbiologic and pharmacy data from 171 hospitals in the United States.
The high-risk antibiotic classes were second-, third-, and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and lincosamides, according to a report by Ying P. Tabak, PhD, of Becton Dickinson in Franklin Lakes, N.J., and colleagues published in Infection Control & Hospital Epidemiology.
Of the 171 study sites studied, 66 (39%) were teaching hospitals and 105 (61%) were nonteaching hospitals. The high-risk antibiotics most frequently used were cephalosporins (47.9%), fluoroquinolones (31.6%), carbapenems (13.0%), and lincosamides (7.6%). The sites were distributed across various regions of the United States. The hospital-level antibiotic use was measured as days of therapy (DOT) per 1,000 days present (DP).
The study was not able to determine specific links to individual antibiotic classes but to the use of high-risk antibiotics as a whole, except for cephalosporins, which were significantly correlated with hospital-acquired CDI (r = 0.23; P less than .01).
The overall correlation of high-risk antibiotic use and hospital-acquired CDI was 0.22 (P = .003). Higher correlation was observed in teaching hospitals (r = 0.38; P = .002) versus nonteaching hospitals (r = 0.19; P = .055), according to the researchers. The authors attributed this to the possibility of teaching hospitals dealing with more elderly and sicker patients.
After adjusting for significant confounders, the use of high-risk antibiotics was still independently associated with significant risk for hospital-acquired CDI. “For every 100-day increase of DOT per 1,000 DP in high-risk antibiotic use, there was a 12% increase in [hospital-acquired] CDI (RR, 1.12; 95% [confidence interval], 1.04-1.21; P = .002),” according to the authors. This translated to four additional hospital-acquired CDI cases with every 100 DOT increase per 1,000 DP.
“Using a large and current dataset, we found an independent impact of hospital-level high-risk antibiotic use on [hospital-acquired] CDI even after adjusting for confounding factors such as community CDI pressure, proportion of patients aged 65 years or older, average length of stay, and hospital teaching status,” the researchers concluded.
Funding was provided by Nabriva Therapeutics, an antibiotic development company. Four of the authors are full-time employees of Becton Dickinson, which sells diagnostics for infectious diseases, including CDI, and one author was an employee of Nabriva Therapeutics.
SOURCE: Tabak YP et al. Infect Control Hosp Epidemiol. 2019 Sep 16. doi: 10.1017/ice.2019.236.
FROM INFECTION CONTROL & HOSPITAL EPIDEMIOLOGY
Key clinical point:
Major finding: For every 100-day increase in high-risk antibiotic therapy, there was a 12% increase in hospital-acquired C. difficile.
Study details: Microbiological and pharmacy data from 171 hospitals comparing hospitalwide use of four antibiotics classes on hospital-acquired C. difficile.
Disclosures: Funding was provided Nabriva Therapeutics, an antibiotic development company. Four of the authors are full-time employees of Becton Dickinson, which sells diagnostics for infectious diseases, including C. difficile, and one author was an employee of Nabriva Therapeutics.
Source: Tabak YP et al. Infect Control Hosp Epidemiol. 2019 Sep 16. doi: 10.1017/ice.2019.236.
FDA issues warning for CDK 4/6 inhibitors
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
Benralizumab trials cast doubt on eosinophil depletion’s role in COPD treatment
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Drug doses for heart failure could possibly be halved for women
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
FROM THE LANCET
Can a novel steroidal anti-inflammatory drug benefit patients with Duchenne muscular dystrophy?
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
FROM NEUROLOGY
Oral drug for postpartum depression aces phase 3 trial
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
REPORTING FROM THE ECNP 2019
NICE issues recommendation for dapagliflozin-insulin therapy in type 1 diabetes
The inadequately controlled by insulin alone.
In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.
In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m2 is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.
Hemoglobin A1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.
Find the full technology appraisal guidance on the NICE website.
The inadequately controlled by insulin alone.
In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.
In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m2 is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.
Hemoglobin A1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.
Find the full technology appraisal guidance on the NICE website.
The inadequately controlled by insulin alone.
In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.
In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m2 is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.
Hemoglobin A1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.
Find the full technology appraisal guidance on the NICE website.
Chlamydia trachomatis is associated with adverse reproductive health outcomes
compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.
The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.
Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.
The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.
For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.
Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).
C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.
While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.
Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.
Iris Krishna, MD, said in an interview, “This is a well-designed population-based retrospective cohort study evaluating the incidence of PID, ectopic pregnancy, and female infertility amongst more than 850,000 women in a primary care setting with a previous diagnosis of C. trachomatis, compared with women who have tested negative for C. trachomatis and women who have not been tested for C. trachomatis. This study also evaluated the impact of antibiotic use on PID.”
Dr. Krishna, assistant professor of gynecology and obstetrics in the division of maternal-fetal medicine at Emory University in Atlanta, continued, “This study demonstrates an association between C. trachomatis infection and adverse reproductive health outcomes. It highlights the importance of prompt diagnosis and treatment of C. trachomatis to reduce the risk of both short- and long-term reproductive health complications, as well as highlighting the importance of preventing recurrent C. trachomatis infections. It also emphasizes the importance of targeted screening for high-risk groups and appropriate follow-up to ensure that optimal antibiotic treatment is provided, especially amongst women who have recently used C. trachomatis–effective antibiotics.
“The finding of progression to PID despite C. trachomatis-effective antibiotic use indicates a more complex relationship where perhaps host immunological factors or effects of antibiotics on the vaginal microbiome may play a role and requires further study,” concluded Dr. Krishna. She was not involved in the current study, and was asked to comment on the findings.
The study was supported by the Netherlands Organization for Health Research and Development. Dr. den Heijer had no relevant disclosures. Dr. Krishna said she had no relevant financial disclosures.
SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.
compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.
The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.
Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.
The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.
For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.
Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).
C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.
While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.
Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.
Iris Krishna, MD, said in an interview, “This is a well-designed population-based retrospective cohort study evaluating the incidence of PID, ectopic pregnancy, and female infertility amongst more than 850,000 women in a primary care setting with a previous diagnosis of C. trachomatis, compared with women who have tested negative for C. trachomatis and women who have not been tested for C. trachomatis. This study also evaluated the impact of antibiotic use on PID.”
Dr. Krishna, assistant professor of gynecology and obstetrics in the division of maternal-fetal medicine at Emory University in Atlanta, continued, “This study demonstrates an association between C. trachomatis infection and adverse reproductive health outcomes. It highlights the importance of prompt diagnosis and treatment of C. trachomatis to reduce the risk of both short- and long-term reproductive health complications, as well as highlighting the importance of preventing recurrent C. trachomatis infections. It also emphasizes the importance of targeted screening for high-risk groups and appropriate follow-up to ensure that optimal antibiotic treatment is provided, especially amongst women who have recently used C. trachomatis–effective antibiotics.
“The finding of progression to PID despite C. trachomatis-effective antibiotic use indicates a more complex relationship where perhaps host immunological factors or effects of antibiotics on the vaginal microbiome may play a role and requires further study,” concluded Dr. Krishna. She was not involved in the current study, and was asked to comment on the findings.
The study was supported by the Netherlands Organization for Health Research and Development. Dr. den Heijer had no relevant disclosures. Dr. Krishna said she had no relevant financial disclosures.
SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.
compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.
The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.
Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.
The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.
For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.
Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).
C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.
While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.
Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.
Iris Krishna, MD, said in an interview, “This is a well-designed population-based retrospective cohort study evaluating the incidence of PID, ectopic pregnancy, and female infertility amongst more than 850,000 women in a primary care setting with a previous diagnosis of C. trachomatis, compared with women who have tested negative for C. trachomatis and women who have not been tested for C. trachomatis. This study also evaluated the impact of antibiotic use on PID.”
Dr. Krishna, assistant professor of gynecology and obstetrics in the division of maternal-fetal medicine at Emory University in Atlanta, continued, “This study demonstrates an association between C. trachomatis infection and adverse reproductive health outcomes. It highlights the importance of prompt diagnosis and treatment of C. trachomatis to reduce the risk of both short- and long-term reproductive health complications, as well as highlighting the importance of preventing recurrent C. trachomatis infections. It also emphasizes the importance of targeted screening for high-risk groups and appropriate follow-up to ensure that optimal antibiotic treatment is provided, especially amongst women who have recently used C. trachomatis–effective antibiotics.
“The finding of progression to PID despite C. trachomatis-effective antibiotic use indicates a more complex relationship where perhaps host immunological factors or effects of antibiotics on the vaginal microbiome may play a role and requires further study,” concluded Dr. Krishna. She was not involved in the current study, and was asked to comment on the findings.
The study was supported by the Netherlands Organization for Health Research and Development. Dr. den Heijer had no relevant disclosures. Dr. Krishna said she had no relevant financial disclosures.
SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.
FROM CLINICAL INFECTIOUS DISEASES