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LONDON – Receipt of early, intensive blood pressure–lowering treatment improved functional outcomes in patients with acute intracerebral hemorrhage in a large, randomized trial.
There was a significant, favorable shift in the distribution of modified Rankin Scale (mRS) scores with a more intensive approach to blood pressuring lowering than guideline-recommended treatment, resulting in lower levels of disability (odds ratio, 0.87; P = .04).
However, the results of the eagerly anticipated INTERACT2 trial showed only a modest and nonsignificant reduction in the primary endpoint of death and disability (OR, 0.87; P less than .06).
The trial’s findings are still clinically relevant, the study’s investigators believe, and the approach now warrants implementation in routine clinical practice in most patients with acute intracerebral hemorrhage (ICH), particularly as there were no undue safety concerns when compared with the guideline-recommended approach.
"Blood pressure lowering in acute ICH is safe, so go early, go intensive, and go sustained in most of our patients because it improves the chances of a better recovery in survivors," said Dr. Craig Anderson, of the George Institute for Global Health in Sydney, Australia. "Ultimately, that’s what patients and families want us to do."
Dr. Anderson, who is the study’s chief investigator and is also professor of stroke medicine and clinical neuroscience at the University of Sydney, presented the study’s findings on May 29 at the annual European Stroke Conference; the results were also published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214609).
Design of INTERACT2
INTERACT2 (Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) was an international, multicenter, prospective, open-label, blinded-endpoint, randomized trial of 2,839 patients. Patients were recruited within 6 hours of onset of spontaneous ICH and had elevated systolic blood pressure (150-220 mm Hg). The mean age was 63.5 years, and most patients were men (63%), Chinese (68%), and hypertensive (72%).
Patients were centrally allocated to randomly receive either intensive (n = 1,399) or guideline-recommended (n = 1,430) blood pressure–lowering treatment. Intensive treatment aimed to lower the systolic blood pressure rapidly, within 1 hour, to a target of less than 140 mm Hg. By contrast, guideline-recommended treatment aimed to reduce systolic blood pressure below a target of 180 mm Hg with no time limit.
The antihypertensive agents used were not stipulated in the study protocol, and hence a variety of agents were used by the 141 hospitals that participated in the trial. Intravenous agents were used in 90% of patients in the intensive-treatment arm versus 43% in the conventionally treated arm. Intensively managed patients were more likely to receive an IV bolus dose and an infusion (30% vs. 18%) or multiple agents (27% vs. 8%). The most commonly used agent was urapidil, an alpha-blocker available in some parts of Europe, but not in the United States.
Key findings
The primary measure of a poor outcome, defined as an mRS score of 3-6 at 90 days, was observed in 719 (52%) of intensively treated patients versus 785 (55.6%) of guideline-treated patients. An mRS score of 6 indicates death, and 3-5 denotes major disability.
An ordinal analysis of the mRS showed lower scores with the intensive than with the guideline-recommended blood pressure–lowering approach, with more patients able to remain independent despite having some level of disability (mRS score 0-2 in 48% of intensively treated vs. 44% of guideline-treated patients).
Health-related quality of life was assessed using the European Quality of Life-5 Dimensions questionnaire, and intensively treated patients reported fewer problems in mobility (64% vs. 67%; P = .13), self-care (47% vs. 52%; P = .02), usual activities (61% vs. 66%; P = .006), pain or discomfort (40% vs. 45%; P = .01), and anxiety or depression (34% vs. 38%, P = .05) than did those in the standard-treatment arm.
"I’ve never seen this in a clinical trial before," Dr. Anderson observed. "It’s very hard to find a signal in clinical trials, and I guess I was surprised by the degree of significance in benefit on usual activities, which is a very high measure of functional recovery when the patient is home."
Nonfatal serious adverse events occurred in a similar proportion of intensively treated and guideline-treated patients (23.3% and 23.6%, respectively). "The important thing is that we tried to look for any hazard, and we found no excess harms any way we looked at it," Dr. Anderson reported.
Implications for current practice
"If the results of this study with respect to the primary outcome were not as robust as some may have hoped, practitioners should be reassured by the safety data," Dr. Jennifer Frontera of the Cleveland Clinic Foundation commented in an editorial accompanying the NEJM paper.
There were no significant differences between the two treatment approaches in terms of neurologic deterioration, expansion of the ICH, ischemic stroke, cardiovascular events, or severe symptomatic hypotension, she noted.
The ongoing ATACH II (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trial should hopefully shed more light on the benefit of early blood pressure lowering after ICH onset. ATACH II has similar blood pressure–lowering targets and primary and secondary endpoints as INTERACT2. A key difference, however, is that nicardipine is being used as the sole blood pressure–lowering agent. Results should be available in 2016.
Dr. Philip Bath, professor of stroke medicine and chair of the division of stroke at the University of Nottingham, England, who chaired the session in which the INTERACT2 findings were revealed, said that it is still too early to change the guidelines, particularly in view of the fact that several other trials are also ongoing. These include the ENOS (Efficacy of Nitric Oxide on Stroke) trial, of which he is the principal investigator.
"I think randomized data that are near are probably more important than guidelines, so I would always favor more data. It’s not as if we are going to have to wait a very long time; they will be there in the next year or two," Dr. Bath argued.
Study investigator Dr. Christian Stapf, professor of neurology at Université Diderot–Sorbonne Paris Cité, France, commented that, as a clinical scientist, he agreed that more data would be preferable before changing practice.
As a clinician, however, he said, "At this stage I don’t see the risk of any harm. I have no reason not to do it, and if anything it will only help."
Dr. Anderson further commented at a press briefing: "We have presented, for the first time, a strategy that can improve recovery from ICH, the most devastating type of stroke." He emphasized that it was rapid and intensive blood pressure lowering, rather than the use of any specific treatment, that was important in the trial.
This is very good news for the stroke community, Dr. Anderson argued. "We would expect guidelines to change and clinical practice to change as a result of this strategy."
The National Health and Medical Research Council of Australia funded INTERACT2, which was an investigator-led trial. The experts cited in this report had no relevant disclosures.
LONDON – Receipt of early, intensive blood pressure–lowering treatment improved functional outcomes in patients with acute intracerebral hemorrhage in a large, randomized trial.
There was a significant, favorable shift in the distribution of modified Rankin Scale (mRS) scores with a more intensive approach to blood pressuring lowering than guideline-recommended treatment, resulting in lower levels of disability (odds ratio, 0.87; P = .04).
However, the results of the eagerly anticipated INTERACT2 trial showed only a modest and nonsignificant reduction in the primary endpoint of death and disability (OR, 0.87; P less than .06).
The trial’s findings are still clinically relevant, the study’s investigators believe, and the approach now warrants implementation in routine clinical practice in most patients with acute intracerebral hemorrhage (ICH), particularly as there were no undue safety concerns when compared with the guideline-recommended approach.
"Blood pressure lowering in acute ICH is safe, so go early, go intensive, and go sustained in most of our patients because it improves the chances of a better recovery in survivors," said Dr. Craig Anderson, of the George Institute for Global Health in Sydney, Australia. "Ultimately, that’s what patients and families want us to do."
Dr. Anderson, who is the study’s chief investigator and is also professor of stroke medicine and clinical neuroscience at the University of Sydney, presented the study’s findings on May 29 at the annual European Stroke Conference; the results were also published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214609).
Design of INTERACT2
INTERACT2 (Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) was an international, multicenter, prospective, open-label, blinded-endpoint, randomized trial of 2,839 patients. Patients were recruited within 6 hours of onset of spontaneous ICH and had elevated systolic blood pressure (150-220 mm Hg). The mean age was 63.5 years, and most patients were men (63%), Chinese (68%), and hypertensive (72%).
Patients were centrally allocated to randomly receive either intensive (n = 1,399) or guideline-recommended (n = 1,430) blood pressure–lowering treatment. Intensive treatment aimed to lower the systolic blood pressure rapidly, within 1 hour, to a target of less than 140 mm Hg. By contrast, guideline-recommended treatment aimed to reduce systolic blood pressure below a target of 180 mm Hg with no time limit.
The antihypertensive agents used were not stipulated in the study protocol, and hence a variety of agents were used by the 141 hospitals that participated in the trial. Intravenous agents were used in 90% of patients in the intensive-treatment arm versus 43% in the conventionally treated arm. Intensively managed patients were more likely to receive an IV bolus dose and an infusion (30% vs. 18%) or multiple agents (27% vs. 8%). The most commonly used agent was urapidil, an alpha-blocker available in some parts of Europe, but not in the United States.
Key findings
The primary measure of a poor outcome, defined as an mRS score of 3-6 at 90 days, was observed in 719 (52%) of intensively treated patients versus 785 (55.6%) of guideline-treated patients. An mRS score of 6 indicates death, and 3-5 denotes major disability.
An ordinal analysis of the mRS showed lower scores with the intensive than with the guideline-recommended blood pressure–lowering approach, with more patients able to remain independent despite having some level of disability (mRS score 0-2 in 48% of intensively treated vs. 44% of guideline-treated patients).
Health-related quality of life was assessed using the European Quality of Life-5 Dimensions questionnaire, and intensively treated patients reported fewer problems in mobility (64% vs. 67%; P = .13), self-care (47% vs. 52%; P = .02), usual activities (61% vs. 66%; P = .006), pain or discomfort (40% vs. 45%; P = .01), and anxiety or depression (34% vs. 38%, P = .05) than did those in the standard-treatment arm.
"I’ve never seen this in a clinical trial before," Dr. Anderson observed. "It’s very hard to find a signal in clinical trials, and I guess I was surprised by the degree of significance in benefit on usual activities, which is a very high measure of functional recovery when the patient is home."
Nonfatal serious adverse events occurred in a similar proportion of intensively treated and guideline-treated patients (23.3% and 23.6%, respectively). "The important thing is that we tried to look for any hazard, and we found no excess harms any way we looked at it," Dr. Anderson reported.
Implications for current practice
"If the results of this study with respect to the primary outcome were not as robust as some may have hoped, practitioners should be reassured by the safety data," Dr. Jennifer Frontera of the Cleveland Clinic Foundation commented in an editorial accompanying the NEJM paper.
There were no significant differences between the two treatment approaches in terms of neurologic deterioration, expansion of the ICH, ischemic stroke, cardiovascular events, or severe symptomatic hypotension, she noted.
The ongoing ATACH II (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trial should hopefully shed more light on the benefit of early blood pressure lowering after ICH onset. ATACH II has similar blood pressure–lowering targets and primary and secondary endpoints as INTERACT2. A key difference, however, is that nicardipine is being used as the sole blood pressure–lowering agent. Results should be available in 2016.
Dr. Philip Bath, professor of stroke medicine and chair of the division of stroke at the University of Nottingham, England, who chaired the session in which the INTERACT2 findings were revealed, said that it is still too early to change the guidelines, particularly in view of the fact that several other trials are also ongoing. These include the ENOS (Efficacy of Nitric Oxide on Stroke) trial, of which he is the principal investigator.
"I think randomized data that are near are probably more important than guidelines, so I would always favor more data. It’s not as if we are going to have to wait a very long time; they will be there in the next year or two," Dr. Bath argued.
Study investigator Dr. Christian Stapf, professor of neurology at Université Diderot–Sorbonne Paris Cité, France, commented that, as a clinical scientist, he agreed that more data would be preferable before changing practice.
As a clinician, however, he said, "At this stage I don’t see the risk of any harm. I have no reason not to do it, and if anything it will only help."
Dr. Anderson further commented at a press briefing: "We have presented, for the first time, a strategy that can improve recovery from ICH, the most devastating type of stroke." He emphasized that it was rapid and intensive blood pressure lowering, rather than the use of any specific treatment, that was important in the trial.
This is very good news for the stroke community, Dr. Anderson argued. "We would expect guidelines to change and clinical practice to change as a result of this strategy."
The National Health and Medical Research Council of Australia funded INTERACT2, which was an investigator-led trial. The experts cited in this report had no relevant disclosures.
LONDON – Receipt of early, intensive blood pressure–lowering treatment improved functional outcomes in patients with acute intracerebral hemorrhage in a large, randomized trial.
There was a significant, favorable shift in the distribution of modified Rankin Scale (mRS) scores with a more intensive approach to blood pressuring lowering than guideline-recommended treatment, resulting in lower levels of disability (odds ratio, 0.87; P = .04).
However, the results of the eagerly anticipated INTERACT2 trial showed only a modest and nonsignificant reduction in the primary endpoint of death and disability (OR, 0.87; P less than .06).
The trial’s findings are still clinically relevant, the study’s investigators believe, and the approach now warrants implementation in routine clinical practice in most patients with acute intracerebral hemorrhage (ICH), particularly as there were no undue safety concerns when compared with the guideline-recommended approach.
"Blood pressure lowering in acute ICH is safe, so go early, go intensive, and go sustained in most of our patients because it improves the chances of a better recovery in survivors," said Dr. Craig Anderson, of the George Institute for Global Health in Sydney, Australia. "Ultimately, that’s what patients and families want us to do."
Dr. Anderson, who is the study’s chief investigator and is also professor of stroke medicine and clinical neuroscience at the University of Sydney, presented the study’s findings on May 29 at the annual European Stroke Conference; the results were also published simultaneously in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214609).
Design of INTERACT2
INTERACT2 (Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) was an international, multicenter, prospective, open-label, blinded-endpoint, randomized trial of 2,839 patients. Patients were recruited within 6 hours of onset of spontaneous ICH and had elevated systolic blood pressure (150-220 mm Hg). The mean age was 63.5 years, and most patients were men (63%), Chinese (68%), and hypertensive (72%).
Patients were centrally allocated to randomly receive either intensive (n = 1,399) or guideline-recommended (n = 1,430) blood pressure–lowering treatment. Intensive treatment aimed to lower the systolic blood pressure rapidly, within 1 hour, to a target of less than 140 mm Hg. By contrast, guideline-recommended treatment aimed to reduce systolic blood pressure below a target of 180 mm Hg with no time limit.
The antihypertensive agents used were not stipulated in the study protocol, and hence a variety of agents were used by the 141 hospitals that participated in the trial. Intravenous agents were used in 90% of patients in the intensive-treatment arm versus 43% in the conventionally treated arm. Intensively managed patients were more likely to receive an IV bolus dose and an infusion (30% vs. 18%) or multiple agents (27% vs. 8%). The most commonly used agent was urapidil, an alpha-blocker available in some parts of Europe, but not in the United States.
Key findings
The primary measure of a poor outcome, defined as an mRS score of 3-6 at 90 days, was observed in 719 (52%) of intensively treated patients versus 785 (55.6%) of guideline-treated patients. An mRS score of 6 indicates death, and 3-5 denotes major disability.
An ordinal analysis of the mRS showed lower scores with the intensive than with the guideline-recommended blood pressure–lowering approach, with more patients able to remain independent despite having some level of disability (mRS score 0-2 in 48% of intensively treated vs. 44% of guideline-treated patients).
Health-related quality of life was assessed using the European Quality of Life-5 Dimensions questionnaire, and intensively treated patients reported fewer problems in mobility (64% vs. 67%; P = .13), self-care (47% vs. 52%; P = .02), usual activities (61% vs. 66%; P = .006), pain or discomfort (40% vs. 45%; P = .01), and anxiety or depression (34% vs. 38%, P = .05) than did those in the standard-treatment arm.
"I’ve never seen this in a clinical trial before," Dr. Anderson observed. "It’s very hard to find a signal in clinical trials, and I guess I was surprised by the degree of significance in benefit on usual activities, which is a very high measure of functional recovery when the patient is home."
Nonfatal serious adverse events occurred in a similar proportion of intensively treated and guideline-treated patients (23.3% and 23.6%, respectively). "The important thing is that we tried to look for any hazard, and we found no excess harms any way we looked at it," Dr. Anderson reported.
Implications for current practice
"If the results of this study with respect to the primary outcome were not as robust as some may have hoped, practitioners should be reassured by the safety data," Dr. Jennifer Frontera of the Cleveland Clinic Foundation commented in an editorial accompanying the NEJM paper.
There were no significant differences between the two treatment approaches in terms of neurologic deterioration, expansion of the ICH, ischemic stroke, cardiovascular events, or severe symptomatic hypotension, she noted.
The ongoing ATACH II (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trial should hopefully shed more light on the benefit of early blood pressure lowering after ICH onset. ATACH II has similar blood pressure–lowering targets and primary and secondary endpoints as INTERACT2. A key difference, however, is that nicardipine is being used as the sole blood pressure–lowering agent. Results should be available in 2016.
Dr. Philip Bath, professor of stroke medicine and chair of the division of stroke at the University of Nottingham, England, who chaired the session in which the INTERACT2 findings were revealed, said that it is still too early to change the guidelines, particularly in view of the fact that several other trials are also ongoing. These include the ENOS (Efficacy of Nitric Oxide on Stroke) trial, of which he is the principal investigator.
"I think randomized data that are near are probably more important than guidelines, so I would always favor more data. It’s not as if we are going to have to wait a very long time; they will be there in the next year or two," Dr. Bath argued.
Study investigator Dr. Christian Stapf, professor of neurology at Université Diderot–Sorbonne Paris Cité, France, commented that, as a clinical scientist, he agreed that more data would be preferable before changing practice.
As a clinician, however, he said, "At this stage I don’t see the risk of any harm. I have no reason not to do it, and if anything it will only help."
Dr. Anderson further commented at a press briefing: "We have presented, for the first time, a strategy that can improve recovery from ICH, the most devastating type of stroke." He emphasized that it was rapid and intensive blood pressure lowering, rather than the use of any specific treatment, that was important in the trial.
This is very good news for the stroke community, Dr. Anderson argued. "We would expect guidelines to change and clinical practice to change as a result of this strategy."
The National Health and Medical Research Council of Australia funded INTERACT2, which was an investigator-led trial. The experts cited in this report had no relevant disclosures.
AT THE EUROPEAN STROKE CONFERENCE
Major finding: The odds ratio for intensive blood pressure lowering preventing death or disability, compared with guideline-recommended treatment, was 0.87 (P = .06).
Data source: INTERACT2, an international, multicenter, prospective, open-label, blinded-endpoint, randomized trial of 2,839 patients with elevated systolic blood pressure after spontaneous intracerebral hemorrhage, who were treated with an intensive or guideline-recommended blood pressure–lowering approach.
Disclosures: The National Health and Medical Research Council of Australia funded INTERACT2, which was an investigator-led trial. The experts cited in this report had no relevant disclosures.
