Thrombosis

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.

Replacing dual-antiplatelet therapy (DAPT) with clopidogrel alone 1 month after percutaneous intervention (PCI) offers a lower risk of bleeding with comparable protection against cardiovascular events, according to two subgroup analyses of the Japanese STOPDAPT-2 and STOPDAPT-2 ACS trials.

The objective of these two analyses was to evaluate whether there was a benefit-to-risk ratio advantage for those who entered the study with high bleeding risk or who had undergone a complex PCI. Overall, bleeding risk was reduced without a major increase in cardiovascular events regardless of subgroup, according to results published by a multicenter group of Japanese investigators.

In this substudy, like the previously published studies from which the data were drawn, the primary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, and Thrombolysis In Myocardial Infarction bleeding (major or minor).

The proportion of patients in the 1-month and 12-month DAPT groups reaching this composite endpoint at 1 year was not significantly different among patients stratified by baseline bleeding risk or by PCI complexity, according to a multicenter group of authors led by Takeshi Kimura, MD, department of cardiovascular medicine, Kyoto University.
 

Shortened DAPT is focus of multiple trials

The new analysis, published in JACC Asia, is a follow-up to the 2019 STOPDAPT-2 trial, published in JAMA, and the 2022 STOPDAPT-2 ACS trial, published in JAMA Cardiology. The first tested 1- versus 12-month DAPT in PCI patients receiving a drug-eluting stent. The second study compared the same strategies in patients undergoing PCI to treat an acute coronary syndrome (ACS).

Both studies were conducted in Japan. DAPT consisted of the P2Y12 receptor inhibitor clopidogrel plus aspirin. The experimental arm received this regimen for 1 month followed by clopidogrel monotherapy. The control arm remained on DAPT for 12 months.

The study is potentially important because it addresses the challenge of finding “the sweet spot of antiplatelet therapy in East Asian patients,” according to the coauthors of an accompanying editorial in the same issue of JACC Asia.

Previous data suggest East Asians have a higher risk of bleeding but lower anti-ischemic benefits from DAPT therapy, explained the coauthors, Antonio Greco, MD and Davide Capodanno, MD, PhD, both from the University of Catania (Italy). They praised the effort to explore this question.

In the STOPDAPT-2 trial, the shortened DAPT regimen was associated with a significantly lower rate of a composite endpoint of cardiovascular and bleeding events than standard DAPT, meeting criteria for superiority as well as noninferiority. In the STOPDAPT-2 ACS trial, shortened DAPT failed to achieve noninferiority to standard DAPT because of an increase in cardiovascular events despite a reduction in bleeding events.

Neither of these studies specifically compared shortened to standard DAPT in patients with high bleeding risk or in patients who underwent complex PCI, which are among the most common patient groups in which to consider a modified DAPT regimen. To do this, two new substudies were performed with the combined data from 5,997 patients in the two STOPDAPT-2 trials.
 

Two candidate groups for shortened DAPT evaluated

In the first substudy, the 1,893 patients who met criteria for high bleeding risk were compared with the 4,104 who did not. In those with a high risk of bleeding, the proportion reaching a primary endpoint at 1 year was lower, but not significantly different, for those on 1-month versus standard DAPT (5.01% vs. 5.14%). This was also true in those without an elevated bleeding risk (1.90% vs. 2.02%).

In the second substudy, 999 patients who had a complex PCI, defined by such characteristics as implantation of at least three stents or chronic total occlusion in the target lesions, were compared with the 4,998 who did not. Again, the primary endpoint was lower in both those who had a complex PCI (3.15% vs. 4.07%) and those who did not (2.78% vs. 2.82%).

Not surprisingly, patients with a high bleeding risk benefited from a substantially lower risk of bleeding events on the 1-month DAPT regimen (0.66% vs. 2.27%). The cost was a higher risk of cardiovascular events (4.35% vs. 3.52%), but this difference did not reach significance. Those without an elevated bleeding risk also had a lower risk of bleeding events (0.43% vs. 0.85%) but a higher risk of cardiovascular events (1.56% vs. 1.22%). Again, differences were nonsignificant. In the substudy evaluating DAPT duration in relation to complex PCI, the rate of cardiovascular events at 1 year in those treated with short versus 12-month DAPT was nearly identical (2.53% vs. 2.52%). In the non–complex PCI patients, event rates were nonsignificantly greater on the shortened DAPT regimen (2.38% vs. 1.86%), but the bleeding rate was lower on shortened DAPT whether PCI had been complex (0.63% vs. 1.75%) or not (0.48% vs. 1.22%).

In the absence of any major signal that complex PCI benefited from longer duration DAPT, “complex PCI might not be an appropriate determinant for DAPT durations,” according to Dr. Kimura and coinvestigators.
 

Study data might not be generalizable

Dr. Greco and Dr. Capodanno pointed out that there are differences between patients and PCI practices in Japan relative to other areas of the world, limiting the generalizability of these findings even if the question is relevant.

“This is an approach that might be suggested for patients at high bleeding risk who have the characteristics of the patients enrolled in the STOPDAPT-2 trials,” Dr. Capodanno said in an interview. In his own PCI practice treating ACS patients, “I would not feel safe enough with clopidogrel monotherapy after only 1 month.”

He considers the ACS population to have a particularly “delicate bleeding-ischemia trade-off,” which is why he thinks this question is relevant and needs to be explored further in additional populations. However, he might design trials differently in his own practice setting. For example, he would at the very least be interested in testing a more potent P2Y12 inhibitor such as ticagrelor when considering a single antiplatelet agent after a limited course of DAPT.

One message from this study is that “bleeding risk trumps PCI complexity,” according to Deepak L. Bhatt, MD, who recently assumed the position of director of Mount Sinai Heart in New York. He liked the approach the investigators took to address a complex and relevant clinical issue, but he also expressed reservations about the clinical applicability of this subgroup analysis.

“We really need more data before uniformly shortening DAPT duration in all patients,” Dr. Bhatt said in an interview. He considers this a hot clinical issue that is likely to generate more trials. He hopes these will provide more definitive evidence of when and how DAPT duration can be reduced. Overall, he anticipates progress toward tailoring therapy in specific populations in order to achieve the best risk-to-benefit balance.

Dr. Kimura has financial relationships with Boston Scientific, Daiichi Sankyo, Sanofi, Terumo, and Abbott Medical Japan, which provided funding for the STOPDAPT-2 and STOPDAPT-2 ACS trials. Dr. Capodanno reported financial relationships with Amgen, Arena, Chiesi, Daiichi Sakyo, Sanofi Aventis, and Terumo. Dr. Bhatt reported financial relationships with more than 20 pharmaceutical companies, including Abbott Medical.

Replacing dual-antiplatelet therapy (DAPT) with clopidogrel alone 1 month after percutaneous intervention (PCI) offers a lower risk of bleeding with comparable protection against cardiovascular events, according to two subgroup analyses of the Japanese STOPDAPT-2 and STOPDAPT-2 ACS trials.

The objective of these two analyses was to evaluate whether there was a benefit-to-risk ratio advantage for those who entered the study with high bleeding risk or who had undergone a complex PCI. Overall, bleeding risk was reduced without a major increase in cardiovascular events regardless of subgroup, according to results published by a multicenter group of Japanese investigators.

In this substudy, like the previously published studies from which the data were drawn, the primary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, and Thrombolysis In Myocardial Infarction bleeding (major or minor).

The proportion of patients in the 1-month and 12-month DAPT groups reaching this composite endpoint at 1 year was not significantly different among patients stratified by baseline bleeding risk or by PCI complexity, according to a multicenter group of authors led by Takeshi Kimura, MD, department of cardiovascular medicine, Kyoto University.
 

Shortened DAPT is focus of multiple trials

The new analysis, published in JACC Asia, is a follow-up to the 2019 STOPDAPT-2 trial, published in JAMA, and the 2022 STOPDAPT-2 ACS trial, published in JAMA Cardiology. The first tested 1- versus 12-month DAPT in PCI patients receiving a drug-eluting stent. The second study compared the same strategies in patients undergoing PCI to treat an acute coronary syndrome (ACS).

Both studies were conducted in Japan. DAPT consisted of the P2Y12 receptor inhibitor clopidogrel plus aspirin. The experimental arm received this regimen for 1 month followed by clopidogrel monotherapy. The control arm remained on DAPT for 12 months.

The study is potentially important because it addresses the challenge of finding “the sweet spot of antiplatelet therapy in East Asian patients,” according to the coauthors of an accompanying editorial in the same issue of JACC Asia.

Previous data suggest East Asians have a higher risk of bleeding but lower anti-ischemic benefits from DAPT therapy, explained the coauthors, Antonio Greco, MD and Davide Capodanno, MD, PhD, both from the University of Catania (Italy). They praised the effort to explore this question.

In the STOPDAPT-2 trial, the shortened DAPT regimen was associated with a significantly lower rate of a composite endpoint of cardiovascular and bleeding events than standard DAPT, meeting criteria for superiority as well as noninferiority. In the STOPDAPT-2 ACS trial, shortened DAPT failed to achieve noninferiority to standard DAPT because of an increase in cardiovascular events despite a reduction in bleeding events.

Neither of these studies specifically compared shortened to standard DAPT in patients with high bleeding risk or in patients who underwent complex PCI, which are among the most common patient groups in which to consider a modified DAPT regimen. To do this, two new substudies were performed with the combined data from 5,997 patients in the two STOPDAPT-2 trials.
 

Two candidate groups for shortened DAPT evaluated

In the first substudy, the 1,893 patients who met criteria for high bleeding risk were compared with the 4,104 who did not. In those with a high risk of bleeding, the proportion reaching a primary endpoint at 1 year was lower, but not significantly different, for those on 1-month versus standard DAPT (5.01% vs. 5.14%). This was also true in those without an elevated bleeding risk (1.90% vs. 2.02%).

In the second substudy, 999 patients who had a complex PCI, defined by such characteristics as implantation of at least three stents or chronic total occlusion in the target lesions, were compared with the 4,998 who did not. Again, the primary endpoint was lower in both those who had a complex PCI (3.15% vs. 4.07%) and those who did not (2.78% vs. 2.82%).

Not surprisingly, patients with a high bleeding risk benefited from a substantially lower risk of bleeding events on the 1-month DAPT regimen (0.66% vs. 2.27%). The cost was a higher risk of cardiovascular events (4.35% vs. 3.52%), but this difference did not reach significance. Those without an elevated bleeding risk also had a lower risk of bleeding events (0.43% vs. 0.85%) but a higher risk of cardiovascular events (1.56% vs. 1.22%). Again, differences were nonsignificant. In the substudy evaluating DAPT duration in relation to complex PCI, the rate of cardiovascular events at 1 year in those treated with short versus 12-month DAPT was nearly identical (2.53% vs. 2.52%). In the non–complex PCI patients, event rates were nonsignificantly greater on the shortened DAPT regimen (2.38% vs. 1.86%), but the bleeding rate was lower on shortened DAPT whether PCI had been complex (0.63% vs. 1.75%) or not (0.48% vs. 1.22%).

In the absence of any major signal that complex PCI benefited from longer duration DAPT, “complex PCI might not be an appropriate determinant for DAPT durations,” according to Dr. Kimura and coinvestigators.
 

Study data might not be generalizable

Dr. Greco and Dr. Capodanno pointed out that there are differences between patients and PCI practices in Japan relative to other areas of the world, limiting the generalizability of these findings even if the question is relevant.

“This is an approach that might be suggested for patients at high bleeding risk who have the characteristics of the patients enrolled in the STOPDAPT-2 trials,” Dr. Capodanno said in an interview. In his own PCI practice treating ACS patients, “I would not feel safe enough with clopidogrel monotherapy after only 1 month.”

He considers the ACS population to have a particularly “delicate bleeding-ischemia trade-off,” which is why he thinks this question is relevant and needs to be explored further in additional populations. However, he might design trials differently in his own practice setting. For example, he would at the very least be interested in testing a more potent P2Y12 inhibitor such as ticagrelor when considering a single antiplatelet agent after a limited course of DAPT.

One message from this study is that “bleeding risk trumps PCI complexity,” according to Deepak L. Bhatt, MD, who recently assumed the position of director of Mount Sinai Heart in New York. He liked the approach the investigators took to address a complex and relevant clinical issue, but he also expressed reservations about the clinical applicability of this subgroup analysis.

“We really need more data before uniformly shortening DAPT duration in all patients,” Dr. Bhatt said in an interview. He considers this a hot clinical issue that is likely to generate more trials. He hopes these will provide more definitive evidence of when and how DAPT duration can be reduced. Overall, he anticipates progress toward tailoring therapy in specific populations in order to achieve the best risk-to-benefit balance.

Dr. Kimura has financial relationships with Boston Scientific, Daiichi Sankyo, Sanofi, Terumo, and Abbott Medical Japan, which provided funding for the STOPDAPT-2 and STOPDAPT-2 ACS trials. Dr. Capodanno reported financial relationships with Amgen, Arena, Chiesi, Daiichi Sakyo, Sanofi Aventis, and Terumo. Dr. Bhatt reported financial relationships with more than 20 pharmaceutical companies, including Abbott Medical.

Replacing dual-antiplatelet therapy (DAPT) with clopidogrel alone 1 month after percutaneous intervention (PCI) offers a lower risk of bleeding with comparable protection against cardiovascular events, according to two subgroup analyses of the Japanese STOPDAPT-2 and STOPDAPT-2 ACS trials.

The objective of these two analyses was to evaluate whether there was a benefit-to-risk ratio advantage for those who entered the study with high bleeding risk or who had undergone a complex PCI. Overall, bleeding risk was reduced without a major increase in cardiovascular events regardless of subgroup, according to results published by a multicenter group of Japanese investigators.

In this substudy, like the previously published studies from which the data were drawn, the primary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, stroke, and Thrombolysis In Myocardial Infarction bleeding (major or minor).

The proportion of patients in the 1-month and 12-month DAPT groups reaching this composite endpoint at 1 year was not significantly different among patients stratified by baseline bleeding risk or by PCI complexity, according to a multicenter group of authors led by Takeshi Kimura, MD, department of cardiovascular medicine, Kyoto University.
 

Shortened DAPT is focus of multiple trials

The new analysis, published in JACC Asia, is a follow-up to the 2019 STOPDAPT-2 trial, published in JAMA, and the 2022 STOPDAPT-2 ACS trial, published in JAMA Cardiology. The first tested 1- versus 12-month DAPT in PCI patients receiving a drug-eluting stent. The second study compared the same strategies in patients undergoing PCI to treat an acute coronary syndrome (ACS).

Both studies were conducted in Japan. DAPT consisted of the P2Y12 receptor inhibitor clopidogrel plus aspirin. The experimental arm received this regimen for 1 month followed by clopidogrel monotherapy. The control arm remained on DAPT for 12 months.

The study is potentially important because it addresses the challenge of finding “the sweet spot of antiplatelet therapy in East Asian patients,” according to the coauthors of an accompanying editorial in the same issue of JACC Asia.

Previous data suggest East Asians have a higher risk of bleeding but lower anti-ischemic benefits from DAPT therapy, explained the coauthors, Antonio Greco, MD and Davide Capodanno, MD, PhD, both from the University of Catania (Italy). They praised the effort to explore this question.

In the STOPDAPT-2 trial, the shortened DAPT regimen was associated with a significantly lower rate of a composite endpoint of cardiovascular and bleeding events than standard DAPT, meeting criteria for superiority as well as noninferiority. In the STOPDAPT-2 ACS trial, shortened DAPT failed to achieve noninferiority to standard DAPT because of an increase in cardiovascular events despite a reduction in bleeding events.

Neither of these studies specifically compared shortened to standard DAPT in patients with high bleeding risk or in patients who underwent complex PCI, which are among the most common patient groups in which to consider a modified DAPT regimen. To do this, two new substudies were performed with the combined data from 5,997 patients in the two STOPDAPT-2 trials.
 

Two candidate groups for shortened DAPT evaluated

In the first substudy, the 1,893 patients who met criteria for high bleeding risk were compared with the 4,104 who did not. In those with a high risk of bleeding, the proportion reaching a primary endpoint at 1 year was lower, but not significantly different, for those on 1-month versus standard DAPT (5.01% vs. 5.14%). This was also true in those without an elevated bleeding risk (1.90% vs. 2.02%).

In the second substudy, 999 patients who had a complex PCI, defined by such characteristics as implantation of at least three stents or chronic total occlusion in the target lesions, were compared with the 4,998 who did not. Again, the primary endpoint was lower in both those who had a complex PCI (3.15% vs. 4.07%) and those who did not (2.78% vs. 2.82%).

Not surprisingly, patients with a high bleeding risk benefited from a substantially lower risk of bleeding events on the 1-month DAPT regimen (0.66% vs. 2.27%). The cost was a higher risk of cardiovascular events (4.35% vs. 3.52%), but this difference did not reach significance. Those without an elevated bleeding risk also had a lower risk of bleeding events (0.43% vs. 0.85%) but a higher risk of cardiovascular events (1.56% vs. 1.22%). Again, differences were nonsignificant. In the substudy evaluating DAPT duration in relation to complex PCI, the rate of cardiovascular events at 1 year in those treated with short versus 12-month DAPT was nearly identical (2.53% vs. 2.52%). In the non–complex PCI patients, event rates were nonsignificantly greater on the shortened DAPT regimen (2.38% vs. 1.86%), but the bleeding rate was lower on shortened DAPT whether PCI had been complex (0.63% vs. 1.75%) or not (0.48% vs. 1.22%).

In the absence of any major signal that complex PCI benefited from longer duration DAPT, “complex PCI might not be an appropriate determinant for DAPT durations,” according to Dr. Kimura and coinvestigators.
 

Study data might not be generalizable

Dr. Greco and Dr. Capodanno pointed out that there are differences between patients and PCI practices in Japan relative to other areas of the world, limiting the generalizability of these findings even if the question is relevant.

“This is an approach that might be suggested for patients at high bleeding risk who have the characteristics of the patients enrolled in the STOPDAPT-2 trials,” Dr. Capodanno said in an interview. In his own PCI practice treating ACS patients, “I would not feel safe enough with clopidogrel monotherapy after only 1 month.”

He considers the ACS population to have a particularly “delicate bleeding-ischemia trade-off,” which is why he thinks this question is relevant and needs to be explored further in additional populations. However, he might design trials differently in his own practice setting. For example, he would at the very least be interested in testing a more potent P2Y12 inhibitor such as ticagrelor when considering a single antiplatelet agent after a limited course of DAPT.

One message from this study is that “bleeding risk trumps PCI complexity,” according to Deepak L. Bhatt, MD, who recently assumed the position of director of Mount Sinai Heart in New York. He liked the approach the investigators took to address a complex and relevant clinical issue, but he also expressed reservations about the clinical applicability of this subgroup analysis.

“We really need more data before uniformly shortening DAPT duration in all patients,” Dr. Bhatt said in an interview. He considers this a hot clinical issue that is likely to generate more trials. He hopes these will provide more definitive evidence of when and how DAPT duration can be reduced. Overall, he anticipates progress toward tailoring therapy in specific populations in order to achieve the best risk-to-benefit balance.

Dr. Kimura has financial relationships with Boston Scientific, Daiichi Sankyo, Sanofi, Terumo, and Abbott Medical Japan, which provided funding for the STOPDAPT-2 and STOPDAPT-2 ACS trials. Dr. Capodanno reported financial relationships with Amgen, Arena, Chiesi, Daiichi Sakyo, Sanofi Aventis, and Terumo. Dr. Bhatt reported financial relationships with more than 20 pharmaceutical companies, including Abbott Medical.

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

NEW ORLEANS – Addressing an audience of hematologists, an immunologist and a thrombosis specialist presented insights on two hot COVID-19 topics: strategies the virus uses to breach the immune system and the diagnosis and treatment of vaccine-related blood clots.

In a presidential symposium at the annual meeting of the American Society of Hematology, La Jolla Institute of Immunology scientist Shane Crotty, PhD, explained that COVID-19 has a “superpower” that allows it to be “extraordinarily stealthy.”

The virus, he said, can sneak past the body’s innate immune system, which normally responds to viral invaders within minutes to hours. “This is why you have people with high viral loads who are presymptomatic. Their innate immune system hasn’t even recognized that these people are infected.”

The adaptive immune system kicks in later. As Dr. Crotty noted, adaptive immunity is composed of three branches: B cells (the source of antibodies), CD4 “helper” T cells, and CD8 “killer” T cells. In the first year of COVID-19, his team tracked 188 subjects post infection in what he said was the largest study of its kind ever for any viral infection.

“In 8 months, 95% of people who had been infected still had measurable immune memory. In fact, most of them had multiple different compartments of immune memory still detectable, and it was likely that these individuals would still have that memory years into the future. Based on that, we made the prediction that most people who have had COVID-19 would likely be protected from reinfection – at least by severe infections – for 3 years into the future. That prediction has widely held up even in the presence of variants which weren’t around at the time.”

How do vaccines fit into the immunity picture? Dr. Crotty’s lab has tracked subjects who received 4 vaccines – Moderna, Pfizer/BioNTech, Janssen/Johnson & Johnson, and Novavax. Researchers found that the mRNA vaccines, Moderna and Pfizer/BioNTech, “are fantastic at eliciting neutralizing antibodies quickly, but then they drop off rapidly at two doses and actually continue to drop for 10 months.”

Still, he said, “when we take a look at 6 months, actually the vaccines are doing pretty incredibly well. If we compare them to an average infected individual, the mRNA vaccines all have higher neutralizing antibody titers.”

What’s happening? According to Dr. Crotty, B cells are “making guesses about what other variants might look like.” But he said research suggests that an important component of this process – germinal centers – aren’t made in some vaccinated people who are immunocompromised. (Germinal centers have been described as “microbial boot camps” for B cells.)

The good news, Dr. Crotty noted, is that a greater understanding of how COVID-19 penetrates various layers of adaptive immune defenses will lead to better ways to protect the immunocompromised. “If you think about immunity in this layered defense way, there are various ways that it could be enhanced for individuals in different categories,” he said.

Hematologist Beverley J. Hunt, MD, OBE, of St. Thomas’ Hospital/King’s Healthcare Partners in London, spoke at the ASH presidential symposium about blood clots and COVID-19. As she noted, concern arose about vaccine-related blood clots. A British team “managed quickly to come up with a diagnostic criteria,” she said. “We looked at nearly 300 patients and essentially came up with a scoring system.”

The diagnostic criteria was based on an analysis of definite or probable cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) – all related to the AstraZeneca vaccine. The criteria appeared in a 2021 study in the New England Journal of Medicine.

The report’s data didn’t allow it to compare the efficacy of anticoagulants. However, Dr. Hunt noted that clinicians turned to plasma exchange in patients with low platelet counts and extensive thrombosis. The report stated “survival after plasma exchange was 90%, considerably better than would be predicted given the baseline characteristics.”

“Now we’re following up,” Dr. Hunt said. One question to answer: Is long-term anticoagulation helpful? “We have many patients,” she said, “who are taking an anti-platelet factor out of habit.”

Dr. Crotty and Dr. Hunt report no disclosures. This reporter is a paid participant in a COVID vaccine study run by Dr. Crotty’s lab.

NEW ORLEANS – Addressing an audience of hematologists, an immunologist and a thrombosis specialist presented insights on two hot COVID-19 topics: strategies the virus uses to breach the immune system and the diagnosis and treatment of vaccine-related blood clots.

In a presidential symposium at the annual meeting of the American Society of Hematology, La Jolla Institute of Immunology scientist Shane Crotty, PhD, explained that COVID-19 has a “superpower” that allows it to be “extraordinarily stealthy.”

The virus, he said, can sneak past the body’s innate immune system, which normally responds to viral invaders within minutes to hours. “This is why you have people with high viral loads who are presymptomatic. Their innate immune system hasn’t even recognized that these people are infected.”

The adaptive immune system kicks in later. As Dr. Crotty noted, adaptive immunity is composed of three branches: B cells (the source of antibodies), CD4 “helper” T cells, and CD8 “killer” T cells. In the first year of COVID-19, his team tracked 188 subjects post infection in what he said was the largest study of its kind ever for any viral infection.

“In 8 months, 95% of people who had been infected still had measurable immune memory. In fact, most of them had multiple different compartments of immune memory still detectable, and it was likely that these individuals would still have that memory years into the future. Based on that, we made the prediction that most people who have had COVID-19 would likely be protected from reinfection – at least by severe infections – for 3 years into the future. That prediction has widely held up even in the presence of variants which weren’t around at the time.”

How do vaccines fit into the immunity picture? Dr. Crotty’s lab has tracked subjects who received 4 vaccines – Moderna, Pfizer/BioNTech, Janssen/Johnson & Johnson, and Novavax. Researchers found that the mRNA vaccines, Moderna and Pfizer/BioNTech, “are fantastic at eliciting neutralizing antibodies quickly, but then they drop off rapidly at two doses and actually continue to drop for 10 months.”

Still, he said, “when we take a look at 6 months, actually the vaccines are doing pretty incredibly well. If we compare them to an average infected individual, the mRNA vaccines all have higher neutralizing antibody titers.”

What’s happening? According to Dr. Crotty, B cells are “making guesses about what other variants might look like.” But he said research suggests that an important component of this process – germinal centers – aren’t made in some vaccinated people who are immunocompromised. (Germinal centers have been described as “microbial boot camps” for B cells.)

The good news, Dr. Crotty noted, is that a greater understanding of how COVID-19 penetrates various layers of adaptive immune defenses will lead to better ways to protect the immunocompromised. “If you think about immunity in this layered defense way, there are various ways that it could be enhanced for individuals in different categories,” he said.

Hematologist Beverley J. Hunt, MD, OBE, of St. Thomas’ Hospital/King’s Healthcare Partners in London, spoke at the ASH presidential symposium about blood clots and COVID-19. As she noted, concern arose about vaccine-related blood clots. A British team “managed quickly to come up with a diagnostic criteria,” she said. “We looked at nearly 300 patients and essentially came up with a scoring system.”

The diagnostic criteria was based on an analysis of definite or probable cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) – all related to the AstraZeneca vaccine. The criteria appeared in a 2021 study in the New England Journal of Medicine.

The report’s data didn’t allow it to compare the efficacy of anticoagulants. However, Dr. Hunt noted that clinicians turned to plasma exchange in patients with low platelet counts and extensive thrombosis. The report stated “survival after plasma exchange was 90%, considerably better than would be predicted given the baseline characteristics.”

“Now we’re following up,” Dr. Hunt said. One question to answer: Is long-term anticoagulation helpful? “We have many patients,” she said, “who are taking an anti-platelet factor out of habit.”

Dr. Crotty and Dr. Hunt report no disclosures. This reporter is a paid participant in a COVID vaccine study run by Dr. Crotty’s lab.

NEW ORLEANS – Addressing an audience of hematologists, an immunologist and a thrombosis specialist presented insights on two hot COVID-19 topics: strategies the virus uses to breach the immune system and the diagnosis and treatment of vaccine-related blood clots.

In a presidential symposium at the annual meeting of the American Society of Hematology, La Jolla Institute of Immunology scientist Shane Crotty, PhD, explained that COVID-19 has a “superpower” that allows it to be “extraordinarily stealthy.”

The virus, he said, can sneak past the body’s innate immune system, which normally responds to viral invaders within minutes to hours. “This is why you have people with high viral loads who are presymptomatic. Their innate immune system hasn’t even recognized that these people are infected.”

The adaptive immune system kicks in later. As Dr. Crotty noted, adaptive immunity is composed of three branches: B cells (the source of antibodies), CD4 “helper” T cells, and CD8 “killer” T cells. In the first year of COVID-19, his team tracked 188 subjects post infection in what he said was the largest study of its kind ever for any viral infection.

“In 8 months, 95% of people who had been infected still had measurable immune memory. In fact, most of them had multiple different compartments of immune memory still detectable, and it was likely that these individuals would still have that memory years into the future. Based on that, we made the prediction that most people who have had COVID-19 would likely be protected from reinfection – at least by severe infections – for 3 years into the future. That prediction has widely held up even in the presence of variants which weren’t around at the time.”

How do vaccines fit into the immunity picture? Dr. Crotty’s lab has tracked subjects who received 4 vaccines – Moderna, Pfizer/BioNTech, Janssen/Johnson & Johnson, and Novavax. Researchers found that the mRNA vaccines, Moderna and Pfizer/BioNTech, “are fantastic at eliciting neutralizing antibodies quickly, but then they drop off rapidly at two doses and actually continue to drop for 10 months.”

Still, he said, “when we take a look at 6 months, actually the vaccines are doing pretty incredibly well. If we compare them to an average infected individual, the mRNA vaccines all have higher neutralizing antibody titers.”

What’s happening? According to Dr. Crotty, B cells are “making guesses about what other variants might look like.” But he said research suggests that an important component of this process – germinal centers – aren’t made in some vaccinated people who are immunocompromised. (Germinal centers have been described as “microbial boot camps” for B cells.)

The good news, Dr. Crotty noted, is that a greater understanding of how COVID-19 penetrates various layers of adaptive immune defenses will lead to better ways to protect the immunocompromised. “If you think about immunity in this layered defense way, there are various ways that it could be enhanced for individuals in different categories,” he said.

Hematologist Beverley J. Hunt, MD, OBE, of St. Thomas’ Hospital/King’s Healthcare Partners in London, spoke at the ASH presidential symposium about blood clots and COVID-19. As she noted, concern arose about vaccine-related blood clots. A British team “managed quickly to come up with a diagnostic criteria,” she said. “We looked at nearly 300 patients and essentially came up with a scoring system.”

The diagnostic criteria was based on an analysis of definite or probable cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) – all related to the AstraZeneca vaccine. The criteria appeared in a 2021 study in the New England Journal of Medicine.

The report’s data didn’t allow it to compare the efficacy of anticoagulants. However, Dr. Hunt noted that clinicians turned to plasma exchange in patients with low platelet counts and extensive thrombosis. The report stated “survival after plasma exchange was 90%, considerably better than would be predicted given the baseline characteristics.”

“Now we’re following up,” Dr. Hunt said. One question to answer: Is long-term anticoagulation helpful? “We have many patients,” she said, “who are taking an anti-platelet factor out of habit.”

Dr. Crotty and Dr. Hunt report no disclosures. This reporter is a paid participant in a COVID vaccine study run by Dr. Crotty’s lab.

NEW ORLEANS – Patients with chronic immune thrombocytopenia (ITP) fared better on intravenous efgartigimod (Vyvgart) than a placebo, a new study found. Still, only 21.8% of subjects who received the biologic reached the primary endpoint of sustained platelet count response, an indication that most patients won’t benefit.

Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.

“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.

In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”

The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.

Treatment options include corticosteroids and intravenous immunoglobulin.

“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.

For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).

Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.

Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.

Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).

“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”

She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”

Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.

Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.

In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.

Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.

As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”

It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”

For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”

What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.

The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.

NEW ORLEANS – Patients with chronic immune thrombocytopenia (ITP) fared better on intravenous efgartigimod (Vyvgart) than a placebo, a new study found. Still, only 21.8% of subjects who received the biologic reached the primary endpoint of sustained platelet count response, an indication that most patients won’t benefit.

Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.

“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.

In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”

The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.

Treatment options include corticosteroids and intravenous immunoglobulin.

“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.

For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).

Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.

Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.

Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).

“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”

She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”

Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.

Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.

In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.

Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.

As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”

It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”

For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”

What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.

The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.

NEW ORLEANS – Patients with chronic immune thrombocytopenia (ITP) fared better on intravenous efgartigimod (Vyvgart) than a placebo, a new study found. Still, only 21.8% of subjects who received the biologic reached the primary endpoint of sustained platelet count response, an indication that most patients won’t benefit.

Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.

“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.

In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”

The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.

Treatment options include corticosteroids and intravenous immunoglobulin.

“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.

For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).

Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.

Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.

Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).

“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”

She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”

Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.

Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.

In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.

Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.

As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”

It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”

For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”

What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.

The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

NEW ORLEANS – In yet another indication of health disparities facing ethnic minorities, new research found that non-White patients with pulmonary embolism (PE) were less likely to get advanced therapies. Hispanics and Asians/Pacific Islanders, meanwhile, had higher death rates than Whites.

According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).

“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.

As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.

The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.

Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.

With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.

These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.

As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.

In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).

Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.

The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).

As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”

Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”

In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”

In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”

For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said. 

Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”

Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.

NEW ORLEANS – In yet another indication of health disparities facing ethnic minorities, new research found that non-White patients with pulmonary embolism (PE) were less likely to get advanced therapies. Hispanics and Asians/Pacific Islanders, meanwhile, had higher death rates than Whites.

According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).

“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.

As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.

The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.

Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.

With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.

These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.

As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.

In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).

Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.

The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).

As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”

Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”

In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”

In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”

For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said. 

Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”

Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.

NEW ORLEANS – In yet another indication of health disparities facing ethnic minorities, new research found that non-White patients with pulmonary embolism (PE) were less likely to get advanced therapies. Hispanics and Asians/Pacific Islanders, meanwhile, had higher death rates than Whites.

According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).

“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.

As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.

The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.

Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.

With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.

These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.

As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.

In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).

Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.

The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).

As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”

Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”

In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”

In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”

For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said. 

Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”

Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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