Susan Hughes

BASEL, SWITZERLAND — The anti-inflammatory agent colchicine failed to show significant benefit in the treatment of patients with non-cardioembolic ischemic stroke in the primary analysis of the CONVINCE trial. However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.

“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.

The results were presented at the European Stroke Organization Conference (ESOC) 2024.

Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.

Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.

The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.

Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.

Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.

The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.

Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.

Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.

In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
 

A Novel Target for Stroke Treatment

In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.

In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).

“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.

He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.

“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.

Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.

“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.

“I think we have a new tool, but of course we need further trials to confirm that,” she added.

The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — The anti-inflammatory agent colchicine failed to show significant benefit in the treatment of patients with non-cardioembolic ischemic stroke in the primary analysis of the CONVINCE trial. However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.

“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.

The results were presented at the European Stroke Organization Conference (ESOC) 2024.

Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.

Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.

The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.

Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.

Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.

The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.

Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.

Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.

In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
 

A Novel Target for Stroke Treatment

In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.

In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).

“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.

He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.

“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.

Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.

“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.

“I think we have a new tool, but of course we need further trials to confirm that,” she added.

The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — The anti-inflammatory agent colchicine failed to show significant benefit in the treatment of patients with non-cardioembolic ischemic stroke in the primary analysis of the CONVINCE trial. However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.

“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.

The results were presented at the European Stroke Organization Conference (ESOC) 2024.

Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.

Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.

The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.

Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.

Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.

The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.

Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.

Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.

In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
 

A Novel Target for Stroke Treatment

In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.

In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).

“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.

He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.

“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.

Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.

“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.

“I think we have a new tool, but of course we need further trials to confirm that,” she added.

The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.

The observational cluster study showed that patients treated in hospitals that followed the guideline-recommended practice of rapidly reducing BP did no better — and actually showed a trend toward worse outcomes — than those treated in hospitals that did not lower BP, even though this meant fewer patient received thrombolysis. 

“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands. 

“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.

The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology. 
 

Guidelines Without Evidence?

Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines. 

Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital. 

“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted. 

However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.

For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy. 

Baseline characteristics of participants in the two groups were similar. 

Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68). 

This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering). 

Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
 

Reconsider Guidelines?

These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.

“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said. 

But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.

Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients. 

“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added. 

Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis. 

“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
 

Caution Advised

Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”

Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding. 

“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said. 

In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”

But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.

He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy. 

“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said. 

“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.

INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed. 

“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said. 

The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.

The observational cluster study showed that patients treated in hospitals that followed the guideline-recommended practice of rapidly reducing BP did no better — and actually showed a trend toward worse outcomes — than those treated in hospitals that did not lower BP, even though this meant fewer patient received thrombolysis. 

“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands. 

“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.

The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology. 
 

Guidelines Without Evidence?

Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines. 

Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital. 

“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted. 

However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.

For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy. 

Baseline characteristics of participants in the two groups were similar. 

Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68). 

This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering). 

Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
 

Reconsider Guidelines?

These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.

“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said. 

But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.

Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients. 

“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added. 

Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis. 

“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
 

Caution Advised

Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”

Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding. 

“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said. 

In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”

But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.

He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy. 

“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said. 

“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.

INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed. 

“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said. 

The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.

The observational cluster study showed that patients treated in hospitals that followed the guideline-recommended practice of rapidly reducing BP did no better — and actually showed a trend toward worse outcomes — than those treated in hospitals that did not lower BP, even though this meant fewer patient received thrombolysis. 

“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands. 

“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.

The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology. 
 

Guidelines Without Evidence?

Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines. 

Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital. 

“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted. 

However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.

For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy. 

Baseline characteristics of participants in the two groups were similar. 

Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68). 

This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering). 

Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
 

Reconsider Guidelines?

These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.

“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said. 

But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.

Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients. 

“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added. 

Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis. 

“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
 

Caution Advised

Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”

Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding. 

“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said. 

In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”

But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.

He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy. 

“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said. 

“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.

INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed. 

“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said. 

The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.