Clinician Reviews

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

MILAN – Application of topical or both topical and oral polypodium leucotomos extract (PLE) was associated with significant reversal of adverse skin changes in patients with severe actinic keratoses (AKs) treated over 12 months, in a randomized, blinded study presented at the annual congress of the European Academy of Dermatology and Venereology.

At 12 months, the percentage of patients with a normal or almost normal honeycomb pattern when evaluated blindly with reflectance confocal microscopy (RCM) was about twice as great in either of the two groups that received PLE relative to those treated with topical photoprotection alone, according to Giovanni Pellacani, MD, PhD, chair of dermatology, University of Sapienza, Rome.

“In patients with severe actinic keratosis, the 12-month use of a PLE-based topical or oral photoprotection is associated with positive clinical and anatomical outcomes,” Dr. Pellacani said.

PLE, which is already commonly used in sun protection products, is derived from a South American species of fern and has been proposed for a broad array of dermatologic diseases. According to Dr. Pellacani, in vivo studies associating PLE with immune photoprotection make this agent particularly promising for severe AKs.

In this study involving two clinical research centers in Italy, 131 patients with photoaging and at least three AKs were randomized to one of three treatment arms. The control arm received topical photoprotection with an SPF of 100 or higher applied twice daily to all sun-exposed areas. The two treatment arms received the same topical photoprotection plus either a PLE-containing topical cream alone or a PLE-containing topical cream plus PLE in an oral form (240 mg) once daily

Patients were evaluated at 3 months, 6 months, and 1 year with several measures, including the Actinic Keratosis Area Score Index (AKASI) and the AK Field Assessment Scale Area (AK-FAS). They were also assessed with RCM. All clinical assessments and RCM evaluations, which assessed seven different parameters, such as honeycomb pattern, mottled pigmentation, and reticulated collagen, were performed by dermatologists blinded to the treatment assignment.

Complete data were available for 116 patients who completed all three evaluations over the 12 months of follow-up. On RCM, 50% of those receiving the oral and topical forms of PLE and 45% of those receiving topical PLE had normalization of the honeycomb pattern. These responses were significantly greater (P = .04 for both) than the 26% with normalization in the control group.

Although there were no significant differences in any of the other parameters evaluated by RCM, the improvement in the honeycomb pattern was accompanied by a 7% improvement in the AKASI score in patients taking PLE, either topically or orally and topically, while there was a 6% worsening (P < .001) among controls.

The AK-FAS score improved at 12 months by 26% in the group on oral/topical PLE and by 4% in the group on topical PLE. The score worsened by 13% among controls.

Over the course of the study, patients were permitted to take an appropriate therapy, such as imiquimod, cryotherapy, or 5-flourouracil if there was worsening of the AK-FAS score or if new lesions appeared.

On this measure, 38% of controls and 11% of those randomized to topical PLE had progressive disease versus only 2% of those randomized to take both topical and oral PLE, Dr. Pellacani reported.

The lower rate of new lesions or a start of a new drug over the course of the study in the group receiving both the topical and the oral formulations of PLE relative to those receiving topical PLE alone did not reach statistical significance, but Dr. Pellacani concluded that the addition of PLE to topical photoprotection without PLE seemed to provide a potentially clinically meaningful advantage.

Larger studies and longer term studies are needed, according to Dr. Pellacani, who noted that the substantial body of clinical studies associating PLE with benefit in a variety of dermatologic disorders has been weakened by the absence of well-designed studies that are adequately powered to guide clinical use.

Salvador González, MD, PhD, a dermatology specialist at Alcalá University, Madrid, also believes that PLE deserves further evaluation not just for photoprotection but for reinvigorating damaged skin due to its antioxidant and anti-inflammatory properties. He was the senior author of a 2020 paper in Photochemical and Photobiological Sciences that summarized the potential benefits of PLE in preventing damage related to sun exposure.

Among its mechanism, PLE generates reactive oxygen species (ROS) and prevents depletion of Langerhans cells induced by ultraviolet (UV) light, Dr. González explained in an interview. “At the cellular level, PLE activates tumor suppression p53, inhibits UV-induced COX-2 expression, reduces inflammation, and preventions immunosuppression,” he continued. In addition, he said PLE also prevents UV-A-induced common deletions related to mitochondrial damage and MMP1 expression induced by various UV wavelengths. 
“These molecular and cellular effects may translate into long-term inhibition of carcinogenesis including actinic keratosis,” he said, noting that all of these findings “justify the work by Pellacani and collaborators.”

Dr. Pellacani reports no potential conflicts of interest. Dr. González has a financial relationship with Cantabria Laboratories.

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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

Two large studies out of the United Kingdom and Norway show vitamin D supplementation has no benefit – as low dose, high dose, or in the form of cod liver oil supplementation – in preventing COVID-19 or acute respiratory tract infections, regardless of whether individuals are deficient or not.

copyright Joss/Fotolia.com

The studies, published in the BMJ, underscore that “vaccination is still the most effective way to protect people from COVID-19, and vitamin D and cod liver oil supplementation should not be offered to healthy people with normal vitamin D levels,” writes Peter Bergman, MD, of the Karolinska Institute, Stockholm, in an editorial published alongside the studies.

Suboptimal levels of vitamin D are known to be associated with an increased risk of acute respiratory infections, and some observational studies have linked low 25-hydroxyvitamin D (25[OH]D) with more severe COVID-19; however, data on a possible protective effect of vitamin D supplementation in preventing infection have been inconsistent.
 

U.K. study compares doses

To further investigate the relationship with infections, including COVID-19, in a large cohort, the authors of the first of the two BMJ studies, a phase 3 open-label trial, enrolled 6,200 people in the United Kingdom aged 16 and older between December 2020 and June 2021 who were not taking vitamin D supplements at baseline.

Half of participants were offered a finger-prick blood test, and of the 2,674 who accepted, 86.3% were found to have low concentrations of 25(OH)D (< 75 nmol/L). These participants were provided with vitamin D supplementation at a lower (800 IU/day; n = 1328) or higher dose (3,200 IU/day; n = 1,346) for 6 months. The other half of the group received no tests or supplements.

The results showed minimal differences between groups in terms of rates of developing at least one acute respiratory infection, which occurred in 5% of those in the lower-dose group, 5.7% in the higher-dose group, and 4.6% of participants not offered supplementation.

Similarly, there were no significant differences in the development of real-time PCR-confirmed COVID-19, with rates of 3.6% in the lower-dose group, 3.0% in the higher-dose group, and 2.6% in the group not offered supplementation.

The study is “the first phase 3 randomized controlled trial to evaluate the effectiveness of a test-and-treat approach for correction of suboptimal vitamin D status to prevent acute respiratory tract infections,” report the authors, led by Adrian R. Martineau, MD, PhD, of Barts and The London School of Medicine and Dentistry, Queen Mary University of London.

While uptake and supplementation in the study were favorable, “no statistically significant effect of either dose was seen on the primary outcome of swab test, doctor-confirmed acute respiratory tract infection, or on the major secondary outcome of swab test-confirmed COVID-19,” they conclude.
 

Traditional use of cod liver oil of benefit?

In the second study, researchers in Norway, led by Arne Soraas, MD, PhD, of the department of microbiology, Oslo University Hospital, evaluated whether that country’s long-held tradition of consuming cod liver oil during the winter to prevent vitamin D deficiency could affect the development of COVID-19 or outcomes.

For the Cod Liver Oil for COVID-19 Prevention Study (CLOC), a large cohort of 34,601 adults with a mean age of 44.9 years who were not taking daily vitamin D supplements were randomized to receive 5 mL/day of cod liver oil, representing a surrogate dose of 400 IU/day of vitamin D (n = 17,278), or placebo (n = 17,323) for up to 6 months.

In contrast with the first study, the vast majority of patients in the CLOC study (86%) had adequate vitamin D levels, defined as greater than 50 nmol/L, at baseline.

Again, however, the results showed no association between increased vitamin D supplementation with cod liver oil and PCR-confirmed COVID-19 or acute respiratory infections, with approximately 1.3% in each group testing positive for COVID-19 over a median of 164 days.

Supplementation with cod liver oil was also not associated with a reduced risk of any of the coprimary endpoints, including other acute respiratory infections.

“Daily supplementation with cod liver oil, a low-dose vitamin D, eicosapentaenoic acid, and docosahexaenoic acid supplement, for 6 months during the SARS-CoV-2pandemic among Norwegian adults did not reduce the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections,” the authors report.
 

Key study limitations

In his editorial, Dr. Bergman underscores the limitations of two studies – also acknowledged by the authors – including the key confounding role of vaccines that emerged during the studies.

“The null findings of the studies should be interpreted in the context of a highly effective vaccine rolled out during both studies,” Dr. Bergman writes.

In the U.K. study, for instance, whereas only 1.2% of participants were vaccinated at baseline, the rate soared to 89.1% having received at least one dose by study end, potentially masking any effect of vitamin D, he says.

Additionally, for the Norway study, Dr. Bergman notes that cod liver oil also contains a substantial amount of vitamin A, which can be a potent immunomodulator.

“Excessive intake of vitamin A can cause adverse effects and may also interfere with vitamin D-mediated effects on the immune system,” he writes.

With two recent large meta-analyses showing benefits of vitamin D supplementation to be specifically among people who are vitamin D deficient, “a pragmatic approach for the clinician could be to focus on risk groups” for supplementation, Dr. Bergman writes.

“[These include] those who could be tested before supplementation, including people with dark skin, or skin that is rarely exposed to the sun, pregnant women, and elderly people with chronic diseases.”

The U.K. trial was supported by Barts Charity, Pharma Nord, the Fischer Family Foundation, DSM Nutritional Products, the Exilarch’s Foundation, the Karl R. Pfleger Foundation, the AIM Foundation, Synergy Biologics, Cytoplan, the Clinical Research Network of the U.K. National Institute for Health and Care Research, the HDR UK BREATHE Hub, the U.K. Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Hyphens Pharma, and philanthropist Matthew Isaacs.

The CLOC trial was funded by Orkla Health, the manufacturer of the cod liver oil used in the trial. Dr. Bergman has reported no relevant financial relationships.

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

Two large studies out of the United Kingdom and Norway show vitamin D supplementation has no benefit – as low dose, high dose, or in the form of cod liver oil supplementation – in preventing COVID-19 or acute respiratory tract infections, regardless of whether individuals are deficient or not.

copyright Joss/Fotolia.com

The studies, published in the BMJ, underscore that “vaccination is still the most effective way to protect people from COVID-19, and vitamin D and cod liver oil supplementation should not be offered to healthy people with normal vitamin D levels,” writes Peter Bergman, MD, of the Karolinska Institute, Stockholm, in an editorial published alongside the studies.

Suboptimal levels of vitamin D are known to be associated with an increased risk of acute respiratory infections, and some observational studies have linked low 25-hydroxyvitamin D (25[OH]D) with more severe COVID-19; however, data on a possible protective effect of vitamin D supplementation in preventing infection have been inconsistent.
 

U.K. study compares doses

To further investigate the relationship with infections, including COVID-19, in a large cohort, the authors of the first of the two BMJ studies, a phase 3 open-label trial, enrolled 6,200 people in the United Kingdom aged 16 and older between December 2020 and June 2021 who were not taking vitamin D supplements at baseline.

Half of participants were offered a finger-prick blood test, and of the 2,674 who accepted, 86.3% were found to have low concentrations of 25(OH)D (< 75 nmol/L). These participants were provided with vitamin D supplementation at a lower (800 IU/day; n = 1328) or higher dose (3,200 IU/day; n = 1,346) for 6 months. The other half of the group received no tests or supplements.

The results showed minimal differences between groups in terms of rates of developing at least one acute respiratory infection, which occurred in 5% of those in the lower-dose group, 5.7% in the higher-dose group, and 4.6% of participants not offered supplementation.

Similarly, there were no significant differences in the development of real-time PCR-confirmed COVID-19, with rates of 3.6% in the lower-dose group, 3.0% in the higher-dose group, and 2.6% in the group not offered supplementation.

The study is “the first phase 3 randomized controlled trial to evaluate the effectiveness of a test-and-treat approach for correction of suboptimal vitamin D status to prevent acute respiratory tract infections,” report the authors, led by Adrian R. Martineau, MD, PhD, of Barts and The London School of Medicine and Dentistry, Queen Mary University of London.

While uptake and supplementation in the study were favorable, “no statistically significant effect of either dose was seen on the primary outcome of swab test, doctor-confirmed acute respiratory tract infection, or on the major secondary outcome of swab test-confirmed COVID-19,” they conclude.
 

Traditional use of cod liver oil of benefit?

In the second study, researchers in Norway, led by Arne Soraas, MD, PhD, of the department of microbiology, Oslo University Hospital, evaluated whether that country’s long-held tradition of consuming cod liver oil during the winter to prevent vitamin D deficiency could affect the development of COVID-19 or outcomes.

For the Cod Liver Oil for COVID-19 Prevention Study (CLOC), a large cohort of 34,601 adults with a mean age of 44.9 years who were not taking daily vitamin D supplements were randomized to receive 5 mL/day of cod liver oil, representing a surrogate dose of 400 IU/day of vitamin D (n = 17,278), or placebo (n = 17,323) for up to 6 months.

In contrast with the first study, the vast majority of patients in the CLOC study (86%) had adequate vitamin D levels, defined as greater than 50 nmol/L, at baseline.

Again, however, the results showed no association between increased vitamin D supplementation with cod liver oil and PCR-confirmed COVID-19 or acute respiratory infections, with approximately 1.3% in each group testing positive for COVID-19 over a median of 164 days.

Supplementation with cod liver oil was also not associated with a reduced risk of any of the coprimary endpoints, including other acute respiratory infections.

“Daily supplementation with cod liver oil, a low-dose vitamin D, eicosapentaenoic acid, and docosahexaenoic acid supplement, for 6 months during the SARS-CoV-2pandemic among Norwegian adults did not reduce the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections,” the authors report.
 

Key study limitations

In his editorial, Dr. Bergman underscores the limitations of two studies – also acknowledged by the authors – including the key confounding role of vaccines that emerged during the studies.

“The null findings of the studies should be interpreted in the context of a highly effective vaccine rolled out during both studies,” Dr. Bergman writes.

In the U.K. study, for instance, whereas only 1.2% of participants were vaccinated at baseline, the rate soared to 89.1% having received at least one dose by study end, potentially masking any effect of vitamin D, he says.

Additionally, for the Norway study, Dr. Bergman notes that cod liver oil also contains a substantial amount of vitamin A, which can be a potent immunomodulator.

“Excessive intake of vitamin A can cause adverse effects and may also interfere with vitamin D-mediated effects on the immune system,” he writes.

With two recent large meta-analyses showing benefits of vitamin D supplementation to be specifically among people who are vitamin D deficient, “a pragmatic approach for the clinician could be to focus on risk groups” for supplementation, Dr. Bergman writes.

“[These include] those who could be tested before supplementation, including people with dark skin, or skin that is rarely exposed to the sun, pregnant women, and elderly people with chronic diseases.”

The U.K. trial was supported by Barts Charity, Pharma Nord, the Fischer Family Foundation, DSM Nutritional Products, the Exilarch’s Foundation, the Karl R. Pfleger Foundation, the AIM Foundation, Synergy Biologics, Cytoplan, the Clinical Research Network of the U.K. National Institute for Health and Care Research, the HDR UK BREATHE Hub, the U.K. Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Hyphens Pharma, and philanthropist Matthew Isaacs.

The CLOC trial was funded by Orkla Health, the manufacturer of the cod liver oil used in the trial. Dr. Bergman has reported no relevant financial relationships.

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

Two large studies out of the United Kingdom and Norway show vitamin D supplementation has no benefit – as low dose, high dose, or in the form of cod liver oil supplementation – in preventing COVID-19 or acute respiratory tract infections, regardless of whether individuals are deficient or not.

copyright Joss/Fotolia.com

The studies, published in the BMJ, underscore that “vaccination is still the most effective way to protect people from COVID-19, and vitamin D and cod liver oil supplementation should not be offered to healthy people with normal vitamin D levels,” writes Peter Bergman, MD, of the Karolinska Institute, Stockholm, in an editorial published alongside the studies.

Suboptimal levels of vitamin D are known to be associated with an increased risk of acute respiratory infections, and some observational studies have linked low 25-hydroxyvitamin D (25[OH]D) with more severe COVID-19; however, data on a possible protective effect of vitamin D supplementation in preventing infection have been inconsistent.
 

U.K. study compares doses

To further investigate the relationship with infections, including COVID-19, in a large cohort, the authors of the first of the two BMJ studies, a phase 3 open-label trial, enrolled 6,200 people in the United Kingdom aged 16 and older between December 2020 and June 2021 who were not taking vitamin D supplements at baseline.

Half of participants were offered a finger-prick blood test, and of the 2,674 who accepted, 86.3% were found to have low concentrations of 25(OH)D (< 75 nmol/L). These participants were provided with vitamin D supplementation at a lower (800 IU/day; n = 1328) or higher dose (3,200 IU/day; n = 1,346) for 6 months. The other half of the group received no tests or supplements.

The results showed minimal differences between groups in terms of rates of developing at least one acute respiratory infection, which occurred in 5% of those in the lower-dose group, 5.7% in the higher-dose group, and 4.6% of participants not offered supplementation.

Similarly, there were no significant differences in the development of real-time PCR-confirmed COVID-19, with rates of 3.6% in the lower-dose group, 3.0% in the higher-dose group, and 2.6% in the group not offered supplementation.

The study is “the first phase 3 randomized controlled trial to evaluate the effectiveness of a test-and-treat approach for correction of suboptimal vitamin D status to prevent acute respiratory tract infections,” report the authors, led by Adrian R. Martineau, MD, PhD, of Barts and The London School of Medicine and Dentistry, Queen Mary University of London.

While uptake and supplementation in the study were favorable, “no statistically significant effect of either dose was seen on the primary outcome of swab test, doctor-confirmed acute respiratory tract infection, or on the major secondary outcome of swab test-confirmed COVID-19,” they conclude.
 

Traditional use of cod liver oil of benefit?

In the second study, researchers in Norway, led by Arne Soraas, MD, PhD, of the department of microbiology, Oslo University Hospital, evaluated whether that country’s long-held tradition of consuming cod liver oil during the winter to prevent vitamin D deficiency could affect the development of COVID-19 or outcomes.

For the Cod Liver Oil for COVID-19 Prevention Study (CLOC), a large cohort of 34,601 adults with a mean age of 44.9 years who were not taking daily vitamin D supplements were randomized to receive 5 mL/day of cod liver oil, representing a surrogate dose of 400 IU/day of vitamin D (n = 17,278), or placebo (n = 17,323) for up to 6 months.

In contrast with the first study, the vast majority of patients in the CLOC study (86%) had adequate vitamin D levels, defined as greater than 50 nmol/L, at baseline.

Again, however, the results showed no association between increased vitamin D supplementation with cod liver oil and PCR-confirmed COVID-19 or acute respiratory infections, with approximately 1.3% in each group testing positive for COVID-19 over a median of 164 days.

Supplementation with cod liver oil was also not associated with a reduced risk of any of the coprimary endpoints, including other acute respiratory infections.

“Daily supplementation with cod liver oil, a low-dose vitamin D, eicosapentaenoic acid, and docosahexaenoic acid supplement, for 6 months during the SARS-CoV-2pandemic among Norwegian adults did not reduce the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections,” the authors report.
 

Key study limitations

In his editorial, Dr. Bergman underscores the limitations of two studies – also acknowledged by the authors – including the key confounding role of vaccines that emerged during the studies.

“The null findings of the studies should be interpreted in the context of a highly effective vaccine rolled out during both studies,” Dr. Bergman writes.

In the U.K. study, for instance, whereas only 1.2% of participants were vaccinated at baseline, the rate soared to 89.1% having received at least one dose by study end, potentially masking any effect of vitamin D, he says.

Additionally, for the Norway study, Dr. Bergman notes that cod liver oil also contains a substantial amount of vitamin A, which can be a potent immunomodulator.

“Excessive intake of vitamin A can cause adverse effects and may also interfere with vitamin D-mediated effects on the immune system,” he writes.

With two recent large meta-analyses showing benefits of vitamin D supplementation to be specifically among people who are vitamin D deficient, “a pragmatic approach for the clinician could be to focus on risk groups” for supplementation, Dr. Bergman writes.

“[These include] those who could be tested before supplementation, including people with dark skin, or skin that is rarely exposed to the sun, pregnant women, and elderly people with chronic diseases.”

The U.K. trial was supported by Barts Charity, Pharma Nord, the Fischer Family Foundation, DSM Nutritional Products, the Exilarch’s Foundation, the Karl R. Pfleger Foundation, the AIM Foundation, Synergy Biologics, Cytoplan, the Clinical Research Network of the U.K. National Institute for Health and Care Research, the HDR UK BREATHE Hub, the U.K. Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Hyphens Pharma, and philanthropist Matthew Isaacs.

The CLOC trial was funded by Orkla Health, the manufacturer of the cod liver oil used in the trial. Dr. Bergman has reported no relevant financial relationships.

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

Among men who have not been vaccinated against COVID-19, having low levels of testosterone may increase the risk of hospitalization from the disease – but hormone therapy appears to reduce the likelihood of severe COVID, researchers have found.

Low testosterone has long been linked to multiple chronic conditions, including obesity, heart disease, and type 2 diabetes, as well as acute conditions, such as heart attack and stroke. A study published earlier in the pandemic suggested that suppressing the sex hormone might protect against COVID-19. The new study, published in JAMA Network Open, is among the first to suggest a link between low testosterone and the risk for severe COVID.

Researchers at Washington University in St. Louis evaluated data from 723 unvaccinated men who had been infected with SARS-CoV-2. Of those, 116 had been diagnosed with hypogonadism, and 180 were receiving testosterone supplementation.

The study found that men whose testosterone levels were less than 200 ng/dL were 2.4 times more likely to experience a severe case of COVID-19 that required hospitalization than were those with normal levels of the hormone. The study accounted for the fact that participants with low testosterone were also more likely to have comorbidities such as diabetes and obesity.

Paresh Dandona, MD, PhD, distinguished professor of medicine and endocrinology at the State University of New York at Buffalo, called the findings “very exciting” and “fundamental.”

“In the world of hypogonadism, this is the first to show that low testosterone makes you vulnerable” to COVID, added Dr. Dandona, who was not involved with the research.

Men who were receiving hormone replacement therapy were at lower risk of hospitalization, compared with those who were not receiving treatment, the study found.

“Testosterone therapy seemed to negate the harmful effects of COVID,” said Sandeep Dhindsa, MD, an endocrinologist at Saint Louis University and lead author of the study.

Approximately 50% more men have died from confirmed COVID-19 than women since the start of the pandemic, according to the Sex, Gender and COVID-19 Project. Previous findings suggesting that sex may be a risk factor for death from COVID prompted researchers to consider whether hormones may play a role in the increased risk among men and whether treatments that suppress androgen levels could cut hospitalizations, but researchers consistently found that androgen suppression was not effective.

“There are other reasons women might be doing better – they may have followed public health guidelines a lot better,” according to Abhinav Diwan, MD, professor of medicine at Washington University in St. Louis, who helped conduct the new study. “It may be chromosomal and not necessarily just hormonal. The differences between men and women go beyond one factor.”

According to the researchers, the findings do not suggest that hormone therapy be used as a preventive measure against COVID.

“We don’t want patients to get excited and start to ask their doctors for testosterone,” Dr. Dhindsa said.

However, viewing low testosterone as a risk factor for COVID could be considered a shift in thinking for some clinicians, according to Dr. Dandana.

“All obese and all [men with] type 2 diabetes should be tested for testosterone, which is the practice in my clinic right now, even if they have no symptoms,” Dr. Dandana said. “Certainly, those with symptoms [of low testosterone] but no diagnosis, they should be tested, too.”

Participants in the study were infected with SARS-CoV-2 early in 2020, before vaccines were available. The researchers did not assess whether the rate of hospitalizations among participants with low testosterone would be different had they been vaccinated.

“Whatever benefits we saw with testosterone might be minor compared to getting the vaccine,” Dr. Dhindsa said.

Dr. Diwan agreed. “COVID hospitalization continues to be a problem, the strains are evolving, and new vaccines are coming in,” he said. “The bottom line is to get vaccinated.”

Dr. Dhindsa has received personal fees from Bayer and Acerus Pharmaceuticals and grants from Clarus Therapeutics outside the submitted work. Dr. Diwan has served as a consultant for the interpretation of echocardiograms for clinical trials for Clario (previously ERT) and has received nonfinancial support from Dewpoint Therapeutics outside the submitted work. Dr. Dandana has disclosed no relevant financial relationships.

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

Among men who have not been vaccinated against COVID-19, having low levels of testosterone may increase the risk of hospitalization from the disease – but hormone therapy appears to reduce the likelihood of severe COVID, researchers have found.

Low testosterone has long been linked to multiple chronic conditions, including obesity, heart disease, and type 2 diabetes, as well as acute conditions, such as heart attack and stroke. A study published earlier in the pandemic suggested that suppressing the sex hormone might protect against COVID-19. The new study, published in JAMA Network Open, is among the first to suggest a link between low testosterone and the risk for severe COVID.

Researchers at Washington University in St. Louis evaluated data from 723 unvaccinated men who had been infected with SARS-CoV-2. Of those, 116 had been diagnosed with hypogonadism, and 180 were receiving testosterone supplementation.

The study found that men whose testosterone levels were less than 200 ng/dL were 2.4 times more likely to experience a severe case of COVID-19 that required hospitalization than were those with normal levels of the hormone. The study accounted for the fact that participants with low testosterone were also more likely to have comorbidities such as diabetes and obesity.

Paresh Dandona, MD, PhD, distinguished professor of medicine and endocrinology at the State University of New York at Buffalo, called the findings “very exciting” and “fundamental.”

“In the world of hypogonadism, this is the first to show that low testosterone makes you vulnerable” to COVID, added Dr. Dandona, who was not involved with the research.

Men who were receiving hormone replacement therapy were at lower risk of hospitalization, compared with those who were not receiving treatment, the study found.

“Testosterone therapy seemed to negate the harmful effects of COVID,” said Sandeep Dhindsa, MD, an endocrinologist at Saint Louis University and lead author of the study.

Approximately 50% more men have died from confirmed COVID-19 than women since the start of the pandemic, according to the Sex, Gender and COVID-19 Project. Previous findings suggesting that sex may be a risk factor for death from COVID prompted researchers to consider whether hormones may play a role in the increased risk among men and whether treatments that suppress androgen levels could cut hospitalizations, but researchers consistently found that androgen suppression was not effective.

“There are other reasons women might be doing better – they may have followed public health guidelines a lot better,” according to Abhinav Diwan, MD, professor of medicine at Washington University in St. Louis, who helped conduct the new study. “It may be chromosomal and not necessarily just hormonal. The differences between men and women go beyond one factor.”

According to the researchers, the findings do not suggest that hormone therapy be used as a preventive measure against COVID.

“We don’t want patients to get excited and start to ask their doctors for testosterone,” Dr. Dhindsa said.

However, viewing low testosterone as a risk factor for COVID could be considered a shift in thinking for some clinicians, according to Dr. Dandana.

“All obese and all [men with] type 2 diabetes should be tested for testosterone, which is the practice in my clinic right now, even if they have no symptoms,” Dr. Dandana said. “Certainly, those with symptoms [of low testosterone] but no diagnosis, they should be tested, too.”

Participants in the study were infected with SARS-CoV-2 early in 2020, before vaccines were available. The researchers did not assess whether the rate of hospitalizations among participants with low testosterone would be different had they been vaccinated.

“Whatever benefits we saw with testosterone might be minor compared to getting the vaccine,” Dr. Dhindsa said.

Dr. Diwan agreed. “COVID hospitalization continues to be a problem, the strains are evolving, and new vaccines are coming in,” he said. “The bottom line is to get vaccinated.”

Dr. Dhindsa has received personal fees from Bayer and Acerus Pharmaceuticals and grants from Clarus Therapeutics outside the submitted work. Dr. Diwan has served as a consultant for the interpretation of echocardiograms for clinical trials for Clario (previously ERT) and has received nonfinancial support from Dewpoint Therapeutics outside the submitted work. Dr. Dandana has disclosed no relevant financial relationships.

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

Among men who have not been vaccinated against COVID-19, having low levels of testosterone may increase the risk of hospitalization from the disease – but hormone therapy appears to reduce the likelihood of severe COVID, researchers have found.

Low testosterone has long been linked to multiple chronic conditions, including obesity, heart disease, and type 2 diabetes, as well as acute conditions, such as heart attack and stroke. A study published earlier in the pandemic suggested that suppressing the sex hormone might protect against COVID-19. The new study, published in JAMA Network Open, is among the first to suggest a link between low testosterone and the risk for severe COVID.

Researchers at Washington University in St. Louis evaluated data from 723 unvaccinated men who had been infected with SARS-CoV-2. Of those, 116 had been diagnosed with hypogonadism, and 180 were receiving testosterone supplementation.

The study found that men whose testosterone levels were less than 200 ng/dL were 2.4 times more likely to experience a severe case of COVID-19 that required hospitalization than were those with normal levels of the hormone. The study accounted for the fact that participants with low testosterone were also more likely to have comorbidities such as diabetes and obesity.

Paresh Dandona, MD, PhD, distinguished professor of medicine and endocrinology at the State University of New York at Buffalo, called the findings “very exciting” and “fundamental.”

“In the world of hypogonadism, this is the first to show that low testosterone makes you vulnerable” to COVID, added Dr. Dandona, who was not involved with the research.

Men who were receiving hormone replacement therapy were at lower risk of hospitalization, compared with those who were not receiving treatment, the study found.

“Testosterone therapy seemed to negate the harmful effects of COVID,” said Sandeep Dhindsa, MD, an endocrinologist at Saint Louis University and lead author of the study.

Approximately 50% more men have died from confirmed COVID-19 than women since the start of the pandemic, according to the Sex, Gender and COVID-19 Project. Previous findings suggesting that sex may be a risk factor for death from COVID prompted researchers to consider whether hormones may play a role in the increased risk among men and whether treatments that suppress androgen levels could cut hospitalizations, but researchers consistently found that androgen suppression was not effective.

“There are other reasons women might be doing better – they may have followed public health guidelines a lot better,” according to Abhinav Diwan, MD, professor of medicine at Washington University in St. Louis, who helped conduct the new study. “It may be chromosomal and not necessarily just hormonal. The differences between men and women go beyond one factor.”

According to the researchers, the findings do not suggest that hormone therapy be used as a preventive measure against COVID.

“We don’t want patients to get excited and start to ask their doctors for testosterone,” Dr. Dhindsa said.

However, viewing low testosterone as a risk factor for COVID could be considered a shift in thinking for some clinicians, according to Dr. Dandana.

“All obese and all [men with] type 2 diabetes should be tested for testosterone, which is the practice in my clinic right now, even if they have no symptoms,” Dr. Dandana said. “Certainly, those with symptoms [of low testosterone] but no diagnosis, they should be tested, too.”

Participants in the study were infected with SARS-CoV-2 early in 2020, before vaccines were available. The researchers did not assess whether the rate of hospitalizations among participants with low testosterone would be different had they been vaccinated.

“Whatever benefits we saw with testosterone might be minor compared to getting the vaccine,” Dr. Dhindsa said.

Dr. Diwan agreed. “COVID hospitalization continues to be a problem, the strains are evolving, and new vaccines are coming in,” he said. “The bottom line is to get vaccinated.”

Dr. Dhindsa has received personal fees from Bayer and Acerus Pharmaceuticals and grants from Clarus Therapeutics outside the submitted work. Dr. Diwan has served as a consultant for the interpretation of echocardiograms for clinical trials for Clario (previously ERT) and has received nonfinancial support from Dewpoint Therapeutics outside the submitted work. Dr. Dandana has disclosed no relevant financial relationships.

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

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

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

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

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

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

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

A new study has found no convincing evidence to suggest a causal relationship between nonsteroidal anti-inflammatory drug (NSAID) use and inflammatory bowel disease (IBD) exacerbations.

Rather, the study suggests that observed associations between IBD exacerbation and NSAID exposure may be explained by preexisting underlying risks for IBD flares, residual confounding, and reverse causality.

“We hope these study findings will aid providers in better directing IBD patients on their risk for IBD exacerbation with NSAID use,” write Shirley Cohen-Mekelburg, MD, with University of Michigan Medicine, Ann Arbor, and colleagues.

“This may guide therapy for both IBD and non-IBD related pain management, and the comfort of patients with IBD and the clinicians who treat them when considering NSAIDs as a non-opioid treatment option,” they add.

The study was published online in the American Journal of Gastroenterology.
 

Taking a second look

Patients with IBD (Crohn’s disease and ulcerative colitis) are prone to both inflammatory and noninflammatory pain, and there has been long-standing concern that NSAIDs may play a role in disease flare-ups.

To see whether a true association exists, Dr. Cohen-Mekelburg and colleagues conducted a series of studies that involved roughly 35,000 patients with IBD.

First, they created a propensity-matched cohort of 15,705 patients who had received NSAIDs and 19,326 who had not taken NSAIDs. Findings from a Cox proportional hazards model suggested a higher likelihood of IBD exacerbation in the group that had taken NSAIDs (hazard ratio, 1.24; 95% confidence interval, 1.16-1.33), after adjusting for age, gender, race, Charlson comorbidity index, smoking status, IBD type, and use of immunomodulator or biologic medications.

However, those who received NSAIDs were already at increased risk of experiencing a disease flare. And the prior event rate ratio for IBD exacerbation, as determined by dividing the adjusted HR after NSAID exposure by the adjusted HR for pre-NSAID exposure, was 0.95 (95% CI, 0.89-1.01).

The researchers used a self-controlled case series to verify their findings and to adjust for other immeasurable patient-level confounders. In this analysis, which involved 3,968 patients, the risk of IBD flare did not increase in the period from 2 weeks to 6 months after exposure to an NSAID.

The incidence of IBD exacerbations was higher in the 0- to 2-week transition period after an NSAID was prescribed, but it dropped after the 2-week “risk” window. This suggests that these short-term flares may be secondary to residual confounding related to reverse causality, rather than the NSAIDs themselves, the researchers say.

While NSAIDs represent the most common first-line analgesic, their use for patients with IBD is variable, in part due to the suspected risk of IBD exacerbation “despite inconclusive evidence of harm to date,” Dr. Cohen-Mekelburg and colleagues note.

They also note that about 36% of patients with IBD in their cohort received at least one NSAID prescription, and three-quarters of these patients did not experience an IBD exacerbation during an average of 5.9 years of follow-up.
 

Good study, reassuring data

“This is a good study trying to understand the potential sources of bias in associations,” Ashwin Ananthakrishnan, MD, MPH, with Massachusetts General Hospital and Harvard Medical School in Boston, who wasn’t involved in the study, told this news organization.

Overall, he said the study “provides reassurance that cautious, short-duration or low-dose use is likely well tolerated in most patients with IBD. But more work is needed to understand the impact of higher dose or more frequent use.”

Also weighing in, Adam Steinlauf, MD, with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, noted that patients with IBD experience pain throughout the course of their disease, both intestinal and extraintestinal.

“Treating the underlying IBD is important, but medications used to treat joint pain and inflammation specifically are few,” said Dr. Steinlauf, who wasn’t involved in the new study.

“Sulfasalazine has been used with success, but it does not work in everyone, and many are allergic to the sulfa component, limiting its use. Narcotics are often reluctantly used for these issues as well. Medical marijuana has emerged on the scene to control both types of pain, but to date, there is inconclusive evidence that it significantly treats both pain and underlying inflammation,” Dr. Steinlauf pointed out.

NSAIDs, on the other hand, are “excellent” choices for treating joint pain and inflammation, but gastroenterologists often try to avoid these medications, given the fear of triggering flares of underlying IBD, Dr. Steinlauf told this news organization.

In his view, this new study is “important in that it quite elegantly challenges the notion that gastroenterologists should avoid NSAIDs in patients with IBD.”

Although more data are clearly needed, Dr. Steinlauf said this study “should give practitioners a bit more confidence in prescribing NSAIDs for their patients with IBD if absolutely necessary to control pain and inflammation and improve quality of life when other standard treatments fail.

“The association of NSAIDs with subsequent flares, of which we are all so well aware of and afraid of, may in fact be related more to our patients’ underlying risks for IBD and reverse causality rather than the NSAIDs themselves. Future studies should further clarify this notion,” Dr. Steinlauf said.

The study received no commercial funding. Dr. Cohen-Mekelburg, Dr. Ananthakrishnan, and Dr. Steinlauf have disclosed no relevant financial relationships.

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

A new study has found no convincing evidence to suggest a causal relationship between nonsteroidal anti-inflammatory drug (NSAID) use and inflammatory bowel disease (IBD) exacerbations.

Rather, the study suggests that observed associations between IBD exacerbation and NSAID exposure may be explained by preexisting underlying risks for IBD flares, residual confounding, and reverse causality.

“We hope these study findings will aid providers in better directing IBD patients on their risk for IBD exacerbation with NSAID use,” write Shirley Cohen-Mekelburg, MD, with University of Michigan Medicine, Ann Arbor, and colleagues.

“This may guide therapy for both IBD and non-IBD related pain management, and the comfort of patients with IBD and the clinicians who treat them when considering NSAIDs as a non-opioid treatment option,” they add.

The study was published online in the American Journal of Gastroenterology.
 

Taking a second look

Patients with IBD (Crohn’s disease and ulcerative colitis) are prone to both inflammatory and noninflammatory pain, and there has been long-standing concern that NSAIDs may play a role in disease flare-ups.

To see whether a true association exists, Dr. Cohen-Mekelburg and colleagues conducted a series of studies that involved roughly 35,000 patients with IBD.

First, they created a propensity-matched cohort of 15,705 patients who had received NSAIDs and 19,326 who had not taken NSAIDs. Findings from a Cox proportional hazards model suggested a higher likelihood of IBD exacerbation in the group that had taken NSAIDs (hazard ratio, 1.24; 95% confidence interval, 1.16-1.33), after adjusting for age, gender, race, Charlson comorbidity index, smoking status, IBD type, and use of immunomodulator or biologic medications.

However, those who received NSAIDs were already at increased risk of experiencing a disease flare. And the prior event rate ratio for IBD exacerbation, as determined by dividing the adjusted HR after NSAID exposure by the adjusted HR for pre-NSAID exposure, was 0.95 (95% CI, 0.89-1.01).

The researchers used a self-controlled case series to verify their findings and to adjust for other immeasurable patient-level confounders. In this analysis, which involved 3,968 patients, the risk of IBD flare did not increase in the period from 2 weeks to 6 months after exposure to an NSAID.

The incidence of IBD exacerbations was higher in the 0- to 2-week transition period after an NSAID was prescribed, but it dropped after the 2-week “risk” window. This suggests that these short-term flares may be secondary to residual confounding related to reverse causality, rather than the NSAIDs themselves, the researchers say.

While NSAIDs represent the most common first-line analgesic, their use for patients with IBD is variable, in part due to the suspected risk of IBD exacerbation “despite inconclusive evidence of harm to date,” Dr. Cohen-Mekelburg and colleagues note.

They also note that about 36% of patients with IBD in their cohort received at least one NSAID prescription, and three-quarters of these patients did not experience an IBD exacerbation during an average of 5.9 years of follow-up.
 

Good study, reassuring data

“This is a good study trying to understand the potential sources of bias in associations,” Ashwin Ananthakrishnan, MD, MPH, with Massachusetts General Hospital and Harvard Medical School in Boston, who wasn’t involved in the study, told this news organization.

Overall, he said the study “provides reassurance that cautious, short-duration or low-dose use is likely well tolerated in most patients with IBD. But more work is needed to understand the impact of higher dose or more frequent use.”

Also weighing in, Adam Steinlauf, MD, with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, noted that patients with IBD experience pain throughout the course of their disease, both intestinal and extraintestinal.

“Treating the underlying IBD is important, but medications used to treat joint pain and inflammation specifically are few,” said Dr. Steinlauf, who wasn’t involved in the new study.

“Sulfasalazine has been used with success, but it does not work in everyone, and many are allergic to the sulfa component, limiting its use. Narcotics are often reluctantly used for these issues as well. Medical marijuana has emerged on the scene to control both types of pain, but to date, there is inconclusive evidence that it significantly treats both pain and underlying inflammation,” Dr. Steinlauf pointed out.

NSAIDs, on the other hand, are “excellent” choices for treating joint pain and inflammation, but gastroenterologists often try to avoid these medications, given the fear of triggering flares of underlying IBD, Dr. Steinlauf told this news organization.

In his view, this new study is “important in that it quite elegantly challenges the notion that gastroenterologists should avoid NSAIDs in patients with IBD.”

Although more data are clearly needed, Dr. Steinlauf said this study “should give practitioners a bit more confidence in prescribing NSAIDs for their patients with IBD if absolutely necessary to control pain and inflammation and improve quality of life when other standard treatments fail.

“The association of NSAIDs with subsequent flares, of which we are all so well aware of and afraid of, may in fact be related more to our patients’ underlying risks for IBD and reverse causality rather than the NSAIDs themselves. Future studies should further clarify this notion,” Dr. Steinlauf said.

The study received no commercial funding. Dr. Cohen-Mekelburg, Dr. Ananthakrishnan, and Dr. Steinlauf have disclosed no relevant financial relationships.

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

A new study has found no convincing evidence to suggest a causal relationship between nonsteroidal anti-inflammatory drug (NSAID) use and inflammatory bowel disease (IBD) exacerbations.

Rather, the study suggests that observed associations between IBD exacerbation and NSAID exposure may be explained by preexisting underlying risks for IBD flares, residual confounding, and reverse causality.

“We hope these study findings will aid providers in better directing IBD patients on their risk for IBD exacerbation with NSAID use,” write Shirley Cohen-Mekelburg, MD, with University of Michigan Medicine, Ann Arbor, and colleagues.

“This may guide therapy for both IBD and non-IBD related pain management, and the comfort of patients with IBD and the clinicians who treat them when considering NSAIDs as a non-opioid treatment option,” they add.

The study was published online in the American Journal of Gastroenterology.
 

Taking a second look

Patients with IBD (Crohn’s disease and ulcerative colitis) are prone to both inflammatory and noninflammatory pain, and there has been long-standing concern that NSAIDs may play a role in disease flare-ups.

To see whether a true association exists, Dr. Cohen-Mekelburg and colleagues conducted a series of studies that involved roughly 35,000 patients with IBD.

First, they created a propensity-matched cohort of 15,705 patients who had received NSAIDs and 19,326 who had not taken NSAIDs. Findings from a Cox proportional hazards model suggested a higher likelihood of IBD exacerbation in the group that had taken NSAIDs (hazard ratio, 1.24; 95% confidence interval, 1.16-1.33), after adjusting for age, gender, race, Charlson comorbidity index, smoking status, IBD type, and use of immunomodulator or biologic medications.

However, those who received NSAIDs were already at increased risk of experiencing a disease flare. And the prior event rate ratio for IBD exacerbation, as determined by dividing the adjusted HR after NSAID exposure by the adjusted HR for pre-NSAID exposure, was 0.95 (95% CI, 0.89-1.01).

The researchers used a self-controlled case series to verify their findings and to adjust for other immeasurable patient-level confounders. In this analysis, which involved 3,968 patients, the risk of IBD flare did not increase in the period from 2 weeks to 6 months after exposure to an NSAID.

The incidence of IBD exacerbations was higher in the 0- to 2-week transition period after an NSAID was prescribed, but it dropped after the 2-week “risk” window. This suggests that these short-term flares may be secondary to residual confounding related to reverse causality, rather than the NSAIDs themselves, the researchers say.

While NSAIDs represent the most common first-line analgesic, their use for patients with IBD is variable, in part due to the suspected risk of IBD exacerbation “despite inconclusive evidence of harm to date,” Dr. Cohen-Mekelburg and colleagues note.

They also note that about 36% of patients with IBD in their cohort received at least one NSAID prescription, and three-quarters of these patients did not experience an IBD exacerbation during an average of 5.9 years of follow-up.
 

Good study, reassuring data

“This is a good study trying to understand the potential sources of bias in associations,” Ashwin Ananthakrishnan, MD, MPH, with Massachusetts General Hospital and Harvard Medical School in Boston, who wasn’t involved in the study, told this news organization.

Overall, he said the study “provides reassurance that cautious, short-duration or low-dose use is likely well tolerated in most patients with IBD. But more work is needed to understand the impact of higher dose or more frequent use.”

Also weighing in, Adam Steinlauf, MD, with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, noted that patients with IBD experience pain throughout the course of their disease, both intestinal and extraintestinal.

“Treating the underlying IBD is important, but medications used to treat joint pain and inflammation specifically are few,” said Dr. Steinlauf, who wasn’t involved in the new study.

“Sulfasalazine has been used with success, but it does not work in everyone, and many are allergic to the sulfa component, limiting its use. Narcotics are often reluctantly used for these issues as well. Medical marijuana has emerged on the scene to control both types of pain, but to date, there is inconclusive evidence that it significantly treats both pain and underlying inflammation,” Dr. Steinlauf pointed out.

NSAIDs, on the other hand, are “excellent” choices for treating joint pain and inflammation, but gastroenterologists often try to avoid these medications, given the fear of triggering flares of underlying IBD, Dr. Steinlauf told this news organization.

In his view, this new study is “important in that it quite elegantly challenges the notion that gastroenterologists should avoid NSAIDs in patients with IBD.”

Although more data are clearly needed, Dr. Steinlauf said this study “should give practitioners a bit more confidence in prescribing NSAIDs for their patients with IBD if absolutely necessary to control pain and inflammation and improve quality of life when other standard treatments fail.

“The association of NSAIDs with subsequent flares, of which we are all so well aware of and afraid of, may in fact be related more to our patients’ underlying risks for IBD and reverse causality rather than the NSAIDs themselves. Future studies should further clarify this notion,” Dr. Steinlauf said.

The study received no commercial funding. Dr. Cohen-Mekelburg, Dr. Ananthakrishnan, and Dr. Steinlauf have disclosed no relevant financial relationships.

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

The influenza vaccine is linked to a significantly lower risk of ischemic stroke, with the reduced risk apparent at a population level even outside of flu season, in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.

“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.

Jovanmandic/Thinkstock

“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”

The study was published online in Neurology.
 

‘Not a spurious association’

While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.

In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.

Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).

Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).

Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).

The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.

The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.

Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).

“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
 

Anti-inflammatory effect?

Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.

The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.

“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.

In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.

“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
 

‘More than just flu prevention’

In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.

“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.

Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.

“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”

Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”

The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.

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

The influenza vaccine is linked to a significantly lower risk of ischemic stroke, with the reduced risk apparent at a population level even outside of flu season, in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.

“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.

Jovanmandic/Thinkstock

“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”

The study was published online in Neurology.
 

‘Not a spurious association’

While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.

In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.

Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).

Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).

Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).

The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.

The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.

Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).

“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
 

Anti-inflammatory effect?

Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.

The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.

“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.

In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.

“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
 

‘More than just flu prevention’

In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.

“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.

Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.

“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”

Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”

The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.

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

The influenza vaccine is linked to a significantly lower risk of ischemic stroke, with the reduced risk apparent at a population level even outside of flu season, in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.

“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.

Jovanmandic/Thinkstock

“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”

The study was published online in Neurology.
 

‘Not a spurious association’

While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.

In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.

Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).

Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).

Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).

The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.

The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.

Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).

“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
 

Anti-inflammatory effect?

Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.

The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.

“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.

In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.

“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
 

‘More than just flu prevention’

In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.

“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.

Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.

“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”

Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”

The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.

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