Stroke

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

Although not quite meeting its primary endpoint, a new trial (TESLA) has added to evidence suggesting that patients with large ischemic strokes who have a significant amount of brain tissue damage may still benefit from thrombectomy. 

And a new meta-analysis (MAGNA) of previous studies in a similar population has provided more detailed estimates of the treatment benefit of thrombectomy in these patients. 

The TESLA trial, which included patients with large-core infarcts (ASPECTS score 2-5) within 24 hours of symptom onset, showed encouraging trends towards a benefit with thrombectomy for the primary outcome of 90-day utility-weighted scores on the modified Rankin scale (mRS), but this did not reach the prespecified Bayesian superiority threshold.

Several secondary efficacy endpoints also showed suggestions of benefits with thrombectomy.

“The interventional group had higher mean or average utility-weighted mRS scores than the control group which means that their functional recovery at 90 days was trending for better outcome and less disability,” lead TESLA investigator, Osama Zaidat, MD, neuroscience & stroke director at Mercy St. Vincent Medical Center, Toledo, Ohio, said in an interview. “They also showed better neurological improvement and a higher chance of achieving a good outcome (mRS 0-3).”

These patients with large-core infarct strokes were not included in the initial trials of endovascular therapy in patients presenting in the late time window, up to 24 hours, as it was thought they would not benefit. However, three recent trials (RESCUE-Japan LIMIT; ANGEL ASPECT; and SELECT 2) have shown that patients with large core infarcts can still benefit from endovascular thrombectomy.

While these three previous trials used sophisticated imaging techniques (MRI or CT perfusion) to select patients, and restricted patients included to those with an ASPECTS score of 3-5, the TESLA study had a more pragmatic design, using just noncontrast CT scan evaluation without advanced imaging to select patients, and extending the inclusion criteria to patients with an ASPECTS score of 2.

“Noncontrast CT scans are available at all stroke centers so this study is more practical, highly generalizable, and more applicable globally,” Dr. Zaidat commented.

“However, our results suggest that when using noncontrast CT only to select patients, the gain or treatment effect of thrombectomy seems to be smaller than when using sophisticated advanced imaging to make the decision to go for thrombectomy or not as in the other trials,” he added.

The TESLA trial results were presented at the recent European Stroke Organisation Conference, held in Munich.

The study included 300 stroke patients with anterior circulation large‐vessel occlusion (NIHSS of 6 or more) with a large‐core infarction (investigator read ASPECTS Score 2-5), selected on the basis of noncontrast CT scan, who were randomized to undergo intra-arterial thrombectomy or best medical management (control) up to 24 hours from last known well.

The trial had a Bayesian probabilities design, with a primary endpoint of the 90-day utility-weighted mRS (uw-mRS), a relatively new patient-centered outcome used in stroke trials, which includes a quality-of-life measurement. Utilities represent preferences for mRS health states and range from 0 (death) to 1 (perfect health), so in contrast to the traditional mRS scores, a higher uw-mRS score is better.

The 90-day uw-MRS scores were 2.93 in the thrombectomy group vs. 2.27 in the control group.  

The Bayesian probability of thrombectomy superiority was 0.957, which Dr. Zaidat said was “similar” to a P value of .043, but this was less than the prespecified superiority probability of > .975 to declare efficacy.

A separate analysis in a population of patients selected by core-lab read noncontrast CT scan, showed a Bayesian probability of benefit with thrombectomy of 0.98, “similar” to one-sided P value of .02. 

In terms of secondary endpoints, there were also some encouraging trends, including a suggestion of benefit in the 90-day mRS ordinal shift (odds ratio 1.40; P = .06). 

The number of patients achieving functional independence (mRS 0-2) was 14% in the thrombectomy groups vs. 9% in the control group (P = .09); and a good functional outcome (mRS 0-3) was achieved in 30% of thrombectomy patients vs. 20% of those in the control group (P = .03).  

Major neurological improvement (NIHSS scale of 0-2 or improvement of 8 points or more) occurred in 26% of thrombectomy patients vs. 13% of controls (P = .0008).

Quality of life, measured by the EuroQol 5-Dimension 5-Level survey, also showed a trend towards improvement in the thrombectomy group with mean scores of 53 vs. 46 (P = .058).  

In terms of safety, all-cause mortality was similar in the two groups (35% thrombectomy and 33% control) and symptomatic intracerebral hemmorhage (ICH) occurred in 3.97% of thrombectomy vs. 1.34% of control patients (relative risk, 2.96).

“Cost-effective analysis and additional subgroup studies will provide more insight about the training needs to read the CT scan and if there is any value to treat patients with an ASPECTS score of 2,” Dr. Zaidat concluded.

“Larger pooled analysis will also be very useful in understanding the threshold of brain volume with irreversible damage beyond which thrombectomy wouldn’t be helpful,” he added.
 

Meta-analysis of previous studies: MAGNA

Another presentation at the ESOC meeting reported an individual patient data meta-analysis (MAGNA) of the three previous trials suggesting benefit of thrombectomy in patients with large-core ischemic strokes of the anterior circulation up to 24 hours of last known well.

The RESCUE Japan Limit trial was conducted in Japan; the SELECT-2 trial in North America, Europe, Australia, and New Zealand; and the ANGEL ASPECT trial in China.

In total, the meta-analysis included 1,009 patients, half of whom received thrombectomy and half received medical management only.

Results showed that in the whole population in the three trials, the use of thrombectomy improved functional outcomes, with an adjusted odds ratio of 1.78 (P < .001).

Functional independence (mRS 0-2) was also increased (23% vs. 9%; adjusted risk ratio, 2.62; P < .001); as was independent ambulation (mRS, 0-3; 41% vs. 24%; aRR, 1.76; P < .001).

But early neurological worsening was more frequent with thrombectomy (aRR 1.42, 1.09-1.84, P = .010).

No difference in mortality was identified between thrombectomy (27%) and medical management (28%) or in rates of symptomatic ICH (1.8% thrombectomy vs. 1.6% medical management). 

“The results from the previously published large-core trials and from this pooled dataset provide unequivocal evidence on the efficacy and safety of endovascular thrombectomy in patients with large-core infarcts,” lead author of the MAGNA meta-analysis, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center, affiliate of Case Western Reserve University in Cleveland, concluded.

“The benefit persists across the spectrum of age, clinical severity, and time, with clear benefit up to an estimated ischemic core volume of 150 mL,” he added. “We have great hopes that these results will lead to more patients being treated and achieving improved functional outcomes.”

On how the TESLA results fit in with the previous three trials, Dr. Sarraj pointed out to this news organization that the TESLA trial was conducted in the United States and enrolled patients based on ASPECTS 2-5 on noncontrast CT.

“The primary outcome for intention-to-treat analysis did not reach the prespecified threshold for efficacy, but the results were largely in the same direction as shown in SELECT2, ANGEL ASPECT, and RESCUE Japan Limit,” he said. “These findings further emphasize the efficacy and safety of thrombectomy in patients with large ischemic core, at the same time reinforcing the need to provide results from pooled data from all large-core trials.”

He noted that results from two further trials of thrombectomy in large core strokes, TENSION and LASTE – both of which have now been stopped early because of the positive findings from the previous studies – are expected soon, and the MAGNA meta-analysis will be updated to include data from all six trials. 

“This will increase the accuracy of the estimation of the treatment effect and will give even more power to look further into the details related to subgroups and selection imaging modalities,” Dr. Sarraj added.

The research team hopes that this joint effort will eventually set the pathway for selection algorithms and treatment boundaries in patients with large-vessel occlusion.

TESLA was an investigator-initiated study funded by unrestricted grants from Cerenovus, Penumbra, Medtronic, Stryker, and Genentech. Dr. Zaidat is a consultant for Stryker, Cerenovus, Penumbra, and Medtronic.

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

Although not quite meeting its primary endpoint, a new trial (TESLA) has added to evidence suggesting that patients with large ischemic strokes who have a significant amount of brain tissue damage may still benefit from thrombectomy. 

And a new meta-analysis (MAGNA) of previous studies in a similar population has provided more detailed estimates of the treatment benefit of thrombectomy in these patients. 

The TESLA trial, which included patients with large-core infarcts (ASPECTS score 2-5) within 24 hours of symptom onset, showed encouraging trends towards a benefit with thrombectomy for the primary outcome of 90-day utility-weighted scores on the modified Rankin scale (mRS), but this did not reach the prespecified Bayesian superiority threshold.

Several secondary efficacy endpoints also showed suggestions of benefits with thrombectomy.

“The interventional group had higher mean or average utility-weighted mRS scores than the control group which means that their functional recovery at 90 days was trending for better outcome and less disability,” lead TESLA investigator, Osama Zaidat, MD, neuroscience & stroke director at Mercy St. Vincent Medical Center, Toledo, Ohio, said in an interview. “They also showed better neurological improvement and a higher chance of achieving a good outcome (mRS 0-3).”

These patients with large-core infarct strokes were not included in the initial trials of endovascular therapy in patients presenting in the late time window, up to 24 hours, as it was thought they would not benefit. However, three recent trials (RESCUE-Japan LIMIT; ANGEL ASPECT; and SELECT 2) have shown that patients with large core infarcts can still benefit from endovascular thrombectomy.

While these three previous trials used sophisticated imaging techniques (MRI or CT perfusion) to select patients, and restricted patients included to those with an ASPECTS score of 3-5, the TESLA study had a more pragmatic design, using just noncontrast CT scan evaluation without advanced imaging to select patients, and extending the inclusion criteria to patients with an ASPECTS score of 2.

“Noncontrast CT scans are available at all stroke centers so this study is more practical, highly generalizable, and more applicable globally,” Dr. Zaidat commented.

“However, our results suggest that when using noncontrast CT only to select patients, the gain or treatment effect of thrombectomy seems to be smaller than when using sophisticated advanced imaging to make the decision to go for thrombectomy or not as in the other trials,” he added.

The TESLA trial results were presented at the recent European Stroke Organisation Conference, held in Munich.

The study included 300 stroke patients with anterior circulation large‐vessel occlusion (NIHSS of 6 or more) with a large‐core infarction (investigator read ASPECTS Score 2-5), selected on the basis of noncontrast CT scan, who were randomized to undergo intra-arterial thrombectomy or best medical management (control) up to 24 hours from last known well.

The trial had a Bayesian probabilities design, with a primary endpoint of the 90-day utility-weighted mRS (uw-mRS), a relatively new patient-centered outcome used in stroke trials, which includes a quality-of-life measurement. Utilities represent preferences for mRS health states and range from 0 (death) to 1 (perfect health), so in contrast to the traditional mRS scores, a higher uw-mRS score is better.

The 90-day uw-MRS scores were 2.93 in the thrombectomy group vs. 2.27 in the control group.  

The Bayesian probability of thrombectomy superiority was 0.957, which Dr. Zaidat said was “similar” to a P value of .043, but this was less than the prespecified superiority probability of > .975 to declare efficacy.

A separate analysis in a population of patients selected by core-lab read noncontrast CT scan, showed a Bayesian probability of benefit with thrombectomy of 0.98, “similar” to one-sided P value of .02. 

In terms of secondary endpoints, there were also some encouraging trends, including a suggestion of benefit in the 90-day mRS ordinal shift (odds ratio 1.40; P = .06). 

The number of patients achieving functional independence (mRS 0-2) was 14% in the thrombectomy groups vs. 9% in the control group (P = .09); and a good functional outcome (mRS 0-3) was achieved in 30% of thrombectomy patients vs. 20% of those in the control group (P = .03).  

Major neurological improvement (NIHSS scale of 0-2 or improvement of 8 points or more) occurred in 26% of thrombectomy patients vs. 13% of controls (P = .0008).

Quality of life, measured by the EuroQol 5-Dimension 5-Level survey, also showed a trend towards improvement in the thrombectomy group with mean scores of 53 vs. 46 (P = .058).  

In terms of safety, all-cause mortality was similar in the two groups (35% thrombectomy and 33% control) and symptomatic intracerebral hemmorhage (ICH) occurred in 3.97% of thrombectomy vs. 1.34% of control patients (relative risk, 2.96).

“Cost-effective analysis and additional subgroup studies will provide more insight about the training needs to read the CT scan and if there is any value to treat patients with an ASPECTS score of 2,” Dr. Zaidat concluded.

“Larger pooled analysis will also be very useful in understanding the threshold of brain volume with irreversible damage beyond which thrombectomy wouldn’t be helpful,” he added.
 

Meta-analysis of previous studies: MAGNA

Another presentation at the ESOC meeting reported an individual patient data meta-analysis (MAGNA) of the three previous trials suggesting benefit of thrombectomy in patients with large-core ischemic strokes of the anterior circulation up to 24 hours of last known well.

The RESCUE Japan Limit trial was conducted in Japan; the SELECT-2 trial in North America, Europe, Australia, and New Zealand; and the ANGEL ASPECT trial in China.

In total, the meta-analysis included 1,009 patients, half of whom received thrombectomy and half received medical management only.

Results showed that in the whole population in the three trials, the use of thrombectomy improved functional outcomes, with an adjusted odds ratio of 1.78 (P < .001).

Functional independence (mRS 0-2) was also increased (23% vs. 9%; adjusted risk ratio, 2.62; P < .001); as was independent ambulation (mRS, 0-3; 41% vs. 24%; aRR, 1.76; P < .001).

But early neurological worsening was more frequent with thrombectomy (aRR 1.42, 1.09-1.84, P = .010).

No difference in mortality was identified between thrombectomy (27%) and medical management (28%) or in rates of symptomatic ICH (1.8% thrombectomy vs. 1.6% medical management). 

“The results from the previously published large-core trials and from this pooled dataset provide unequivocal evidence on the efficacy and safety of endovascular thrombectomy in patients with large-core infarcts,” lead author of the MAGNA meta-analysis, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center, affiliate of Case Western Reserve University in Cleveland, concluded.

“The benefit persists across the spectrum of age, clinical severity, and time, with clear benefit up to an estimated ischemic core volume of 150 mL,” he added. “We have great hopes that these results will lead to more patients being treated and achieving improved functional outcomes.”

On how the TESLA results fit in with the previous three trials, Dr. Sarraj pointed out to this news organization that the TESLA trial was conducted in the United States and enrolled patients based on ASPECTS 2-5 on noncontrast CT.

“The primary outcome for intention-to-treat analysis did not reach the prespecified threshold for efficacy, but the results were largely in the same direction as shown in SELECT2, ANGEL ASPECT, and RESCUE Japan Limit,” he said. “These findings further emphasize the efficacy and safety of thrombectomy in patients with large ischemic core, at the same time reinforcing the need to provide results from pooled data from all large-core trials.”

He noted that results from two further trials of thrombectomy in large core strokes, TENSION and LASTE – both of which have now been stopped early because of the positive findings from the previous studies – are expected soon, and the MAGNA meta-analysis will be updated to include data from all six trials. 

“This will increase the accuracy of the estimation of the treatment effect and will give even more power to look further into the details related to subgroups and selection imaging modalities,” Dr. Sarraj added.

The research team hopes that this joint effort will eventually set the pathway for selection algorithms and treatment boundaries in patients with large-vessel occlusion.

TESLA was an investigator-initiated study funded by unrestricted grants from Cerenovus, Penumbra, Medtronic, Stryker, and Genentech. Dr. Zaidat is a consultant for Stryker, Cerenovus, Penumbra, and Medtronic.

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

Although not quite meeting its primary endpoint, a new trial (TESLA) has added to evidence suggesting that patients with large ischemic strokes who have a significant amount of brain tissue damage may still benefit from thrombectomy. 

And a new meta-analysis (MAGNA) of previous studies in a similar population has provided more detailed estimates of the treatment benefit of thrombectomy in these patients. 

The TESLA trial, which included patients with large-core infarcts (ASPECTS score 2-5) within 24 hours of symptom onset, showed encouraging trends towards a benefit with thrombectomy for the primary outcome of 90-day utility-weighted scores on the modified Rankin scale (mRS), but this did not reach the prespecified Bayesian superiority threshold.

Several secondary efficacy endpoints also showed suggestions of benefits with thrombectomy.

“The interventional group had higher mean or average utility-weighted mRS scores than the control group which means that their functional recovery at 90 days was trending for better outcome and less disability,” lead TESLA investigator, Osama Zaidat, MD, neuroscience & stroke director at Mercy St. Vincent Medical Center, Toledo, Ohio, said in an interview. “They also showed better neurological improvement and a higher chance of achieving a good outcome (mRS 0-3).”

These patients with large-core infarct strokes were not included in the initial trials of endovascular therapy in patients presenting in the late time window, up to 24 hours, as it was thought they would not benefit. However, three recent trials (RESCUE-Japan LIMIT; ANGEL ASPECT; and SELECT 2) have shown that patients with large core infarcts can still benefit from endovascular thrombectomy.

While these three previous trials used sophisticated imaging techniques (MRI or CT perfusion) to select patients, and restricted patients included to those with an ASPECTS score of 3-5, the TESLA study had a more pragmatic design, using just noncontrast CT scan evaluation without advanced imaging to select patients, and extending the inclusion criteria to patients with an ASPECTS score of 2.

“Noncontrast CT scans are available at all stroke centers so this study is more practical, highly generalizable, and more applicable globally,” Dr. Zaidat commented.

“However, our results suggest that when using noncontrast CT only to select patients, the gain or treatment effect of thrombectomy seems to be smaller than when using sophisticated advanced imaging to make the decision to go for thrombectomy or not as in the other trials,” he added.

The TESLA trial results were presented at the recent European Stroke Organisation Conference, held in Munich.

The study included 300 stroke patients with anterior circulation large‐vessel occlusion (NIHSS of 6 or more) with a large‐core infarction (investigator read ASPECTS Score 2-5), selected on the basis of noncontrast CT scan, who were randomized to undergo intra-arterial thrombectomy or best medical management (control) up to 24 hours from last known well.

The trial had a Bayesian probabilities design, with a primary endpoint of the 90-day utility-weighted mRS (uw-mRS), a relatively new patient-centered outcome used in stroke trials, which includes a quality-of-life measurement. Utilities represent preferences for mRS health states and range from 0 (death) to 1 (perfect health), so in contrast to the traditional mRS scores, a higher uw-mRS score is better.

The 90-day uw-MRS scores were 2.93 in the thrombectomy group vs. 2.27 in the control group.  

The Bayesian probability of thrombectomy superiority was 0.957, which Dr. Zaidat said was “similar” to a P value of .043, but this was less than the prespecified superiority probability of > .975 to declare efficacy.

A separate analysis in a population of patients selected by core-lab read noncontrast CT scan, showed a Bayesian probability of benefit with thrombectomy of 0.98, “similar” to one-sided P value of .02. 

In terms of secondary endpoints, there were also some encouraging trends, including a suggestion of benefit in the 90-day mRS ordinal shift (odds ratio 1.40; P = .06). 

The number of patients achieving functional independence (mRS 0-2) was 14% in the thrombectomy groups vs. 9% in the control group (P = .09); and a good functional outcome (mRS 0-3) was achieved in 30% of thrombectomy patients vs. 20% of those in the control group (P = .03).  

Major neurological improvement (NIHSS scale of 0-2 or improvement of 8 points or more) occurred in 26% of thrombectomy patients vs. 13% of controls (P = .0008).

Quality of life, measured by the EuroQol 5-Dimension 5-Level survey, also showed a trend towards improvement in the thrombectomy group with mean scores of 53 vs. 46 (P = .058).  

In terms of safety, all-cause mortality was similar in the two groups (35% thrombectomy and 33% control) and symptomatic intracerebral hemmorhage (ICH) occurred in 3.97% of thrombectomy vs. 1.34% of control patients (relative risk, 2.96).

“Cost-effective analysis and additional subgroup studies will provide more insight about the training needs to read the CT scan and if there is any value to treat patients with an ASPECTS score of 2,” Dr. Zaidat concluded.

“Larger pooled analysis will also be very useful in understanding the threshold of brain volume with irreversible damage beyond which thrombectomy wouldn’t be helpful,” he added.
 

Meta-analysis of previous studies: MAGNA

Another presentation at the ESOC meeting reported an individual patient data meta-analysis (MAGNA) of the three previous trials suggesting benefit of thrombectomy in patients with large-core ischemic strokes of the anterior circulation up to 24 hours of last known well.

The RESCUE Japan Limit trial was conducted in Japan; the SELECT-2 trial in North America, Europe, Australia, and New Zealand; and the ANGEL ASPECT trial in China.

In total, the meta-analysis included 1,009 patients, half of whom received thrombectomy and half received medical management only.

Results showed that in the whole population in the three trials, the use of thrombectomy improved functional outcomes, with an adjusted odds ratio of 1.78 (P < .001).

Functional independence (mRS 0-2) was also increased (23% vs. 9%; adjusted risk ratio, 2.62; P < .001); as was independent ambulation (mRS, 0-3; 41% vs. 24%; aRR, 1.76; P < .001).

But early neurological worsening was more frequent with thrombectomy (aRR 1.42, 1.09-1.84, P = .010).

No difference in mortality was identified between thrombectomy (27%) and medical management (28%) or in rates of symptomatic ICH (1.8% thrombectomy vs. 1.6% medical management). 

“The results from the previously published large-core trials and from this pooled dataset provide unequivocal evidence on the efficacy and safety of endovascular thrombectomy in patients with large-core infarcts,” lead author of the MAGNA meta-analysis, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center, affiliate of Case Western Reserve University in Cleveland, concluded.

“The benefit persists across the spectrum of age, clinical severity, and time, with clear benefit up to an estimated ischemic core volume of 150 mL,” he added. “We have great hopes that these results will lead to more patients being treated and achieving improved functional outcomes.”

On how the TESLA results fit in with the previous three trials, Dr. Sarraj pointed out to this news organization that the TESLA trial was conducted in the United States and enrolled patients based on ASPECTS 2-5 on noncontrast CT.

“The primary outcome for intention-to-treat analysis did not reach the prespecified threshold for efficacy, but the results were largely in the same direction as shown in SELECT2, ANGEL ASPECT, and RESCUE Japan Limit,” he said. “These findings further emphasize the efficacy and safety of thrombectomy in patients with large ischemic core, at the same time reinforcing the need to provide results from pooled data from all large-core trials.”

He noted that results from two further trials of thrombectomy in large core strokes, TENSION and LASTE – both of which have now been stopped early because of the positive findings from the previous studies – are expected soon, and the MAGNA meta-analysis will be updated to include data from all six trials. 

“This will increase the accuracy of the estimation of the treatment effect and will give even more power to look further into the details related to subgroups and selection imaging modalities,” Dr. Sarraj added.

The research team hopes that this joint effort will eventually set the pathway for selection algorithms and treatment boundaries in patients with large-vessel occlusion.

TESLA was an investigator-initiated study funded by unrestricted grants from Cerenovus, Penumbra, Medtronic, Stryker, and Genentech. Dr. Zaidat is a consultant for Stryker, Cerenovus, Penumbra, and Medtronic.

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

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

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

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

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

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH, GERMANY – Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1,000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented at the annual meeting of the European Stroke Organisation Conference.

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology, Weill Cornell Medicine, New York.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be caused by the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Dr. Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Dr. Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”
 

Similar results

Approached for comment, session cochair Robin Lemmens, MD, PhD, a neurologist in the department of neurosciences, UZ Leuven (Belgium), noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He said, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Dr. Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session cochair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he said in an interview.

Dr. Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.
 

Heterogeneous etiologies?

Dr. Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the United States and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score of 4 or less, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 greater than 5,000mcV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels greater than 250 pg/mL, or a left atrium diameter of at least 3 cm/m².

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Dr. Kamel reported that, in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three-quarters of the participants were White; 21.1% were Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio of 1.00 (95% confidence interval, 0.64-1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% versus 4.4% (HR, 0.92; 95% CI, 0.59-1.44), and recurrent stroke of any type or death from any cause, at 7.3% versus 6.8% (HR, 1.08; 95% CI, 0.76-1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29-3.51), and were similar for all-cause mortality, at 1.8% versus 1.2% (HR, 1.53; 95% CI, 0.63-3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% versus 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, codirector of the Comprehensive Stroke Center at Brown University, Providence, R.I., added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low [atrial fibrillation] burden or incidental [atrial fibrillation] after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NTproBNP assays was provided by Roche. No relevant financial relationships were reported.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AFib) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel (Switzerland), commented in an interview.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Imaging-based assessment of stroke severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dr. Dawson explained. “This is very straightforward, as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AFib, and now we have a large study showing we can treat them with a DOAC early, and this appears to be safe and it appears also be more effective in terms of outcome events,” Dr. Tsivgoulis said.

But he highlighted one important caveat: The majority of patients had mild or moderate stroke.

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