Thrombosis

BOSTON – Following transradial access for angiography or a percutaneous coronary intervention (PCI), a low dose of the factor Xa inhibitor rivaroxaban for 7 days reduces the risk of an access-site occlusion by 50%, according to results of the randomized RIVARAD trial.

Of two multicenter, randomized trials to address this question it is the larger, according to Rania Hammami, MD, who presented the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

Ted Bosworth/MDedge News

In the open-label RIVARAD trial, 538 patients were randomized to 10 mg rivaroxaban or standard care alone. Standard care at the beginning of the procedure included unfractionated heparin in a dose of 50 IU/kg for angiography and up to 100 IU/kg for PCI. Manual compression was applied at the end of the procedure followed by an evaluation for complications, such as hematoma or aneurysm.

For the primary outcome of radial access occlusion at 30 days, the lower rate in the rivaroxaban arm (6.9% vs. 13.0%) translated into a statistically significant 50% reduction (odds ratio, 0.50; P = .011).
 

Rivaroxaban preserves radial pulse

Rivaroxaban was also favored for the endpoint of inability at 30 days to find a radial pulse (5.8% vs. 12.2%; P = .01). Interestingly, there was some disparity for this endpoint for clinical examination and ultrasound.

“In 12 patients, we were able to palpate a radial pulse, but the ultrasound showed an occlusion of the vessel, while in 7 patients we could not find a radial pulse even though the radial artery was patent on ultrasound,” Dr. Hammami, of the department of cardiology, Hedi Chaker Hospital, Sfax, Tunisia, said at the meeting, sponsored by the Cardiovascular Research Foundation.

The incidence of hemorrhagic complications was higher in the rivaroxaban group (2.7% vs. 1.9%), but the difference did not approach statistical significance (OR, 1.5; P = .54). Moreover, all of the bleeding complications were minor (Bleeding Academic Research Consortium level 1), and none of the bleeding complications were observed in patients receiving rivaroxaban alone. Rather, all patients with bleeding were taking one or more antiplatelet drugs along with rivaroxaban.

On univariate analysis, several baseline characteristics were associated with subsequent radial occlusion, including female sex (P = .02), current smoking (P = .03), renal failure (P = .004), and PCI for acute coronary syndrome (P = .02). On multivariate analysis, female sex (P = .001) and current smoking (P < .0001) became even stronger predictors of occlusion on a statistical basis, while a prior procedure involving radial access was also a significant predictor (P = .029).

“One woman out of two developed radial access occlusion if she had a history of smoking and had a history of a transradial puncture,” Dr. Hammami reported.

In a subgroup analysis, relative protection from radial artery occlusion from a 7-day course of rivaroxaban was particularly pronounced in those with diabetes, renal failure, or hypertension relative to those without these conditions, but the protective effect appeared to be about the same regardless of body mass index, age, sheath size, or current use of statins.

These findings are consistent with other studies evaluating the risk of radial access occlusion, according to Dr. Hammami. While different studies she cited reported incidences ranging from less than 1% to more than 30%, the risk has typically been highest in populations with increased susceptibility for thrombus formation, such as smokers and patients with diabetes.

Preventing radial artery occlusion has several benefits, not least of which is preserving this access point for future interventions, according to Dr. Hammami.

RIVARAD is the largest study to evaluate an anticoagulant for the prevention of radial artery occlusion, but it is not the first. Earlier in 2022, a Chinese trial called RESTORE was published in Circulation: Cardiovascular Interventions. In that placebo-controlled study of 382 patients, 7 days of 10 mg rivaroxaban was also linked to a significant reduction in radial artery occlusion at 30 days (3.8% vs. 11.5%; P = .011).

“We don’t know if a higher dose of rivaroxaban would be more effective and equally safe,” said Dr. Hammami, but added that a Canadian trial called CAPITAL RAPTOR will test this premise. In this trial, there is a planned enrollment of 1,800 patients who will be randomized to 15 mg rivaroxaban or standard treatment.

Occlusion risk appears underappreciated

The risk of radial artery occlusion might be underappreciated. According to data cited by Dr. Hammami, only about half of interventionalists in the United States and fewer than 10% outside of the United States routinely assess radial artery patency in conjunction with radial-access PCI. The data from this trial suggest that the risk can be substantially reduced, particularly in high-risk patients, with anticoagulant therapy.

Mount Sinai Medical Center

Agreeing that this is a potentially avoidable complication, Roxanna Mehran, MD, director of interventional cardiovascular research and clinical trials, Icahn School of Medicine at Mount Sinai, New York, called the RIVARAD study “a clinically meaningful trial,” and valuable for identifying risk factors as well as for showing a treatment effect and acceptable safety from a short course of a factor Xa inhibitor.

“This is very important work,” said Dr. Mehran, who praised the quality of the study and the contribution it makes for considering how and when prophylaxis is needed.

Dr. Hammami reported no potential conflicts of interest. Dr. Mehran has financial relationships with more than 25 pharmaceutical companies but none with the sponsor of this trial, which was funded by Philadelphia Pharma, a drug company based in Tunisia.

BOSTON – Following transradial access for angiography or a percutaneous coronary intervention (PCI), a low dose of the factor Xa inhibitor rivaroxaban for 7 days reduces the risk of an access-site occlusion by 50%, according to results of the randomized RIVARAD trial.

Of two multicenter, randomized trials to address this question it is the larger, according to Rania Hammami, MD, who presented the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

Ted Bosworth/MDedge News

In the open-label RIVARAD trial, 538 patients were randomized to 10 mg rivaroxaban or standard care alone. Standard care at the beginning of the procedure included unfractionated heparin in a dose of 50 IU/kg for angiography and up to 100 IU/kg for PCI. Manual compression was applied at the end of the procedure followed by an evaluation for complications, such as hematoma or aneurysm.

For the primary outcome of radial access occlusion at 30 days, the lower rate in the rivaroxaban arm (6.9% vs. 13.0%) translated into a statistically significant 50% reduction (odds ratio, 0.50; P = .011).
 

Rivaroxaban preserves radial pulse

Rivaroxaban was also favored for the endpoint of inability at 30 days to find a radial pulse (5.8% vs. 12.2%; P = .01). Interestingly, there was some disparity for this endpoint for clinical examination and ultrasound.

“In 12 patients, we were able to palpate a radial pulse, but the ultrasound showed an occlusion of the vessel, while in 7 patients we could not find a radial pulse even though the radial artery was patent on ultrasound,” Dr. Hammami, of the department of cardiology, Hedi Chaker Hospital, Sfax, Tunisia, said at the meeting, sponsored by the Cardiovascular Research Foundation.

The incidence of hemorrhagic complications was higher in the rivaroxaban group (2.7% vs. 1.9%), but the difference did not approach statistical significance (OR, 1.5; P = .54). Moreover, all of the bleeding complications were minor (Bleeding Academic Research Consortium level 1), and none of the bleeding complications were observed in patients receiving rivaroxaban alone. Rather, all patients with bleeding were taking one or more antiplatelet drugs along with rivaroxaban.

On univariate analysis, several baseline characteristics were associated with subsequent radial occlusion, including female sex (P = .02), current smoking (P = .03), renal failure (P = .004), and PCI for acute coronary syndrome (P = .02). On multivariate analysis, female sex (P = .001) and current smoking (P < .0001) became even stronger predictors of occlusion on a statistical basis, while a prior procedure involving radial access was also a significant predictor (P = .029).

“One woman out of two developed radial access occlusion if she had a history of smoking and had a history of a transradial puncture,” Dr. Hammami reported.

In a subgroup analysis, relative protection from radial artery occlusion from a 7-day course of rivaroxaban was particularly pronounced in those with diabetes, renal failure, or hypertension relative to those without these conditions, but the protective effect appeared to be about the same regardless of body mass index, age, sheath size, or current use of statins.

These findings are consistent with other studies evaluating the risk of radial access occlusion, according to Dr. Hammami. While different studies she cited reported incidences ranging from less than 1% to more than 30%, the risk has typically been highest in populations with increased susceptibility for thrombus formation, such as smokers and patients with diabetes.

Preventing radial artery occlusion has several benefits, not least of which is preserving this access point for future interventions, according to Dr. Hammami.

RIVARAD is the largest study to evaluate an anticoagulant for the prevention of radial artery occlusion, but it is not the first. Earlier in 2022, a Chinese trial called RESTORE was published in Circulation: Cardiovascular Interventions. In that placebo-controlled study of 382 patients, 7 days of 10 mg rivaroxaban was also linked to a significant reduction in radial artery occlusion at 30 days (3.8% vs. 11.5%; P = .011).

“We don’t know if a higher dose of rivaroxaban would be more effective and equally safe,” said Dr. Hammami, but added that a Canadian trial called CAPITAL RAPTOR will test this premise. In this trial, there is a planned enrollment of 1,800 patients who will be randomized to 15 mg rivaroxaban or standard treatment.

Occlusion risk appears underappreciated

The risk of radial artery occlusion might be underappreciated. According to data cited by Dr. Hammami, only about half of interventionalists in the United States and fewer than 10% outside of the United States routinely assess radial artery patency in conjunction with radial-access PCI. The data from this trial suggest that the risk can be substantially reduced, particularly in high-risk patients, with anticoagulant therapy.

Mount Sinai Medical Center

Agreeing that this is a potentially avoidable complication, Roxanna Mehran, MD, director of interventional cardiovascular research and clinical trials, Icahn School of Medicine at Mount Sinai, New York, called the RIVARAD study “a clinically meaningful trial,” and valuable for identifying risk factors as well as for showing a treatment effect and acceptable safety from a short course of a factor Xa inhibitor.

“This is very important work,” said Dr. Mehran, who praised the quality of the study and the contribution it makes for considering how and when prophylaxis is needed.

Dr. Hammami reported no potential conflicts of interest. Dr. Mehran has financial relationships with more than 25 pharmaceutical companies but none with the sponsor of this trial, which was funded by Philadelphia Pharma, a drug company based in Tunisia.

BOSTON – Following transradial access for angiography or a percutaneous coronary intervention (PCI), a low dose of the factor Xa inhibitor rivaroxaban for 7 days reduces the risk of an access-site occlusion by 50%, according to results of the randomized RIVARAD trial.

Of two multicenter, randomized trials to address this question it is the larger, according to Rania Hammami, MD, who presented the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

Ted Bosworth/MDedge News

In the open-label RIVARAD trial, 538 patients were randomized to 10 mg rivaroxaban or standard care alone. Standard care at the beginning of the procedure included unfractionated heparin in a dose of 50 IU/kg for angiography and up to 100 IU/kg for PCI. Manual compression was applied at the end of the procedure followed by an evaluation for complications, such as hematoma or aneurysm.

For the primary outcome of radial access occlusion at 30 days, the lower rate in the rivaroxaban arm (6.9% vs. 13.0%) translated into a statistically significant 50% reduction (odds ratio, 0.50; P = .011).
 

Rivaroxaban preserves radial pulse

Rivaroxaban was also favored for the endpoint of inability at 30 days to find a radial pulse (5.8% vs. 12.2%; P = .01). Interestingly, there was some disparity for this endpoint for clinical examination and ultrasound.

“In 12 patients, we were able to palpate a radial pulse, but the ultrasound showed an occlusion of the vessel, while in 7 patients we could not find a radial pulse even though the radial artery was patent on ultrasound,” Dr. Hammami, of the department of cardiology, Hedi Chaker Hospital, Sfax, Tunisia, said at the meeting, sponsored by the Cardiovascular Research Foundation.

The incidence of hemorrhagic complications was higher in the rivaroxaban group (2.7% vs. 1.9%), but the difference did not approach statistical significance (OR, 1.5; P = .54). Moreover, all of the bleeding complications were minor (Bleeding Academic Research Consortium level 1), and none of the bleeding complications were observed in patients receiving rivaroxaban alone. Rather, all patients with bleeding were taking one or more antiplatelet drugs along with rivaroxaban.

On univariate analysis, several baseline characteristics were associated with subsequent radial occlusion, including female sex (P = .02), current smoking (P = .03), renal failure (P = .004), and PCI for acute coronary syndrome (P = .02). On multivariate analysis, female sex (P = .001) and current smoking (P < .0001) became even stronger predictors of occlusion on a statistical basis, while a prior procedure involving radial access was also a significant predictor (P = .029).

“One woman out of two developed radial access occlusion if she had a history of smoking and had a history of a transradial puncture,” Dr. Hammami reported.

In a subgroup analysis, relative protection from radial artery occlusion from a 7-day course of rivaroxaban was particularly pronounced in those with diabetes, renal failure, or hypertension relative to those without these conditions, but the protective effect appeared to be about the same regardless of body mass index, age, sheath size, or current use of statins.

These findings are consistent with other studies evaluating the risk of radial access occlusion, according to Dr. Hammami. While different studies she cited reported incidences ranging from less than 1% to more than 30%, the risk has typically been highest in populations with increased susceptibility for thrombus formation, such as smokers and patients with diabetes.

Preventing radial artery occlusion has several benefits, not least of which is preserving this access point for future interventions, according to Dr. Hammami.

RIVARAD is the largest study to evaluate an anticoagulant for the prevention of radial artery occlusion, but it is not the first. Earlier in 2022, a Chinese trial called RESTORE was published in Circulation: Cardiovascular Interventions. In that placebo-controlled study of 382 patients, 7 days of 10 mg rivaroxaban was also linked to a significant reduction in radial artery occlusion at 30 days (3.8% vs. 11.5%; P = .011).

“We don’t know if a higher dose of rivaroxaban would be more effective and equally safe,” said Dr. Hammami, but added that a Canadian trial called CAPITAL RAPTOR will test this premise. In this trial, there is a planned enrollment of 1,800 patients who will be randomized to 15 mg rivaroxaban or standard treatment.

Occlusion risk appears underappreciated

The risk of radial artery occlusion might be underappreciated. According to data cited by Dr. Hammami, only about half of interventionalists in the United States and fewer than 10% outside of the United States routinely assess radial artery patency in conjunction with radial-access PCI. The data from this trial suggest that the risk can be substantially reduced, particularly in high-risk patients, with anticoagulant therapy.

Mount Sinai Medical Center

Agreeing that this is a potentially avoidable complication, Roxanna Mehran, MD, director of interventional cardiovascular research and clinical trials, Icahn School of Medicine at Mount Sinai, New York, called the RIVARAD study “a clinically meaningful trial,” and valuable for identifying risk factors as well as for showing a treatment effect and acceptable safety from a short course of a factor Xa inhibitor.

“This is very important work,” said Dr. Mehran, who praised the quality of the study and the contribution it makes for considering how and when prophylaxis is needed.

Dr. Hammami reported no potential conflicts of interest. Dr. Mehran has financial relationships with more than 25 pharmaceutical companies but none with the sponsor of this trial, which was funded by Philadelphia Pharma, a drug company based in Tunisia.

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

Individuals with type A blood have a 16% higher risk for early onset stroke (EOS) than those with other blood types, new research shows.

Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.

In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.

“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.

The findings were published online in Neurology.
 

Strong association

The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.

Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.

Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.

Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).

Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).

Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.

While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”

“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”

He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.

“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
 

More research needed on younger patients

In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.

“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.

“This work has deepened our understanding of EOS pathophysiology,” they added.

The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”

Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.

“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”

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

Individuals with type A blood have a 16% higher risk for early onset stroke (EOS) than those with other blood types, new research shows.

Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.

In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.

“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.

The findings were published online in Neurology.
 

Strong association

The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.

Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.

Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.

Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).

Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).

Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.

While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”

“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”

He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.

“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
 

More research needed on younger patients

In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.

“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.

“This work has deepened our understanding of EOS pathophysiology,” they added.

The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”

Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.

“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”

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

Individuals with type A blood have a 16% higher risk for early onset stroke (EOS) than those with other blood types, new research shows.

Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.

In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.

“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.

The findings were published online in Neurology.
 

Strong association

The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.

Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.

Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.

Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).

Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).

Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.

While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”

“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”

He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.

“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
 

More research needed on younger patients

In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.

“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.

“This work has deepened our understanding of EOS pathophysiology,” they added.

The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”

Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.

“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

Elderly patients with atrial fibrillation (AF) who are at high risk of bleeding may benefit from a low 15-mg dose of edoxaban, regardless of their frailty status, a subanalysis of the ELDERCARE-AF trial suggests.  

Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than placebo, the authors reported, with no heterogeneity by frailty status.

The subanalysis extends findings of the overall study by teasing out stroke, systemic embolism (SSE) and bleeding events across frailty status among Japanese patients aged 80 and older who were ineligible for oral anticoagulants (OACs) at usual doses.

Findings from the original phase 3 ELDERCARE-AF study were previously reported during the virtual European Society of Cardiology Congress 2020 and simultaneously published in The New England Journal of Medicine. The current study was published online in JAMA Network Open.
 

All frailty levels benefited

Shintaro Akashi, MD, PhD, of National Hospital Organization Hamada Medical Center, Shimane, Japan, and colleagues analyzed data from 944 patients randomly assigned to edoxaban 15 mg or placebo for about 3 years. The mean age of participants was 86.6 years and 57% were women. Baseline characteristics, including history of bleeding, were similar between groups.

Patient physical condition was assessed via five parameters: weight loss, grip strength, walking speed, exhaustion, and activity level. This yielded a frailty score, with one point given for each parameter: 0 indicated robust; 1 or 2, prefrail; and 3 or higher, frail. For this analysis, robust (6.5% of patients) and prefrail (51%) were combined and categorized as nonfrail.

In the placebo group, estimated event rates for stroke or SSE were 7.1% per patient-year among frail patients and 6.1% per patient-year among those who were nonfrail.

In the edoxaban group, SSE occurred at an estimated event rate of 2.5% of frail patients and 1.5% of nonfrail patients (adjusted HR, 1.41).

The edoxaban group “consistently had fewer SSE events regardless of frailty status including each frailty assessment parameter, and there was no heterogeneity between the groups,” the authors wrote, with similar trends for the association of edoxaban 15 mg for each frailty assessment parameter.

However, major bleeding and major or clinically relevant nonmajor (CRNM) bleeding events were both higher with edoxaban, regardless of frailty status.

More specifically, in the placebo group, the incidence of major bleeding was 2.3% in the frail group and 1.5% in the nonfrail group (adjusted HR, 1.48) versus 3.7% and 2.9%, respectively, in the edoxaban group (adjusted HR, 1.04).

In addition, exhaustion was related to a significantly increased risk of major or CRNM bleeding in frail versus nonfrail patients (16.3% vs. 8.4%; adjusted HR, 1.97). The incidences were all higher in the edoxaban group, irrespective of frailty status.

Furthermore, although both all-cause death and the net clinical composite outcome of stroke or SSE occurred more frequently in frail than in nonfrail patients, there was no association with frailty status between the edoxaban and placebo groups.

Findings unrelated to edoxaban were also noteworthy. “Surprisingly, grip strength showed an association with adverse events,” the authors wrote. Among those with lower grip strength, “there was nearly a 3-fold increase in risk of SSE and major bleeding and a more than 16-fold significant increase in risk of death. In addition, in those with exhaustion, there was nearly a 2-fold significant increase in major or CRNM bleeding.”

Thus, they suggested, in this patient population, “an objective physical assessment of grip strength or exhaustion in addition to the well-known walking speed may more accurately estimate the risks of clinical outcomes than the overall frailty assessment.”

Head-to-head comparisons needed

Commenting on the findings, Richard Kovach, MD, chair of the interventional cardiology division at Deborah Heart and Lung Center, Browns Mills, N.J., said, “It is interesting that the lower dose of edoxaban still appears to have a statistically significant reduction in the incidence of stroke in this subgroup of extremely frail elderly patients, and it may be useful in this highly selected subset.

“That being said,” he added, “the major complication of oral anticoagulants – major bleeding – appears to be similar to other NOACs prescribed more frequently in the U.S., specifically rivaroxaban and apixaban.”

“Furthermore, in the U.S., frail or complex patients who are not candidates for oral anticoagulant therapy are much more likely to receive a left atrial appendage closure device such as a Watchman or Amulet in order to avoid the risk of bleeding complications completely,” he said. “Procedural success with these devices is extremely high and procedural complications are extremely low. With both devices, the long-term reduction in stroke risk is equivalent to the use of anticoagulant therapy.

“Clearly, more research is needed to compare the outcomes with edoxaban against other NOACs,” Dr. Kovach concluded. “A head-to-head comparison of low-dose edoxaban versus left atrial appendage closure in this high-risk group would also be of great clinical value.”

The study was funded by Daiichi Sankyo. Two coauthors are employees of and five have received fees from the company. Dr. Kovach has reported no relevant financial relationships.

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

Elderly patients with atrial fibrillation (AF) who are at high risk of bleeding may benefit from a low 15-mg dose of edoxaban, regardless of their frailty status, a subanalysis of the ELDERCARE-AF trial suggests.  

Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than placebo, the authors reported, with no heterogeneity by frailty status.

The subanalysis extends findings of the overall study by teasing out stroke, systemic embolism (SSE) and bleeding events across frailty status among Japanese patients aged 80 and older who were ineligible for oral anticoagulants (OACs) at usual doses.

Findings from the original phase 3 ELDERCARE-AF study were previously reported during the virtual European Society of Cardiology Congress 2020 and simultaneously published in The New England Journal of Medicine. The current study was published online in JAMA Network Open.
 

All frailty levels benefited

Shintaro Akashi, MD, PhD, of National Hospital Organization Hamada Medical Center, Shimane, Japan, and colleagues analyzed data from 944 patients randomly assigned to edoxaban 15 mg or placebo for about 3 years. The mean age of participants was 86.6 years and 57% were women. Baseline characteristics, including history of bleeding, were similar between groups.

Patient physical condition was assessed via five parameters: weight loss, grip strength, walking speed, exhaustion, and activity level. This yielded a frailty score, with one point given for each parameter: 0 indicated robust; 1 or 2, prefrail; and 3 or higher, frail. For this analysis, robust (6.5% of patients) and prefrail (51%) were combined and categorized as nonfrail.

In the placebo group, estimated event rates for stroke or SSE were 7.1% per patient-year among frail patients and 6.1% per patient-year among those who were nonfrail.

In the edoxaban group, SSE occurred at an estimated event rate of 2.5% of frail patients and 1.5% of nonfrail patients (adjusted HR, 1.41).

The edoxaban group “consistently had fewer SSE events regardless of frailty status including each frailty assessment parameter, and there was no heterogeneity between the groups,” the authors wrote, with similar trends for the association of edoxaban 15 mg for each frailty assessment parameter.

However, major bleeding and major or clinically relevant nonmajor (CRNM) bleeding events were both higher with edoxaban, regardless of frailty status.

More specifically, in the placebo group, the incidence of major bleeding was 2.3% in the frail group and 1.5% in the nonfrail group (adjusted HR, 1.48) versus 3.7% and 2.9%, respectively, in the edoxaban group (adjusted HR, 1.04).

In addition, exhaustion was related to a significantly increased risk of major or CRNM bleeding in frail versus nonfrail patients (16.3% vs. 8.4%; adjusted HR, 1.97). The incidences were all higher in the edoxaban group, irrespective of frailty status.

Furthermore, although both all-cause death and the net clinical composite outcome of stroke or SSE occurred more frequently in frail than in nonfrail patients, there was no association with frailty status between the edoxaban and placebo groups.

Findings unrelated to edoxaban were also noteworthy. “Surprisingly, grip strength showed an association with adverse events,” the authors wrote. Among those with lower grip strength, “there was nearly a 3-fold increase in risk of SSE and major bleeding and a more than 16-fold significant increase in risk of death. In addition, in those with exhaustion, there was nearly a 2-fold significant increase in major or CRNM bleeding.”

Thus, they suggested, in this patient population, “an objective physical assessment of grip strength or exhaustion in addition to the well-known walking speed may more accurately estimate the risks of clinical outcomes than the overall frailty assessment.”

Head-to-head comparisons needed

Commenting on the findings, Richard Kovach, MD, chair of the interventional cardiology division at Deborah Heart and Lung Center, Browns Mills, N.J., said, “It is interesting that the lower dose of edoxaban still appears to have a statistically significant reduction in the incidence of stroke in this subgroup of extremely frail elderly patients, and it may be useful in this highly selected subset.

“That being said,” he added, “the major complication of oral anticoagulants – major bleeding – appears to be similar to other NOACs prescribed more frequently in the U.S., specifically rivaroxaban and apixaban.”

“Furthermore, in the U.S., frail or complex patients who are not candidates for oral anticoagulant therapy are much more likely to receive a left atrial appendage closure device such as a Watchman or Amulet in order to avoid the risk of bleeding complications completely,” he said. “Procedural success with these devices is extremely high and procedural complications are extremely low. With both devices, the long-term reduction in stroke risk is equivalent to the use of anticoagulant therapy.

“Clearly, more research is needed to compare the outcomes with edoxaban against other NOACs,” Dr. Kovach concluded. “A head-to-head comparison of low-dose edoxaban versus left atrial appendage closure in this high-risk group would also be of great clinical value.”

The study was funded by Daiichi Sankyo. Two coauthors are employees of and five have received fees from the company. Dr. Kovach has reported no relevant financial relationships.

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

Elderly patients with atrial fibrillation (AF) who are at high risk of bleeding may benefit from a low 15-mg dose of edoxaban, regardless of their frailty status, a subanalysis of the ELDERCARE-AF trial suggests.  

Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than placebo, the authors reported, with no heterogeneity by frailty status.

The subanalysis extends findings of the overall study by teasing out stroke, systemic embolism (SSE) and bleeding events across frailty status among Japanese patients aged 80 and older who were ineligible for oral anticoagulants (OACs) at usual doses.

Findings from the original phase 3 ELDERCARE-AF study were previously reported during the virtual European Society of Cardiology Congress 2020 and simultaneously published in The New England Journal of Medicine. The current study was published online in JAMA Network Open.
 

All frailty levels benefited

Shintaro Akashi, MD, PhD, of National Hospital Organization Hamada Medical Center, Shimane, Japan, and colleagues analyzed data from 944 patients randomly assigned to edoxaban 15 mg or placebo for about 3 years. The mean age of participants was 86.6 years and 57% were women. Baseline characteristics, including history of bleeding, were similar between groups.

Patient physical condition was assessed via five parameters: weight loss, grip strength, walking speed, exhaustion, and activity level. This yielded a frailty score, with one point given for each parameter: 0 indicated robust; 1 or 2, prefrail; and 3 or higher, frail. For this analysis, robust (6.5% of patients) and prefrail (51%) were combined and categorized as nonfrail.

In the placebo group, estimated event rates for stroke or SSE were 7.1% per patient-year among frail patients and 6.1% per patient-year among those who were nonfrail.

In the edoxaban group, SSE occurred at an estimated event rate of 2.5% of frail patients and 1.5% of nonfrail patients (adjusted HR, 1.41).

The edoxaban group “consistently had fewer SSE events regardless of frailty status including each frailty assessment parameter, and there was no heterogeneity between the groups,” the authors wrote, with similar trends for the association of edoxaban 15 mg for each frailty assessment parameter.

However, major bleeding and major or clinically relevant nonmajor (CRNM) bleeding events were both higher with edoxaban, regardless of frailty status.

More specifically, in the placebo group, the incidence of major bleeding was 2.3% in the frail group and 1.5% in the nonfrail group (adjusted HR, 1.48) versus 3.7% and 2.9%, respectively, in the edoxaban group (adjusted HR, 1.04).

In addition, exhaustion was related to a significantly increased risk of major or CRNM bleeding in frail versus nonfrail patients (16.3% vs. 8.4%; adjusted HR, 1.97). The incidences were all higher in the edoxaban group, irrespective of frailty status.

Furthermore, although both all-cause death and the net clinical composite outcome of stroke or SSE occurred more frequently in frail than in nonfrail patients, there was no association with frailty status between the edoxaban and placebo groups.

Findings unrelated to edoxaban were also noteworthy. “Surprisingly, grip strength showed an association with adverse events,” the authors wrote. Among those with lower grip strength, “there was nearly a 3-fold increase in risk of SSE and major bleeding and a more than 16-fold significant increase in risk of death. In addition, in those with exhaustion, there was nearly a 2-fold significant increase in major or CRNM bleeding.”

Thus, they suggested, in this patient population, “an objective physical assessment of grip strength or exhaustion in addition to the well-known walking speed may more accurately estimate the risks of clinical outcomes than the overall frailty assessment.”

Head-to-head comparisons needed

Commenting on the findings, Richard Kovach, MD, chair of the interventional cardiology division at Deborah Heart and Lung Center, Browns Mills, N.J., said, “It is interesting that the lower dose of edoxaban still appears to have a statistically significant reduction in the incidence of stroke in this subgroup of extremely frail elderly patients, and it may be useful in this highly selected subset.

“That being said,” he added, “the major complication of oral anticoagulants – major bleeding – appears to be similar to other NOACs prescribed more frequently in the U.S., specifically rivaroxaban and apixaban.”

“Furthermore, in the U.S., frail or complex patients who are not candidates for oral anticoagulant therapy are much more likely to receive a left atrial appendage closure device such as a Watchman or Amulet in order to avoid the risk of bleeding complications completely,” he said. “Procedural success with these devices is extremely high and procedural complications are extremely low. With both devices, the long-term reduction in stroke risk is equivalent to the use of anticoagulant therapy.

“Clearly, more research is needed to compare the outcomes with edoxaban against other NOACs,” Dr. Kovach concluded. “A head-to-head comparison of low-dose edoxaban versus left atrial appendage closure in this high-risk group would also be of great clinical value.”

The study was funded by Daiichi Sankyo. Two coauthors are employees of and five have received fees from the company. Dr. Kovach has reported no relevant financial relationships.

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

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

Researchers from the Centers for Disease Control and Prevention report that children and teenagers with long COVID have about twice the risk of getting serious outcomes, compared to others without COVID.

Heart inflammation; a blood clot in the lung; or a blood clot in the lower leg, thigh, or pelvis were the most common bad outcomes in a new study. Even though the risk was higher for these and some other serious events, the overall numbers were small.

“Many of these conditions were rare or uncommon among children in this analysis, but even a small increase in these conditions is notable,” a CDC new release stated.

The investigators said their findings stress the importance of COVID-19 vaccination in Americans under the age of 18.

The study was published online in the CDC’s Morbidity and Mortality Weekly Report.
 

Less is known about long COVID in children

Lyudmyla Kompaniyets, PhD, and colleagues noted that most research on long COVID to date has been done in adults, so little information is available about the risks to Americans ages 17 and younger.

To learn more, they compared post–COVID-19 symptoms and conditions between 781,419 children and teenagers with confirmed COVID-19 to another 2,344,257 without COVID-19. They looked at medical claims and laboratory data for these children and teenagers from March 1, 2020, through Jan. 31, 2022, to see who got any of 15 specific outcomes linked to long COVID-19.

Long COVID was defined as a condition where symptoms that last for or begin at least 4 weeks after a COVID-19 diagnosis.

Compared to children with no history of a COVID-19 diagnosis, the long COVID-19 group was 101% more likely to have an acute pulmonary embolism, 99% more likely to have myocarditis or cardiomyopathy, 87% more likely to have a venous thromboembolic event, 32% more likely to have acute and unspecified renal failure, and 23% more likely to have type 1 diabetes.

“This report points to the fact that the risks of COVID infection itself, both in terms of the acute effects, MIS-C [multisystem inflammatory syndrome in children], as well as the long-term effects, are real, are concerning, and are potentially very serious,” said Stuart Berger, MD, chair of the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery.

“The message that we should take away from this is that we should be very keen on all the methods of prevention for COVID, especially the vaccine,” said Dr. Berger, chief of cardiology in the department of pediatrics at Northwestern University in Chicago.


 

A ‘wake-up call’

The study findings are “sobering” and are “a reminder of the seriousness of COVID infection,” says Gregory Poland, MD, an infectious disease expert at the Mayo Clinic in Rochester, Minn.

“When you look in particular at the more serious complications from COVID in this young age group, those are life-altering complications that will have consequences and ramifications throughout their lives,” he said.

“I would take this as a serious wake-up call to parents [at a time when] the immunization rates in younger children are so pitifully low,” Dr. Poland said.
 

Still early days

The study is suggestive but not definitive, said Peter Katona, MD, professor of medicine and infectious diseases expert at the UCLA Fielding School of Public Health.

It’s still too early to draw conclusions about long COVID, including in children, because many questions remain, he said: Should long COVID be defined as symptoms at 1 month or 3 months after infection? How do you define brain fog?

Dr. Katona and colleagues are studying long COVID intervention among students at UCLA to answer some of these questions, including the incidence and effect of early intervention.

The study had “at least seven limitations,” the researchers noted. Among them was the use of medical claims data that noted long COVID outcomes but not how severe they were; some people in the no COVID group might have had the illness but not been diagnosed; and the researchers did not adjust for vaccination status.

Dr. Poland noted that the study was done during surges in COVID variants including Delta and Omicron. In other words, any long COVID effects linked to more recent variants such as BA.5 or BA.2.75 are unknown.

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

Researchers from the Centers for Disease Control and Prevention report that children and teenagers with long COVID have about twice the risk of getting serious outcomes, compared to others without COVID.

Heart inflammation; a blood clot in the lung; or a blood clot in the lower leg, thigh, or pelvis were the most common bad outcomes in a new study. Even though the risk was higher for these and some other serious events, the overall numbers were small.

“Many of these conditions were rare or uncommon among children in this analysis, but even a small increase in these conditions is notable,” a CDC new release stated.

The investigators said their findings stress the importance of COVID-19 vaccination in Americans under the age of 18.

The study was published online in the CDC’s Morbidity and Mortality Weekly Report.
 

Less is known about long COVID in children

Lyudmyla Kompaniyets, PhD, and colleagues noted that most research on long COVID to date has been done in adults, so little information is available about the risks to Americans ages 17 and younger.

To learn more, they compared post–COVID-19 symptoms and conditions between 781,419 children and teenagers with confirmed COVID-19 to another 2,344,257 without COVID-19. They looked at medical claims and laboratory data for these children and teenagers from March 1, 2020, through Jan. 31, 2022, to see who got any of 15 specific outcomes linked to long COVID-19.

Long COVID was defined as a condition where symptoms that last for or begin at least 4 weeks after a COVID-19 diagnosis.

Compared to children with no history of a COVID-19 diagnosis, the long COVID-19 group was 101% more likely to have an acute pulmonary embolism, 99% more likely to have myocarditis or cardiomyopathy, 87% more likely to have a venous thromboembolic event, 32% more likely to have acute and unspecified renal failure, and 23% more likely to have type 1 diabetes.

“This report points to the fact that the risks of COVID infection itself, both in terms of the acute effects, MIS-C [multisystem inflammatory syndrome in children], as well as the long-term effects, are real, are concerning, and are potentially very serious,” said Stuart Berger, MD, chair of the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery.

“The message that we should take away from this is that we should be very keen on all the methods of prevention for COVID, especially the vaccine,” said Dr. Berger, chief of cardiology in the department of pediatrics at Northwestern University in Chicago.


 

A ‘wake-up call’

The study findings are “sobering” and are “a reminder of the seriousness of COVID infection,” says Gregory Poland, MD, an infectious disease expert at the Mayo Clinic in Rochester, Minn.

“When you look in particular at the more serious complications from COVID in this young age group, those are life-altering complications that will have consequences and ramifications throughout their lives,” he said.

“I would take this as a serious wake-up call to parents [at a time when] the immunization rates in younger children are so pitifully low,” Dr. Poland said.
 

Still early days

The study is suggestive but not definitive, said Peter Katona, MD, professor of medicine and infectious diseases expert at the UCLA Fielding School of Public Health.

It’s still too early to draw conclusions about long COVID, including in children, because many questions remain, he said: Should long COVID be defined as symptoms at 1 month or 3 months after infection? How do you define brain fog?

Dr. Katona and colleagues are studying long COVID intervention among students at UCLA to answer some of these questions, including the incidence and effect of early intervention.

The study had “at least seven limitations,” the researchers noted. Among them was the use of medical claims data that noted long COVID outcomes but not how severe they were; some people in the no COVID group might have had the illness but not been diagnosed; and the researchers did not adjust for vaccination status.

Dr. Poland noted that the study was done during surges in COVID variants including Delta and Omicron. In other words, any long COVID effects linked to more recent variants such as BA.5 or BA.2.75 are unknown.

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

Researchers from the Centers for Disease Control and Prevention report that children and teenagers with long COVID have about twice the risk of getting serious outcomes, compared to others without COVID.

Heart inflammation; a blood clot in the lung; or a blood clot in the lower leg, thigh, or pelvis were the most common bad outcomes in a new study. Even though the risk was higher for these and some other serious events, the overall numbers were small.

“Many of these conditions were rare or uncommon among children in this analysis, but even a small increase in these conditions is notable,” a CDC new release stated.

The investigators said their findings stress the importance of COVID-19 vaccination in Americans under the age of 18.

The study was published online in the CDC’s Morbidity and Mortality Weekly Report.
 

Less is known about long COVID in children

Lyudmyla Kompaniyets, PhD, and colleagues noted that most research on long COVID to date has been done in adults, so little information is available about the risks to Americans ages 17 and younger.

To learn more, they compared post–COVID-19 symptoms and conditions between 781,419 children and teenagers with confirmed COVID-19 to another 2,344,257 without COVID-19. They looked at medical claims and laboratory data for these children and teenagers from March 1, 2020, through Jan. 31, 2022, to see who got any of 15 specific outcomes linked to long COVID-19.

Long COVID was defined as a condition where symptoms that last for or begin at least 4 weeks after a COVID-19 diagnosis.

Compared to children with no history of a COVID-19 diagnosis, the long COVID-19 group was 101% more likely to have an acute pulmonary embolism, 99% more likely to have myocarditis or cardiomyopathy, 87% more likely to have a venous thromboembolic event, 32% more likely to have acute and unspecified renal failure, and 23% more likely to have type 1 diabetes.

“This report points to the fact that the risks of COVID infection itself, both in terms of the acute effects, MIS-C [multisystem inflammatory syndrome in children], as well as the long-term effects, are real, are concerning, and are potentially very serious,” said Stuart Berger, MD, chair of the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery.

“The message that we should take away from this is that we should be very keen on all the methods of prevention for COVID, especially the vaccine,” said Dr. Berger, chief of cardiology in the department of pediatrics at Northwestern University in Chicago.


 

A ‘wake-up call’

The study findings are “sobering” and are “a reminder of the seriousness of COVID infection,” says Gregory Poland, MD, an infectious disease expert at the Mayo Clinic in Rochester, Minn.

“When you look in particular at the more serious complications from COVID in this young age group, those are life-altering complications that will have consequences and ramifications throughout their lives,” he said.

“I would take this as a serious wake-up call to parents [at a time when] the immunization rates in younger children are so pitifully low,” Dr. Poland said.
 

Still early days

The study is suggestive but not definitive, said Peter Katona, MD, professor of medicine and infectious diseases expert at the UCLA Fielding School of Public Health.

It’s still too early to draw conclusions about long COVID, including in children, because many questions remain, he said: Should long COVID be defined as symptoms at 1 month or 3 months after infection? How do you define brain fog?

Dr. Katona and colleagues are studying long COVID intervention among students at UCLA to answer some of these questions, including the incidence and effect of early intervention.

The study had “at least seven limitations,” the researchers noted. Among them was the use of medical claims data that noted long COVID outcomes but not how severe they were; some people in the no COVID group might have had the illness but not been diagnosed; and the researchers did not adjust for vaccination status.

Dr. Poland noted that the study was done during surges in COVID variants including Delta and Omicron. In other words, any long COVID effects linked to more recent variants such as BA.5 or BA.2.75 are unknown.

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

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.


 

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.


 

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.