Sue Hughes

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

For patients with COVID-19 admitted to intensive care, giving atorvastatin 20 mg/d did not result in a significant reduction in risk for venous or arterial thrombosis, for treatment with extracorporeal membrane oxygenation (ECMO), or for all-cause mortality, compared with placebo in the INSPIRATION-S study.

However, there was a suggestion of benefit in the subgroup of patients who were treated within 7 days of COVID-19 symptom onset.

The study was presented by Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, on May 16 at the annual scientific sessions of the American College of Cardiology.

He explained that COVID-19 is characterized by an exuberant immune response and that there is a potential for thrombotic events because of enhanced endothelial activation and a prothrombotic state.

“In this context, it is interesting to think about statins as potential agents to be studied in COVID-19, because as well as having lipid-lowering actions, they are also thought to have anti-inflammatory and antithrombotic effects,” he said.

In the HARP-2 trial of simvastatin in acute respiratory distress syndrome (ARDS), published a few years ago, the main results were neutral, but in the subgroup of patients with hyperinflammatory ARDS, there was a reduction in mortality with simvastatin in comparison with placebo, Dr. Bikdeli noted.

Moreover, in a series of observational studies of patients with COVID-19, use of statins was associated with a reduction in mortality among hospitalized patients. However, there are limited high-quality data to guide clinical practice, he said.

The INSPIRATION study, conducted in 11 hospitals in Iran, had a two-by-two factorial design to investigate different anticoagulant strategies and the use of atorvastatin for COVID-19 patients in the ICU.

In the anticoagulation part of the trial, which was published in JAMA in March 2020, there was no difference in the primary endpoint of an intermediate dose and standard dose of enoxaparin.

For the statin part of the trial (INSPIRATION-S), 605 patients were randomly assigned to receive atorvastatin 20 mg daily or placebo. Patients who had been taking statins beforehand were excluded. Baseline characteristics were similar for the two groups, with around a quarter of patients taking aspirin and more than 90% taking steroids.

Results showed that atorvastatin was not associated with a significant reduction in the primary outcome – a composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days – which occurred in 32.7% of the statin group versus 36.3% of the placebo group (odds ratio, 0.84; P = .35).

Atorvastatin was not associated with any significant differences in any of the individual components of the primary composite endpoint. There was also no significant difference in any of the safety endpoints, which included major bleeding and elevations in liver enzyme levels.

Subgroup analyses were mostly consistent with the main findings, with one exception.

In the subgroup of patients who presented within the first 7 days of COVID-19 symptom onset, there was a hint of a potential protective effect with atorvastatin.

In this group of 171 patients, the primary endpoint occurred in 30.9% of those taking atorvastatin versus 40.3% of those taking placebo (OR, 0.60; P = .055).

“This is an interesting observation, and it is plausible, as these patients may be in a different phase of COVID-19 disease. But we need to be cognizant of the multiplicity of comparisons, and this needs to be further investigated in subsequent studies,” Dr. Bikdeli said.
 

Higher dose in less sick patients a better strategy?

Discussing the study at the ACC presentation, Binita Shah, MD, said the importance of enrolling COVID-19 patients into clinical trials was paramount but that these patients in the ICU may not have been the right population in which to test a statin.

“Maybe for these very sick patients, it is just too late. Trying to rein in the inflammatory cytokine storm and the interaction with thrombosis at this point is very difficult,” Dr. Shah commented.

She suggested that it might be appropriate to try statins in an earlier phase of the disease in order to prevent the inflammatory process, rather than trying to stop it after it had already started.

Dr. Shah also questioned the use of such a low dose of atorvastatin for these patients. “In the cardiovascular literature – at least in ACS [acute coronary syndrome] – high statin doses are used to see short-term benefits. In this very inflammatory milieu, I wonder whether a high-intensity regimen would be more beneficial,” she speculated.

Dr. Bikdeli replied that a low dose of atorvastatin was chosen because early on, several antiviral agents, such as ritonavir, were being used for COVID-19 patients, and these drugs were associated with increases in liver enzyme levels.

“We didn’t want to exacerbate that with high doses of statins,” he said. “But we have now established the safety profile of atorvastatin in these patients, and in retrospect, yes, a higher dose might have been better.”

The INSPIRATION study was funded by the Rajaie Cardiovascular Medical and Research Center, Tehran, Iran. Dr. Bikdeli has disclosed no relevant financial relationships.

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

For patients with COVID-19 admitted to intensive care, giving atorvastatin 20 mg/d did not result in a significant reduction in risk for venous or arterial thrombosis, for treatment with extracorporeal membrane oxygenation (ECMO), or for all-cause mortality, compared with placebo in the INSPIRATION-S study.

However, there was a suggestion of benefit in the subgroup of patients who were treated within 7 days of COVID-19 symptom onset.

The study was presented by Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, on May 16 at the annual scientific sessions of the American College of Cardiology.

He explained that COVID-19 is characterized by an exuberant immune response and that there is a potential for thrombotic events because of enhanced endothelial activation and a prothrombotic state.

“In this context, it is interesting to think about statins as potential agents to be studied in COVID-19, because as well as having lipid-lowering actions, they are also thought to have anti-inflammatory and antithrombotic effects,” he said.

In the HARP-2 trial of simvastatin in acute respiratory distress syndrome (ARDS), published a few years ago, the main results were neutral, but in the subgroup of patients with hyperinflammatory ARDS, there was a reduction in mortality with simvastatin in comparison with placebo, Dr. Bikdeli noted.

Moreover, in a series of observational studies of patients with COVID-19, use of statins was associated with a reduction in mortality among hospitalized patients. However, there are limited high-quality data to guide clinical practice, he said.

The INSPIRATION study, conducted in 11 hospitals in Iran, had a two-by-two factorial design to investigate different anticoagulant strategies and the use of atorvastatin for COVID-19 patients in the ICU.

In the anticoagulation part of the trial, which was published in JAMA in March 2020, there was no difference in the primary endpoint of an intermediate dose and standard dose of enoxaparin.

For the statin part of the trial (INSPIRATION-S), 605 patients were randomly assigned to receive atorvastatin 20 mg daily or placebo. Patients who had been taking statins beforehand were excluded. Baseline characteristics were similar for the two groups, with around a quarter of patients taking aspirin and more than 90% taking steroids.

Results showed that atorvastatin was not associated with a significant reduction in the primary outcome – a composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days – which occurred in 32.7% of the statin group versus 36.3% of the placebo group (odds ratio, 0.84; P = .35).

Atorvastatin was not associated with any significant differences in any of the individual components of the primary composite endpoint. There was also no significant difference in any of the safety endpoints, which included major bleeding and elevations in liver enzyme levels.

Subgroup analyses were mostly consistent with the main findings, with one exception.

In the subgroup of patients who presented within the first 7 days of COVID-19 symptom onset, there was a hint of a potential protective effect with atorvastatin.

In this group of 171 patients, the primary endpoint occurred in 30.9% of those taking atorvastatin versus 40.3% of those taking placebo (OR, 0.60; P = .055).

“This is an interesting observation, and it is plausible, as these patients may be in a different phase of COVID-19 disease. But we need to be cognizant of the multiplicity of comparisons, and this needs to be further investigated in subsequent studies,” Dr. Bikdeli said.
 

Higher dose in less sick patients a better strategy?

Discussing the study at the ACC presentation, Binita Shah, MD, said the importance of enrolling COVID-19 patients into clinical trials was paramount but that these patients in the ICU may not have been the right population in which to test a statin.

“Maybe for these very sick patients, it is just too late. Trying to rein in the inflammatory cytokine storm and the interaction with thrombosis at this point is very difficult,” Dr. Shah commented.

She suggested that it might be appropriate to try statins in an earlier phase of the disease in order to prevent the inflammatory process, rather than trying to stop it after it had already started.

Dr. Shah also questioned the use of such a low dose of atorvastatin for these patients. “In the cardiovascular literature – at least in ACS [acute coronary syndrome] – high statin doses are used to see short-term benefits. In this very inflammatory milieu, I wonder whether a high-intensity regimen would be more beneficial,” she speculated.

Dr. Bikdeli replied that a low dose of atorvastatin was chosen because early on, several antiviral agents, such as ritonavir, were being used for COVID-19 patients, and these drugs were associated with increases in liver enzyme levels.

“We didn’t want to exacerbate that with high doses of statins,” he said. “But we have now established the safety profile of atorvastatin in these patients, and in retrospect, yes, a higher dose might have been better.”

The INSPIRATION study was funded by the Rajaie Cardiovascular Medical and Research Center, Tehran, Iran. Dr. Bikdeli has disclosed no relevant financial relationships.

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

For patients with COVID-19 admitted to intensive care, giving atorvastatin 20 mg/d did not result in a significant reduction in risk for venous or arterial thrombosis, for treatment with extracorporeal membrane oxygenation (ECMO), or for all-cause mortality, compared with placebo in the INSPIRATION-S study.

However, there was a suggestion of benefit in the subgroup of patients who were treated within 7 days of COVID-19 symptom onset.

The study was presented by Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, on May 16 at the annual scientific sessions of the American College of Cardiology.

He explained that COVID-19 is characterized by an exuberant immune response and that there is a potential for thrombotic events because of enhanced endothelial activation and a prothrombotic state.

“In this context, it is interesting to think about statins as potential agents to be studied in COVID-19, because as well as having lipid-lowering actions, they are also thought to have anti-inflammatory and antithrombotic effects,” he said.

In the HARP-2 trial of simvastatin in acute respiratory distress syndrome (ARDS), published a few years ago, the main results were neutral, but in the subgroup of patients with hyperinflammatory ARDS, there was a reduction in mortality with simvastatin in comparison with placebo, Dr. Bikdeli noted.

Moreover, in a series of observational studies of patients with COVID-19, use of statins was associated with a reduction in mortality among hospitalized patients. However, there are limited high-quality data to guide clinical practice, he said.

The INSPIRATION study, conducted in 11 hospitals in Iran, had a two-by-two factorial design to investigate different anticoagulant strategies and the use of atorvastatin for COVID-19 patients in the ICU.

In the anticoagulation part of the trial, which was published in JAMA in March 2020, there was no difference in the primary endpoint of an intermediate dose and standard dose of enoxaparin.

For the statin part of the trial (INSPIRATION-S), 605 patients were randomly assigned to receive atorvastatin 20 mg daily or placebo. Patients who had been taking statins beforehand were excluded. Baseline characteristics were similar for the two groups, with around a quarter of patients taking aspirin and more than 90% taking steroids.

Results showed that atorvastatin was not associated with a significant reduction in the primary outcome – a composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days – which occurred in 32.7% of the statin group versus 36.3% of the placebo group (odds ratio, 0.84; P = .35).

Atorvastatin was not associated with any significant differences in any of the individual components of the primary composite endpoint. There was also no significant difference in any of the safety endpoints, which included major bleeding and elevations in liver enzyme levels.

Subgroup analyses were mostly consistent with the main findings, with one exception.

In the subgroup of patients who presented within the first 7 days of COVID-19 symptom onset, there was a hint of a potential protective effect with atorvastatin.

In this group of 171 patients, the primary endpoint occurred in 30.9% of those taking atorvastatin versus 40.3% of those taking placebo (OR, 0.60; P = .055).

“This is an interesting observation, and it is plausible, as these patients may be in a different phase of COVID-19 disease. But we need to be cognizant of the multiplicity of comparisons, and this needs to be further investigated in subsequent studies,” Dr. Bikdeli said.
 

Higher dose in less sick patients a better strategy?

Discussing the study at the ACC presentation, Binita Shah, MD, said the importance of enrolling COVID-19 patients into clinical trials was paramount but that these patients in the ICU may not have been the right population in which to test a statin.

“Maybe for these very sick patients, it is just too late. Trying to rein in the inflammatory cytokine storm and the interaction with thrombosis at this point is very difficult,” Dr. Shah commented.

She suggested that it might be appropriate to try statins in an earlier phase of the disease in order to prevent the inflammatory process, rather than trying to stop it after it had already started.

Dr. Shah also questioned the use of such a low dose of atorvastatin for these patients. “In the cardiovascular literature – at least in ACS [acute coronary syndrome] – high statin doses are used to see short-term benefits. In this very inflammatory milieu, I wonder whether a high-intensity regimen would be more beneficial,” she speculated.

Dr. Bikdeli replied that a low dose of atorvastatin was chosen because early on, several antiviral agents, such as ritonavir, were being used for COVID-19 patients, and these drugs were associated with increases in liver enzyme levels.

“We didn’t want to exacerbate that with high doses of statins,” he said. “But we have now established the safety profile of atorvastatin in these patients, and in retrospect, yes, a higher dose might have been better.”

The INSPIRATION study was funded by the Rajaie Cardiovascular Medical and Research Center, Tehran, Iran. Dr. Bikdeli has disclosed no relevant financial relationships.

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

Patients who suffer a stroke during hospitalization for infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) have a dismal prognosis, with more than half dying during the index hospitalization and two-thirds within the first year, a new study shows.

The study – the first to evaluate stroke as an IE-related complication following TAVR in a large multicenter cohort – is published in the May 11 issue of the Journal of the American College of Cardiology.

The authors, led by David del Val, MD, Quebec Heart & Lung Institute, Quebec City, explain that IE after TAVR is a rare but serious complication associated with a high mortality rate. Neurologic events, especially stroke, remain one of the most common and potentially disabling IE-related complications, but until now, no study has attempted to evaluate the predictors of stroke and outcomes in patients with IE following TAVR.

For the current study, the authors analyzed data from the Infectious Endocarditis after TAVR International Registry, including 569 patients who developed definite IE following TAVR from 59 centers in 11 countries.

Patients who experienced a stroke during IE admission were compared with patients who did not have a stroke.

Results showed that 57 patients (10%) had a stroke during IE hospitalization, with no differences in the causative microorganism between groups. Stroke patients had higher rates of acute renal failure, systemic embolization, and persistent bacteremia.

Factors associated with a higher risk for stroke during the index IE hospitalization included stroke before IE, moderate or higher residual aortic regurgitation after TAVR, balloon-expandable valves, IE within 30 days after TAVR, and vegetation size greater than 8 mm.

The stroke rate was 3.1% in patients with none of these risk factors; 6.1% with one risk factor; 13.1% with two risk factors; 28.9% with three risk factors, and 60% with four risk factors.

“The presence of such factors (particularly in combination) may be considered for determining an earlier and more aggressive (medical or surgical) treatment in these patients,” the researchers say.

IE patients with stroke had higher rates of in-hospital mortality (54.4% vs. 28.7%) and overall mortality at 1 year (66.3% vs. 45.6%).

Surgery rates were low (25%) even in the presence of stroke and failed to improve outcomes in this population.

Noting that consensus guidelines for managing patients with IE recommend surgery along with antibiotic treatment for patients developing systemic embolism, particularly stroke, the researchers say their findings suggest that such surgery recommendations may not be extrapolated to TAVR-IE patients, and specific guidelines are warranted for this particular population.

Furthermore, the possibility of early surgery in those patients with factors increasing the risk for stroke should be evaluated in future studies.

The authors note that TAVR has revolutionized the treatment of aortic stenosis and is currently moving toward less complex and younger patients with lower surgical risk. Despite the relatively low incidence of IE after TAVR, the number of procedures is expected to grow exponentially, increasing the number of patients at risk of developing this life-threatening complication. Therefore, detailed knowledge of this disease and its complications is essential to improve outcomes.

They point out that the 10% rate of stroke found in this study is substantially lower, compared with the largest surgical prosthetic-valve infective endocarditis registries, but they suggest that the unique clinical profile of TAVR patients may lead to an underdiagnosis of stroke, with a high proportion of elderly patients who more frequently present with nonspecific symptoms.

They conclude that “IE post-TAVR is associated with a poor prognosis with high in-hospital and late mortality rates. Our study reveals that patients with IE after TAVR complicated by stroke showed an even worse prognosis.”

“The progressive implementation of advanced imaging modalities for early IE diagnosis, especially nuclear imaging, may translate into a better prognosis in coming years. Close attention should be paid to early recognition of stroke-associated factors to improve clinical outcomes,” they add.

In an accompanying editorial, Vuyisile Nkomo, MD, Daniel DeSimone, MD, and William Miranda, MD, Mayo Clinic, Rochester, Minn., say the current study “highlights the devastating consequences of IE after TAVR and the even worse consequences when IE was associated with stroke.”

This points to the critical importance of efforts to prevent IE with appropriate antibiotic prophylaxis and addressing potential sources of infection (for example, dental screening) before invasive cardiac procedures.

“Patient education is critical in regard to recognizing early signs and symptoms of IE. In particular, patients must be informed to obtain blood cultures with any episode of fever, as identification of bacteremia is critical in the diagnosis of IE,” the editorialists comment.  

Endocarditis should also be suspected in afebrile patients with increasing transcatheter heart valve gradients or new or worsening regurgitation, they state.

Multimodality imaging is important for the early diagnosis of IE to facilitate prompt antibiotic treatment and potentially decrease the risk for IE complications, especially systemic embolization, they add.

“Despite the unequivocal advances in the safety and periprocedural complications of TAVR, IE with and without stroke in this TAVR population remains a dreadful complication,” they conclude.

Dr. Del Val was supported by a research grant from the Fundación Alfonso Martin Escudero. The editorialists have disclosed no relevant financial relationships.

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

Patients who suffer a stroke during hospitalization for infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) have a dismal prognosis, with more than half dying during the index hospitalization and two-thirds within the first year, a new study shows.

The study – the first to evaluate stroke as an IE-related complication following TAVR in a large multicenter cohort – is published in the May 11 issue of the Journal of the American College of Cardiology.

The authors, led by David del Val, MD, Quebec Heart & Lung Institute, Quebec City, explain that IE after TAVR is a rare but serious complication associated with a high mortality rate. Neurologic events, especially stroke, remain one of the most common and potentially disabling IE-related complications, but until now, no study has attempted to evaluate the predictors of stroke and outcomes in patients with IE following TAVR.

For the current study, the authors analyzed data from the Infectious Endocarditis after TAVR International Registry, including 569 patients who developed definite IE following TAVR from 59 centers in 11 countries.

Patients who experienced a stroke during IE admission were compared with patients who did not have a stroke.

Results showed that 57 patients (10%) had a stroke during IE hospitalization, with no differences in the causative microorganism between groups. Stroke patients had higher rates of acute renal failure, systemic embolization, and persistent bacteremia.

Factors associated with a higher risk for stroke during the index IE hospitalization included stroke before IE, moderate or higher residual aortic regurgitation after TAVR, balloon-expandable valves, IE within 30 days after TAVR, and vegetation size greater than 8 mm.

The stroke rate was 3.1% in patients with none of these risk factors; 6.1% with one risk factor; 13.1% with two risk factors; 28.9% with three risk factors, and 60% with four risk factors.

“The presence of such factors (particularly in combination) may be considered for determining an earlier and more aggressive (medical or surgical) treatment in these patients,” the researchers say.

IE patients with stroke had higher rates of in-hospital mortality (54.4% vs. 28.7%) and overall mortality at 1 year (66.3% vs. 45.6%).

Surgery rates were low (25%) even in the presence of stroke and failed to improve outcomes in this population.

Noting that consensus guidelines for managing patients with IE recommend surgery along with antibiotic treatment for patients developing systemic embolism, particularly stroke, the researchers say their findings suggest that such surgery recommendations may not be extrapolated to TAVR-IE patients, and specific guidelines are warranted for this particular population.

Furthermore, the possibility of early surgery in those patients with factors increasing the risk for stroke should be evaluated in future studies.

The authors note that TAVR has revolutionized the treatment of aortic stenosis and is currently moving toward less complex and younger patients with lower surgical risk. Despite the relatively low incidence of IE after TAVR, the number of procedures is expected to grow exponentially, increasing the number of patients at risk of developing this life-threatening complication. Therefore, detailed knowledge of this disease and its complications is essential to improve outcomes.

They point out that the 10% rate of stroke found in this study is substantially lower, compared with the largest surgical prosthetic-valve infective endocarditis registries, but they suggest that the unique clinical profile of TAVR patients may lead to an underdiagnosis of stroke, with a high proportion of elderly patients who more frequently present with nonspecific symptoms.

They conclude that “IE post-TAVR is associated with a poor prognosis with high in-hospital and late mortality rates. Our study reveals that patients with IE after TAVR complicated by stroke showed an even worse prognosis.”

“The progressive implementation of advanced imaging modalities for early IE diagnosis, especially nuclear imaging, may translate into a better prognosis in coming years. Close attention should be paid to early recognition of stroke-associated factors to improve clinical outcomes,” they add.

In an accompanying editorial, Vuyisile Nkomo, MD, Daniel DeSimone, MD, and William Miranda, MD, Mayo Clinic, Rochester, Minn., say the current study “highlights the devastating consequences of IE after TAVR and the even worse consequences when IE was associated with stroke.”

This points to the critical importance of efforts to prevent IE with appropriate antibiotic prophylaxis and addressing potential sources of infection (for example, dental screening) before invasive cardiac procedures.

“Patient education is critical in regard to recognizing early signs and symptoms of IE. In particular, patients must be informed to obtain blood cultures with any episode of fever, as identification of bacteremia is critical in the diagnosis of IE,” the editorialists comment.  

Endocarditis should also be suspected in afebrile patients with increasing transcatheter heart valve gradients or new or worsening regurgitation, they state.

Multimodality imaging is important for the early diagnosis of IE to facilitate prompt antibiotic treatment and potentially decrease the risk for IE complications, especially systemic embolization, they add.

“Despite the unequivocal advances in the safety and periprocedural complications of TAVR, IE with and without stroke in this TAVR population remains a dreadful complication,” they conclude.

Dr. Del Val was supported by a research grant from the Fundación Alfonso Martin Escudero. The editorialists have disclosed no relevant financial relationships.

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

Patients who suffer a stroke during hospitalization for infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) have a dismal prognosis, with more than half dying during the index hospitalization and two-thirds within the first year, a new study shows.

The study – the first to evaluate stroke as an IE-related complication following TAVR in a large multicenter cohort – is published in the May 11 issue of the Journal of the American College of Cardiology.

The authors, led by David del Val, MD, Quebec Heart & Lung Institute, Quebec City, explain that IE after TAVR is a rare but serious complication associated with a high mortality rate. Neurologic events, especially stroke, remain one of the most common and potentially disabling IE-related complications, but until now, no study has attempted to evaluate the predictors of stroke and outcomes in patients with IE following TAVR.

For the current study, the authors analyzed data from the Infectious Endocarditis after TAVR International Registry, including 569 patients who developed definite IE following TAVR from 59 centers in 11 countries.

Patients who experienced a stroke during IE admission were compared with patients who did not have a stroke.

Results showed that 57 patients (10%) had a stroke during IE hospitalization, with no differences in the causative microorganism between groups. Stroke patients had higher rates of acute renal failure, systemic embolization, and persistent bacteremia.

Factors associated with a higher risk for stroke during the index IE hospitalization included stroke before IE, moderate or higher residual aortic regurgitation after TAVR, balloon-expandable valves, IE within 30 days after TAVR, and vegetation size greater than 8 mm.

The stroke rate was 3.1% in patients with none of these risk factors; 6.1% with one risk factor; 13.1% with two risk factors; 28.9% with three risk factors, and 60% with four risk factors.

“The presence of such factors (particularly in combination) may be considered for determining an earlier and more aggressive (medical or surgical) treatment in these patients,” the researchers say.

IE patients with stroke had higher rates of in-hospital mortality (54.4% vs. 28.7%) and overall mortality at 1 year (66.3% vs. 45.6%).

Surgery rates were low (25%) even in the presence of stroke and failed to improve outcomes in this population.

Noting that consensus guidelines for managing patients with IE recommend surgery along with antibiotic treatment for patients developing systemic embolism, particularly stroke, the researchers say their findings suggest that such surgery recommendations may not be extrapolated to TAVR-IE patients, and specific guidelines are warranted for this particular population.

Furthermore, the possibility of early surgery in those patients with factors increasing the risk for stroke should be evaluated in future studies.

The authors note that TAVR has revolutionized the treatment of aortic stenosis and is currently moving toward less complex and younger patients with lower surgical risk. Despite the relatively low incidence of IE after TAVR, the number of procedures is expected to grow exponentially, increasing the number of patients at risk of developing this life-threatening complication. Therefore, detailed knowledge of this disease and its complications is essential to improve outcomes.

They point out that the 10% rate of stroke found in this study is substantially lower, compared with the largest surgical prosthetic-valve infective endocarditis registries, but they suggest that the unique clinical profile of TAVR patients may lead to an underdiagnosis of stroke, with a high proportion of elderly patients who more frequently present with nonspecific symptoms.

They conclude that “IE post-TAVR is associated with a poor prognosis with high in-hospital and late mortality rates. Our study reveals that patients with IE after TAVR complicated by stroke showed an even worse prognosis.”

“The progressive implementation of advanced imaging modalities for early IE diagnosis, especially nuclear imaging, may translate into a better prognosis in coming years. Close attention should be paid to early recognition of stroke-associated factors to improve clinical outcomes,” they add.

In an accompanying editorial, Vuyisile Nkomo, MD, Daniel DeSimone, MD, and William Miranda, MD, Mayo Clinic, Rochester, Minn., say the current study “highlights the devastating consequences of IE after TAVR and the even worse consequences when IE was associated with stroke.”

This points to the critical importance of efforts to prevent IE with appropriate antibiotic prophylaxis and addressing potential sources of infection (for example, dental screening) before invasive cardiac procedures.

“Patient education is critical in regard to recognizing early signs and symptoms of IE. In particular, patients must be informed to obtain blood cultures with any episode of fever, as identification of bacteremia is critical in the diagnosis of IE,” the editorialists comment.  

Endocarditis should also be suspected in afebrile patients with increasing transcatheter heart valve gradients or new or worsening regurgitation, they state.

Multimodality imaging is important for the early diagnosis of IE to facilitate prompt antibiotic treatment and potentially decrease the risk for IE complications, especially systemic embolization, they add.

“Despite the unequivocal advances in the safety and periprocedural complications of TAVR, IE with and without stroke in this TAVR population remains a dreadful complication,” they conclude.

Dr. Del Val was supported by a research grant from the Fundación Alfonso Martin Escudero. The editorialists have disclosed no relevant financial relationships.

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

For patients with postural tachycardia syndrome (POTS), dietary sodium intake can be increased more confidently, suggests the first study to yield solid evidence to support this treatment strategy.

The results showed that high dietary sodium intake can lower plasma norepinephrine levels and ameliorate standing and orthostatic tachycardia for patients with POTS.

“These results suggest that increasing dietary salt is a good rationale for treatment of this condition, and this study gives reassurance we are doing the right thing for POTS patients by increasing their sodium intake,” senior author Satish R. Raj, MD, said in an interview.

The study, with lead author Emily M. Garland, PhD, was published online April 26, 2021, in the Journal of the American College of Cardiology.

Dr. Raj, who is professor of cardiac science at the University of Calgary (Alta.), explained that POTS includes a spectrum of disorders that affect the automatic nervous system, which regulates heart rate and blood pressure.

“It is a disorder of orthostatic intolerance – patients feel better when they lie down. It differs from orthostatic hypotension in that, when a POTS patient stands up, the blood pressure does not necessarily drop, but the heart rate increases excessively.”

Although it is normal for the heart rate to increase somewhat on standing, among patients with POTS, the heart rate increases excessively. The condition is defined as an orthostatic heart rate increase of at least 30 beats/min (or 40 beats/min among individuals aged 12-19 years ) in the absence of orthostatic hypotension.

The disorder is characterized by a range of symptoms, including lightheadedness, shortness of breath, palpitations, and exertional intolerance, that are worse when in an upright position. Patients also experience chronic fatigue and perceived cognitive impairment, Dr. Raj noted.

The typical demographic for POTS is young women; the condition often starts during the teenage years.

Patients often have low blood volume, so one approach to treatment is to increase the intake of salt and water so as to increase blood volume.

“This is one of the mainstays of treatment, but it has never really been properly studied,” Dr. Raj commented. Increasing salt intake “is an unusual message from a cardiologist, and there have been concerns that we are making recommendations against traditional advice, so we urgently need evidence to support this recommendation.”

The current crossover study enrolled 14 patients with POTS and 13 healthy control persons who, over a period of 6 days, underwent treatment with a low-sodium diet (10 mEq sodium per day) or a high-sodium diet (300 mEq sodium per day).

Supine and standing heart rate, blood pressure, serum aldosterone level, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine levels were measured.

Results showed that, among the POTS patients, the high-sodium diet reduced upright heart rate and the change in heart rate on standing, compared with the low-sodium diet.

Heart rate increased by 46 beats/min with the high-sodium diet versus 60 beats/min with the low-sodium diet.

Total blood volume and plasma volume increased, and standing norepinephrine levels decreased with the high-sodium diet, compared with the low-sodium diet.

However, upright heart rate, change in heart rate, and upright norepinephrine levels remained higher among POTS patients than among control persons receiving the high-sodium diet.

There was a nonsignificant trend for a lower symptom burden score among the POTS patients who received the high-sodium diet in comparison with those taking the low-sodium diet. Scores for mental confusion, palpitations, lightheadedness, and headache trending downward on the high-sodium diet.

“We found that high levels of dietary salt did what we hoped, with increased blood volume and reduced norepinephrine levels on standing and reduced excessive increase in heart rate. While it didn’t completely normalize heart rate, this was reduced significantly,” Dr. Raj said.

Another observation from the study was that the increased salt intake seemed to be beneficial across the whole spectrum of patients.

“There are some patients who have very high levels of sympathetic activation, and there have been anecdotal reports that increasing salt may not work so well in this group,” he said. “In this study, we didn’t differentiate, but average norepinephrine levels were very high, and many patients would be considered to be hyperadrenergic. Our results suggest this treatment will help these patients too.”

He noted that sodium intake was increased in this study just through diet. “We had a special metabolic kitchen. In clinical practice, we advise patients to add regular table salt to their food, and we only use salt tablets when they cannot tolerate so much salt in their diet.”

Recognizing that there may be concerns about hypertension with long-term use of such a treatment, Dr. Raj said there were no signs of an increase in blood pressure in this study. “But this should be considered a short-term therapy for the time being, and patients need to be reassessed every few years as their physiology changes.”

The authors estimated that POTS affects up to 1% of the population. Because there is no diagnostic code for the condition at present, all incidence data are estimates.

Dr. Raj pointed out that potentially a lot of people are affected, but there is little recognition of the condition among patients and physicians.

“Many family doctors are unaware of POTS,” he noted. “Patients often have to research their symptoms themselves and inform their doctor of the condition. Many patients wait years and often see many different doctors before getting a correct diagnosis.”

He explained that patients with POTS are often diagnosed as having a psychiatric illness. “They are mainly young women with palpitations, heart pounding, shakiness, which is often labeled as anxiety.”

Dr. Raj urged clinicians to consider POTS if patients have symptoms that are worse when standing up. The diagnosis is confirmed if their blood pressure doesn’t fall when standing up but their heart rate increases by at least 30 beats/min.

He noted that not enough specialists treat this condition, so family doctors need to be able to diagnose and initiate treatment. If more aggressive treatment is required, patients can be referred to a specialist.

“One of the problems is that this condition pans across different medical specialties. No one field owns it, so it tends to get ignored. But there are clinicians who are interested in POTS, and the key is finding one of these,” he said.

“We have finally established that this high-sodium diet works as treatment for POTS,” he concluded. “We have been using it for some time, but now we have evidence for its use across the whole spectrum of patients.”

In an accompanying editorial (J Am Coll Cardiol. 2021 May 4;77[17]:2185-2186), Blair P. Grubb, MD, University of Toledo (Ohio) Medical Center, wrote that this “superb study by Garland et al. helps better establish our understanding of the pathophysiologic process taking place in POTS while at the same time providing good evidence for the augmentation of dietary sodium as one of the cornerstones of treatment.”

He added that the field needs more such studies “in our quest to better understand POTS and to elaborate therapeutic modalities to help those suffering from this debilitating illness.”

The study was supported in part by the National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Sciences; and the Vanderbilt Hormone and Analytical Services Core. Dr. Raj has served as a consultant for Lundbeck NA and Theravance; has served as chair of the data safety and monitoring board for Arena Pharmaceuticals and as Cardiac Arrhythmia Network of Canada network investigator; and has served on the medical advisory board of Dysautonomia International and PoTS UK, both without financial compensation.

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

For patients with postural tachycardia syndrome (POTS), dietary sodium intake can be increased more confidently, suggests the first study to yield solid evidence to support this treatment strategy.

The results showed that high dietary sodium intake can lower plasma norepinephrine levels and ameliorate standing and orthostatic tachycardia for patients with POTS.

“These results suggest that increasing dietary salt is a good rationale for treatment of this condition, and this study gives reassurance we are doing the right thing for POTS patients by increasing their sodium intake,” senior author Satish R. Raj, MD, said in an interview.

The study, with lead author Emily M. Garland, PhD, was published online April 26, 2021, in the Journal of the American College of Cardiology.

Dr. Raj, who is professor of cardiac science at the University of Calgary (Alta.), explained that POTS includes a spectrum of disorders that affect the automatic nervous system, which regulates heart rate and blood pressure.

“It is a disorder of orthostatic intolerance – patients feel better when they lie down. It differs from orthostatic hypotension in that, when a POTS patient stands up, the blood pressure does not necessarily drop, but the heart rate increases excessively.”

Although it is normal for the heart rate to increase somewhat on standing, among patients with POTS, the heart rate increases excessively. The condition is defined as an orthostatic heart rate increase of at least 30 beats/min (or 40 beats/min among individuals aged 12-19 years ) in the absence of orthostatic hypotension.

The disorder is characterized by a range of symptoms, including lightheadedness, shortness of breath, palpitations, and exertional intolerance, that are worse when in an upright position. Patients also experience chronic fatigue and perceived cognitive impairment, Dr. Raj noted.

The typical demographic for POTS is young women; the condition often starts during the teenage years.

Patients often have low blood volume, so one approach to treatment is to increase the intake of salt and water so as to increase blood volume.

“This is one of the mainstays of treatment, but it has never really been properly studied,” Dr. Raj commented. Increasing salt intake “is an unusual message from a cardiologist, and there have been concerns that we are making recommendations against traditional advice, so we urgently need evidence to support this recommendation.”

The current crossover study enrolled 14 patients with POTS and 13 healthy control persons who, over a period of 6 days, underwent treatment with a low-sodium diet (10 mEq sodium per day) or a high-sodium diet (300 mEq sodium per day).

Supine and standing heart rate, blood pressure, serum aldosterone level, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine levels were measured.

Results showed that, among the POTS patients, the high-sodium diet reduced upright heart rate and the change in heart rate on standing, compared with the low-sodium diet.

Heart rate increased by 46 beats/min with the high-sodium diet versus 60 beats/min with the low-sodium diet.

Total blood volume and plasma volume increased, and standing norepinephrine levels decreased with the high-sodium diet, compared with the low-sodium diet.

However, upright heart rate, change in heart rate, and upright norepinephrine levels remained higher among POTS patients than among control persons receiving the high-sodium diet.

There was a nonsignificant trend for a lower symptom burden score among the POTS patients who received the high-sodium diet in comparison with those taking the low-sodium diet. Scores for mental confusion, palpitations, lightheadedness, and headache trending downward on the high-sodium diet.

“We found that high levels of dietary salt did what we hoped, with increased blood volume and reduced norepinephrine levels on standing and reduced excessive increase in heart rate. While it didn’t completely normalize heart rate, this was reduced significantly,” Dr. Raj said.

Another observation from the study was that the increased salt intake seemed to be beneficial across the whole spectrum of patients.

“There are some patients who have very high levels of sympathetic activation, and there have been anecdotal reports that increasing salt may not work so well in this group,” he said. “In this study, we didn’t differentiate, but average norepinephrine levels were very high, and many patients would be considered to be hyperadrenergic. Our results suggest this treatment will help these patients too.”

He noted that sodium intake was increased in this study just through diet. “We had a special metabolic kitchen. In clinical practice, we advise patients to add regular table salt to their food, and we only use salt tablets when they cannot tolerate so much salt in their diet.”

Recognizing that there may be concerns about hypertension with long-term use of such a treatment, Dr. Raj said there were no signs of an increase in blood pressure in this study. “But this should be considered a short-term therapy for the time being, and patients need to be reassessed every few years as their physiology changes.”

The authors estimated that POTS affects up to 1% of the population. Because there is no diagnostic code for the condition at present, all incidence data are estimates.

Dr. Raj pointed out that potentially a lot of people are affected, but there is little recognition of the condition among patients and physicians.

“Many family doctors are unaware of POTS,” he noted. “Patients often have to research their symptoms themselves and inform their doctor of the condition. Many patients wait years and often see many different doctors before getting a correct diagnosis.”

He explained that patients with POTS are often diagnosed as having a psychiatric illness. “They are mainly young women with palpitations, heart pounding, shakiness, which is often labeled as anxiety.”

Dr. Raj urged clinicians to consider POTS if patients have symptoms that are worse when standing up. The diagnosis is confirmed if their blood pressure doesn’t fall when standing up but their heart rate increases by at least 30 beats/min.

He noted that not enough specialists treat this condition, so family doctors need to be able to diagnose and initiate treatment. If more aggressive treatment is required, patients can be referred to a specialist.

“One of the problems is that this condition pans across different medical specialties. No one field owns it, so it tends to get ignored. But there are clinicians who are interested in POTS, and the key is finding one of these,” he said.

“We have finally established that this high-sodium diet works as treatment for POTS,” he concluded. “We have been using it for some time, but now we have evidence for its use across the whole spectrum of patients.”

In an accompanying editorial (J Am Coll Cardiol. 2021 May 4;77[17]:2185-2186), Blair P. Grubb, MD, University of Toledo (Ohio) Medical Center, wrote that this “superb study by Garland et al. helps better establish our understanding of the pathophysiologic process taking place in POTS while at the same time providing good evidence for the augmentation of dietary sodium as one of the cornerstones of treatment.”

He added that the field needs more such studies “in our quest to better understand POTS and to elaborate therapeutic modalities to help those suffering from this debilitating illness.”

The study was supported in part by the National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Sciences; and the Vanderbilt Hormone and Analytical Services Core. Dr. Raj has served as a consultant for Lundbeck NA and Theravance; has served as chair of the data safety and monitoring board for Arena Pharmaceuticals and as Cardiac Arrhythmia Network of Canada network investigator; and has served on the medical advisory board of Dysautonomia International and PoTS UK, both without financial compensation.

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

For patients with postural tachycardia syndrome (POTS), dietary sodium intake can be increased more confidently, suggests the first study to yield solid evidence to support this treatment strategy.

The results showed that high dietary sodium intake can lower plasma norepinephrine levels and ameliorate standing and orthostatic tachycardia for patients with POTS.

“These results suggest that increasing dietary salt is a good rationale for treatment of this condition, and this study gives reassurance we are doing the right thing for POTS patients by increasing their sodium intake,” senior author Satish R. Raj, MD, said in an interview.

The study, with lead author Emily M. Garland, PhD, was published online April 26, 2021, in the Journal of the American College of Cardiology.

Dr. Raj, who is professor of cardiac science at the University of Calgary (Alta.), explained that POTS includes a spectrum of disorders that affect the automatic nervous system, which regulates heart rate and blood pressure.

“It is a disorder of orthostatic intolerance – patients feel better when they lie down. It differs from orthostatic hypotension in that, when a POTS patient stands up, the blood pressure does not necessarily drop, but the heart rate increases excessively.”

Although it is normal for the heart rate to increase somewhat on standing, among patients with POTS, the heart rate increases excessively. The condition is defined as an orthostatic heart rate increase of at least 30 beats/min (or 40 beats/min among individuals aged 12-19 years ) in the absence of orthostatic hypotension.

The disorder is characterized by a range of symptoms, including lightheadedness, shortness of breath, palpitations, and exertional intolerance, that are worse when in an upright position. Patients also experience chronic fatigue and perceived cognitive impairment, Dr. Raj noted.

The typical demographic for POTS is young women; the condition often starts during the teenage years.

Patients often have low blood volume, so one approach to treatment is to increase the intake of salt and water so as to increase blood volume.

“This is one of the mainstays of treatment, but it has never really been properly studied,” Dr. Raj commented. Increasing salt intake “is an unusual message from a cardiologist, and there have been concerns that we are making recommendations against traditional advice, so we urgently need evidence to support this recommendation.”

The current crossover study enrolled 14 patients with POTS and 13 healthy control persons who, over a period of 6 days, underwent treatment with a low-sodium diet (10 mEq sodium per day) or a high-sodium diet (300 mEq sodium per day).

Supine and standing heart rate, blood pressure, serum aldosterone level, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine levels were measured.

Results showed that, among the POTS patients, the high-sodium diet reduced upright heart rate and the change in heart rate on standing, compared with the low-sodium diet.

Heart rate increased by 46 beats/min with the high-sodium diet versus 60 beats/min with the low-sodium diet.

Total blood volume and plasma volume increased, and standing norepinephrine levels decreased with the high-sodium diet, compared with the low-sodium diet.

However, upright heart rate, change in heart rate, and upright norepinephrine levels remained higher among POTS patients than among control persons receiving the high-sodium diet.

There was a nonsignificant trend for a lower symptom burden score among the POTS patients who received the high-sodium diet in comparison with those taking the low-sodium diet. Scores for mental confusion, palpitations, lightheadedness, and headache trending downward on the high-sodium diet.

“We found that high levels of dietary salt did what we hoped, with increased blood volume and reduced norepinephrine levels on standing and reduced excessive increase in heart rate. While it didn’t completely normalize heart rate, this was reduced significantly,” Dr. Raj said.

Another observation from the study was that the increased salt intake seemed to be beneficial across the whole spectrum of patients.

“There are some patients who have very high levels of sympathetic activation, and there have been anecdotal reports that increasing salt may not work so well in this group,” he said. “In this study, we didn’t differentiate, but average norepinephrine levels were very high, and many patients would be considered to be hyperadrenergic. Our results suggest this treatment will help these patients too.”

He noted that sodium intake was increased in this study just through diet. “We had a special metabolic kitchen. In clinical practice, we advise patients to add regular table salt to their food, and we only use salt tablets when they cannot tolerate so much salt in their diet.”

Recognizing that there may be concerns about hypertension with long-term use of such a treatment, Dr. Raj said there were no signs of an increase in blood pressure in this study. “But this should be considered a short-term therapy for the time being, and patients need to be reassessed every few years as their physiology changes.”

The authors estimated that POTS affects up to 1% of the population. Because there is no diagnostic code for the condition at present, all incidence data are estimates.

Dr. Raj pointed out that potentially a lot of people are affected, but there is little recognition of the condition among patients and physicians.

“Many family doctors are unaware of POTS,” he noted. “Patients often have to research their symptoms themselves and inform their doctor of the condition. Many patients wait years and often see many different doctors before getting a correct diagnosis.”

He explained that patients with POTS are often diagnosed as having a psychiatric illness. “They are mainly young women with palpitations, heart pounding, shakiness, which is often labeled as anxiety.”

Dr. Raj urged clinicians to consider POTS if patients have symptoms that are worse when standing up. The diagnosis is confirmed if their blood pressure doesn’t fall when standing up but their heart rate increases by at least 30 beats/min.

He noted that not enough specialists treat this condition, so family doctors need to be able to diagnose and initiate treatment. If more aggressive treatment is required, patients can be referred to a specialist.

“One of the problems is that this condition pans across different medical specialties. No one field owns it, so it tends to get ignored. But there are clinicians who are interested in POTS, and the key is finding one of these,” he said.

“We have finally established that this high-sodium diet works as treatment for POTS,” he concluded. “We have been using it for some time, but now we have evidence for its use across the whole spectrum of patients.”

In an accompanying editorial (J Am Coll Cardiol. 2021 May 4;77[17]:2185-2186), Blair P. Grubb, MD, University of Toledo (Ohio) Medical Center, wrote that this “superb study by Garland et al. helps better establish our understanding of the pathophysiologic process taking place in POTS while at the same time providing good evidence for the augmentation of dietary sodium as one of the cornerstones of treatment.”

He added that the field needs more such studies “in our quest to better understand POTS and to elaborate therapeutic modalities to help those suffering from this debilitating illness.”

The study was supported in part by the National Heart, Lung, and Blood Institute; the National Center for Advancing Translational Sciences; and the Vanderbilt Hormone and Analytical Services Core. Dr. Raj has served as a consultant for Lundbeck NA and Theravance; has served as chair of the data safety and monitoring board for Arena Pharmaceuticals and as Cardiac Arrhythmia Network of Canada network investigator; and has served on the medical advisory board of Dysautonomia International and PoTS UK, both without financial compensation.

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

Use of mRNA COVID-19 vaccines should be considered as the preferable option in the United States rather than Johnson & Johnson’s (J&J) Janssen COVID-19 vaccine in women aged under 50 years, according to one group of experts.

The group made their recommendation in an editorial in JAMA published online April 30, 2021, accompanying a paper describing details of 12 case reports of cerebral venous sinus thrombosis (CVST) with thrombocytopenia following the J&J COVID-19 vaccine, also known as the Ad26.COV2.S vaccine.

The editorialists are Ruth A. Karron, MD, professor of international health at Johns Hopkins University, Baltimore; Nigel S. Key, MD, professor of hematology at the University of North Carolina at Chapel Hill; and Joshua M. Sharfstein, MD, associate dean for public health practice at Johns Hopkins

They noted that, after an initial pause following reports of thrombosis with thrombocytopenia syndrome (TTS) linked to the J&J vaccine, and on the recommendation of the Advisory Committee on Immunization Practices, the United States has permitted the use of the J&J vaccine in all adults with information on the risk of TTS added to educational materials.

The editorialists pointed out that no cases of TTS have been confirmed following administration of more than 180 million doses of the mRNA vaccines in the United States.

They said that, while the J&J vaccine will still be needed for individuals with allergies to components of the mRNA vaccines and for those who live in remote locations where the cold chain for transport and storage of mRNA vaccines cannot be maintained, “U.S. public health agencies and clinicians should consider recommending mRNA vaccines as safer options for those who may be at substantially higher risk for TTS after Ad26.COV2.S vaccination, currently women younger than 50 years.”

In the main JAMA paper, a group led by Isaac See, MD, Centers for Disease Control and Prevention COVID-19 Response Team, reported full details of 12 cases of CVST with thrombocytopenia following the J&J COVID-19 vaccine reported to the U.S. Vaccine Adverse Event Reporting System (VAERS).

The 12 U.S. case reports, 3 of which were fatal, show many similarities to cases described in Europe after the AstraZeneca vaccine.

The authors noted that, by April 12, approximately 7 million doses of the J&J vaccine had been given in the United States. The 12 cases of CVST and thrombocytopenia following receipt of the vaccine were reported to VAERS between March 2 and April 21. All 12 cases were in White women, 11 of whom were aged under 50 years.

As of April 25, a further two cases have been confirmed and reported to VAERS; one in a man younger than 40 years, the other in a woman aged between 40 and 59 years.

In the 12 cases reported in detail, symptoms started between 6 and 15 days post vaccination.

At least one risk factor for CVST was identified in seven patients (obesity in six, hypothyroidism in one, and use of combined oral contraceptives in one). None of the patients was pregnant or within 12 weeks post partum, had prior thrombosis, a personal or family history of thrombophilia, or documented prior exposure to heparin.

In addition to CVST, seven patients had intracerebral hemorrhage and eight had non-CVST thromboses.

One patient reported a history of SARS-CoV-2 infection approximately 4 months prior to vaccination. Of the other 11 patients, 4 had negative serologic tests and 7 were not tested.

All 12 patients were hospitalized and 10 were admitted to an ICU. At the time of the last follow-up, three patients had died (all of whom had intraparenchymal hemorrhage), three remained in the ICU, two were still hospitalized but not in an ICU, and four had been discharged home.

The authors pointed out that the U.S. cases of CVST with thrombocytopenia following the J&J vaccine have many similarities to those reported in Europe after the AstraZeneca vaccine, occurring primarily in women younger than 40 years and in patients without diagnosed thrombophilia. Both European and U.S. patients had a median platelet nadir count of 19 x 103/mcL and several also had non-CVST large-vessel thrombosis.

In the European cases of CVST with thrombocytopenia, 50% of patients died, compared with 25% of U.S. patients.

Like the European cases, the U.S. cases had positive heparin-PF4 HIT antibody enzyme-linked immunosorbent assay tests in the absence of prior exposure to heparin, as would be seen in autoimmune HIT.

However, in the initial European CVST reports, 88% of patients tested with functional platelet HIT antibody tests had positive results, compared with only 11% of the U.S. cases. But the authors noted that lack of standardization in functional platelet HIT antibody assays may lead to differences in results by different laboratories.

“It may be important to notify testing laboratories that postvaccination TTS is being evaluated, so that testing methods can be adjusted if needed,” they said.

They concluded that these case reports suggest that the pathogenesis of TTS may be similar to autoimmune HIT, triggered by the formation of antibodies directed against PF4, a constituent of platelet alpha granules released during platelet activation. In contrast to classic HIT in which exogenous heparin triggers antibody formation, in autoimmune HIT, an endogenous polyanion triggers PF4 antibody formation.

They noted that the precise mechanism of TTS in relation to COVID-19 vaccination has not yet been established. The Global Advisory Committee on Vaccine Safety has stated that a platform-specific mechanism related to adenovirus vector vaccines cannot be excluded. Both the J&J and AstraZeneca vaccines use an adenoviral vector, but they are different; J&J uses a human vector, while AstraZeneca uses a chimpanzee vector.

They also pointed out that CVST and thrombocytopenia following SARS-CoV-2 infection has been reported in at least two cases, but HIT testing was not done in these cases. There have not so far been any reports to VAERS of CVST with thrombocytopenia following mRNA COVID-19 vaccines.

The authors said these findings have important clinical and public health implications, noting that the CDC has updated its interim clinical considerations for use of authorized COVID-19 vaccines to indicate that women aged 18-49 years should be aware of the increased risk of TTS after receipt of the J&J vaccine, and to use a nonheparin anticoagulant in suspected cases.

They noted that a subacute presentation of headache is present in 90% of patients with typical CVST. While headache is a common symptom after the J&J vaccination, most headaches begin and resolve within 2 days. Whereas in the U.S. cases of CVST after vaccination, headache symptoms began at least 6 days after vaccination and persisted for at least a week for most.

“Urgent consultation with a neurologist is prudent when a patient is suspected or confirmed to have CVST. In addition, since the median time from symptom onset to hospitalization was 7 days in the U.S. CVST case series, patient and clinician education might shorten the time to clinical evaluation and therefore treatment,” they stated.

The authors also note that VAERS is a passive surveillance system, so cases of CVST with thrombocytopenia may be underreported.

In their accompanying editorial, Dr. Karron and colleagues pointed out that, in addition to the 12 patients with CVST with thrombocytopenia described in this case series, at least three patients without CVST but meeting diagnostic criteria for TTS have been reported to VAERS (as of April 21), all in women aged 18-59 years (median age, 37 years).

The editorialists reported that the rate of CVST with thrombocytopenia after the J&J vaccine is approximately 5 per million women aged 18-50 years. This is compared with a background rate of approximately 0.05-0.13 per million per month.

They said that the availability of an interim standardized case definition of this adverse effect will facilitate prospective case ascertainment through review of large linked databases and active case finding.

This will also permit greater understanding of whether individuals who are otherwise at increased risk for hypercoagulation in general and for CVST in particular (for example, women taking hormonal contraceptive medications or who are pregnant) are also at increased risk for TTS.

Obtaining this information will support dynamic country-specific assessments of the risks of each vaccine, compared with the risk of COVID-19 disease for their populations and subpopulations, they added.

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

Use of mRNA COVID-19 vaccines should be considered as the preferable option in the United States rather than Johnson & Johnson’s (J&J) Janssen COVID-19 vaccine in women aged under 50 years, according to one group of experts.

The group made their recommendation in an editorial in JAMA published online April 30, 2021, accompanying a paper describing details of 12 case reports of cerebral venous sinus thrombosis (CVST) with thrombocytopenia following the J&J COVID-19 vaccine, also known as the Ad26.COV2.S vaccine.

The editorialists are Ruth A. Karron, MD, professor of international health at Johns Hopkins University, Baltimore; Nigel S. Key, MD, professor of hematology at the University of North Carolina at Chapel Hill; and Joshua M. Sharfstein, MD, associate dean for public health practice at Johns Hopkins

They noted that, after an initial pause following reports of thrombosis with thrombocytopenia syndrome (TTS) linked to the J&J vaccine, and on the recommendation of the Advisory Committee on Immunization Practices, the United States has permitted the use of the J&J vaccine in all adults with information on the risk of TTS added to educational materials.

The editorialists pointed out that no cases of TTS have been confirmed following administration of more than 180 million doses of the mRNA vaccines in the United States.

They said that, while the J&J vaccine will still be needed for individuals with allergies to components of the mRNA vaccines and for those who live in remote locations where the cold chain for transport and storage of mRNA vaccines cannot be maintained, “U.S. public health agencies and clinicians should consider recommending mRNA vaccines as safer options for those who may be at substantially higher risk for TTS after Ad26.COV2.S vaccination, currently women younger than 50 years.”

In the main JAMA paper, a group led by Isaac See, MD, Centers for Disease Control and Prevention COVID-19 Response Team, reported full details of 12 cases of CVST with thrombocytopenia following the J&J COVID-19 vaccine reported to the U.S. Vaccine Adverse Event Reporting System (VAERS).

The 12 U.S. case reports, 3 of which were fatal, show many similarities to cases described in Europe after the AstraZeneca vaccine.

The authors noted that, by April 12, approximately 7 million doses of the J&J vaccine had been given in the United States. The 12 cases of CVST and thrombocytopenia following receipt of the vaccine were reported to VAERS between March 2 and April 21. All 12 cases were in White women, 11 of whom were aged under 50 years.

As of April 25, a further two cases have been confirmed and reported to VAERS; one in a man younger than 40 years, the other in a woman aged between 40 and 59 years.

In the 12 cases reported in detail, symptoms started between 6 and 15 days post vaccination.

At least one risk factor for CVST was identified in seven patients (obesity in six, hypothyroidism in one, and use of combined oral contraceptives in one). None of the patients was pregnant or within 12 weeks post partum, had prior thrombosis, a personal or family history of thrombophilia, or documented prior exposure to heparin.

In addition to CVST, seven patients had intracerebral hemorrhage and eight had non-CVST thromboses.

One patient reported a history of SARS-CoV-2 infection approximately 4 months prior to vaccination. Of the other 11 patients, 4 had negative serologic tests and 7 were not tested.

All 12 patients were hospitalized and 10 were admitted to an ICU. At the time of the last follow-up, three patients had died (all of whom had intraparenchymal hemorrhage), three remained in the ICU, two were still hospitalized but not in an ICU, and four had been discharged home.

The authors pointed out that the U.S. cases of CVST with thrombocytopenia following the J&J vaccine have many similarities to those reported in Europe after the AstraZeneca vaccine, occurring primarily in women younger than 40 years and in patients without diagnosed thrombophilia. Both European and U.S. patients had a median platelet nadir count of 19 x 103/mcL and several also had non-CVST large-vessel thrombosis.

In the European cases of CVST with thrombocytopenia, 50% of patients died, compared with 25% of U.S. patients.

Like the European cases, the U.S. cases had positive heparin-PF4 HIT antibody enzyme-linked immunosorbent assay tests in the absence of prior exposure to heparin, as would be seen in autoimmune HIT.

However, in the initial European CVST reports, 88% of patients tested with functional platelet HIT antibody tests had positive results, compared with only 11% of the U.S. cases. But the authors noted that lack of standardization in functional platelet HIT antibody assays may lead to differences in results by different laboratories.

“It may be important to notify testing laboratories that postvaccination TTS is being evaluated, so that testing methods can be adjusted if needed,” they said.

They concluded that these case reports suggest that the pathogenesis of TTS may be similar to autoimmune HIT, triggered by the formation of antibodies directed against PF4, a constituent of platelet alpha granules released during platelet activation. In contrast to classic HIT in which exogenous heparin triggers antibody formation, in autoimmune HIT, an endogenous polyanion triggers PF4 antibody formation.

They noted that the precise mechanism of TTS in relation to COVID-19 vaccination has not yet been established. The Global Advisory Committee on Vaccine Safety has stated that a platform-specific mechanism related to adenovirus vector vaccines cannot be excluded. Both the J&J and AstraZeneca vaccines use an adenoviral vector, but they are different; J&J uses a human vector, while AstraZeneca uses a chimpanzee vector.

They also pointed out that CVST and thrombocytopenia following SARS-CoV-2 infection has been reported in at least two cases, but HIT testing was not done in these cases. There have not so far been any reports to VAERS of CVST with thrombocytopenia following mRNA COVID-19 vaccines.

The authors said these findings have important clinical and public health implications, noting that the CDC has updated its interim clinical considerations for use of authorized COVID-19 vaccines to indicate that women aged 18-49 years should be aware of the increased risk of TTS after receipt of the J&J vaccine, and to use a nonheparin anticoagulant in suspected cases.

They noted that a subacute presentation of headache is present in 90% of patients with typical CVST. While headache is a common symptom after the J&J vaccination, most headaches begin and resolve within 2 days. Whereas in the U.S. cases of CVST after vaccination, headache symptoms began at least 6 days after vaccination and persisted for at least a week for most.

“Urgent consultation with a neurologist is prudent when a patient is suspected or confirmed to have CVST. In addition, since the median time from symptom onset to hospitalization was 7 days in the U.S. CVST case series, patient and clinician education might shorten the time to clinical evaluation and therefore treatment,” they stated.

The authors also note that VAERS is a passive surveillance system, so cases of CVST with thrombocytopenia may be underreported.

In their accompanying editorial, Dr. Karron and colleagues pointed out that, in addition to the 12 patients with CVST with thrombocytopenia described in this case series, at least three patients without CVST but meeting diagnostic criteria for TTS have been reported to VAERS (as of April 21), all in women aged 18-59 years (median age, 37 years).

The editorialists reported that the rate of CVST with thrombocytopenia after the J&J vaccine is approximately 5 per million women aged 18-50 years. This is compared with a background rate of approximately 0.05-0.13 per million per month.

They said that the availability of an interim standardized case definition of this adverse effect will facilitate prospective case ascertainment through review of large linked databases and active case finding.

This will also permit greater understanding of whether individuals who are otherwise at increased risk for hypercoagulation in general and for CVST in particular (for example, women taking hormonal contraceptive medications or who are pregnant) are also at increased risk for TTS.

Obtaining this information will support dynamic country-specific assessments of the risks of each vaccine, compared with the risk of COVID-19 disease for their populations and subpopulations, they added.

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

Use of mRNA COVID-19 vaccines should be considered as the preferable option in the United States rather than Johnson & Johnson’s (J&J) Janssen COVID-19 vaccine in women aged under 50 years, according to one group of experts.

The group made their recommendation in an editorial in JAMA published online April 30, 2021, accompanying a paper describing details of 12 case reports of cerebral venous sinus thrombosis (CVST) with thrombocytopenia following the J&J COVID-19 vaccine, also known as the Ad26.COV2.S vaccine.

The editorialists are Ruth A. Karron, MD, professor of international health at Johns Hopkins University, Baltimore; Nigel S. Key, MD, professor of hematology at the University of North Carolina at Chapel Hill; and Joshua M. Sharfstein, MD, associate dean for public health practice at Johns Hopkins

They noted that, after an initial pause following reports of thrombosis with thrombocytopenia syndrome (TTS) linked to the J&J vaccine, and on the recommendation of the Advisory Committee on Immunization Practices, the United States has permitted the use of the J&J vaccine in all adults with information on the risk of TTS added to educational materials.

The editorialists pointed out that no cases of TTS have been confirmed following administration of more than 180 million doses of the mRNA vaccines in the United States.

They said that, while the J&J vaccine will still be needed for individuals with allergies to components of the mRNA vaccines and for those who live in remote locations where the cold chain for transport and storage of mRNA vaccines cannot be maintained, “U.S. public health agencies and clinicians should consider recommending mRNA vaccines as safer options for those who may be at substantially higher risk for TTS after Ad26.COV2.S vaccination, currently women younger than 50 years.”

In the main JAMA paper, a group led by Isaac See, MD, Centers for Disease Control and Prevention COVID-19 Response Team, reported full details of 12 cases of CVST with thrombocytopenia following the J&J COVID-19 vaccine reported to the U.S. Vaccine Adverse Event Reporting System (VAERS).

The 12 U.S. case reports, 3 of which were fatal, show many similarities to cases described in Europe after the AstraZeneca vaccine.

The authors noted that, by April 12, approximately 7 million doses of the J&J vaccine had been given in the United States. The 12 cases of CVST and thrombocytopenia following receipt of the vaccine were reported to VAERS between March 2 and April 21. All 12 cases were in White women, 11 of whom were aged under 50 years.

As of April 25, a further two cases have been confirmed and reported to VAERS; one in a man younger than 40 years, the other in a woman aged between 40 and 59 years.

In the 12 cases reported in detail, symptoms started between 6 and 15 days post vaccination.

At least one risk factor for CVST was identified in seven patients (obesity in six, hypothyroidism in one, and use of combined oral contraceptives in one). None of the patients was pregnant or within 12 weeks post partum, had prior thrombosis, a personal or family history of thrombophilia, or documented prior exposure to heparin.

In addition to CVST, seven patients had intracerebral hemorrhage and eight had non-CVST thromboses.

One patient reported a history of SARS-CoV-2 infection approximately 4 months prior to vaccination. Of the other 11 patients, 4 had negative serologic tests and 7 were not tested.

All 12 patients were hospitalized and 10 were admitted to an ICU. At the time of the last follow-up, three patients had died (all of whom had intraparenchymal hemorrhage), three remained in the ICU, two were still hospitalized but not in an ICU, and four had been discharged home.

The authors pointed out that the U.S. cases of CVST with thrombocytopenia following the J&J vaccine have many similarities to those reported in Europe after the AstraZeneca vaccine, occurring primarily in women younger than 40 years and in patients without diagnosed thrombophilia. Both European and U.S. patients had a median platelet nadir count of 19 x 103/mcL and several also had non-CVST large-vessel thrombosis.

In the European cases of CVST with thrombocytopenia, 50% of patients died, compared with 25% of U.S. patients.

Like the European cases, the U.S. cases had positive heparin-PF4 HIT antibody enzyme-linked immunosorbent assay tests in the absence of prior exposure to heparin, as would be seen in autoimmune HIT.

However, in the initial European CVST reports, 88% of patients tested with functional platelet HIT antibody tests had positive results, compared with only 11% of the U.S. cases. But the authors noted that lack of standardization in functional platelet HIT antibody assays may lead to differences in results by different laboratories.

“It may be important to notify testing laboratories that postvaccination TTS is being evaluated, so that testing methods can be adjusted if needed,” they said.

They concluded that these case reports suggest that the pathogenesis of TTS may be similar to autoimmune HIT, triggered by the formation of antibodies directed against PF4, a constituent of platelet alpha granules released during platelet activation. In contrast to classic HIT in which exogenous heparin triggers antibody formation, in autoimmune HIT, an endogenous polyanion triggers PF4 antibody formation.

They noted that the precise mechanism of TTS in relation to COVID-19 vaccination has not yet been established. The Global Advisory Committee on Vaccine Safety has stated that a platform-specific mechanism related to adenovirus vector vaccines cannot be excluded. Both the J&J and AstraZeneca vaccines use an adenoviral vector, but they are different; J&J uses a human vector, while AstraZeneca uses a chimpanzee vector.

They also pointed out that CVST and thrombocytopenia following SARS-CoV-2 infection has been reported in at least two cases, but HIT testing was not done in these cases. There have not so far been any reports to VAERS of CVST with thrombocytopenia following mRNA COVID-19 vaccines.

The authors said these findings have important clinical and public health implications, noting that the CDC has updated its interim clinical considerations for use of authorized COVID-19 vaccines to indicate that women aged 18-49 years should be aware of the increased risk of TTS after receipt of the J&J vaccine, and to use a nonheparin anticoagulant in suspected cases.

They noted that a subacute presentation of headache is present in 90% of patients with typical CVST. While headache is a common symptom after the J&J vaccination, most headaches begin and resolve within 2 days. Whereas in the U.S. cases of CVST after vaccination, headache symptoms began at least 6 days after vaccination and persisted for at least a week for most.

“Urgent consultation with a neurologist is prudent when a patient is suspected or confirmed to have CVST. In addition, since the median time from symptom onset to hospitalization was 7 days in the U.S. CVST case series, patient and clinician education might shorten the time to clinical evaluation and therefore treatment,” they stated.

The authors also note that VAERS is a passive surveillance system, so cases of CVST with thrombocytopenia may be underreported.

In their accompanying editorial, Dr. Karron and colleagues pointed out that, in addition to the 12 patients with CVST with thrombocytopenia described in this case series, at least three patients without CVST but meeting diagnostic criteria for TTS have been reported to VAERS (as of April 21), all in women aged 18-59 years (median age, 37 years).

The editorialists reported that the rate of CVST with thrombocytopenia after the J&J vaccine is approximately 5 per million women aged 18-50 years. This is compared with a background rate of approximately 0.05-0.13 per million per month.

They said that the availability of an interim standardized case definition of this adverse effect will facilitate prospective case ascertainment through review of large linked databases and active case finding.

This will also permit greater understanding of whether individuals who are otherwise at increased risk for hypercoagulation in general and for CVST in particular (for example, women taking hormonal contraceptive medications or who are pregnant) are also at increased risk for TTS.

Obtaining this information will support dynamic country-specific assessments of the risks of each vaccine, compared with the risk of COVID-19 disease for their populations and subpopulations, they added.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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