November 15, 2011 — A new study points again to evidence of the fabled J-curve of cardiovascular event risk associated with blood pressure (BP). Among patients with recent noncardioembolic stroke, systolic BP (SBP) not only over 140 mm Hg but also under 120 mg Hg were associated with increased risk for recurrent stroke.
The study, a post hoc analysis of data from the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, is published online in the November 16 issue of the Journal of American Medical Association. The new issue, a cardiovascular disease theme issue, was released early to coincide with the American Heart Association Scientific Sessions 2011.
"Our results indicate that there may indeed be thresholds of benefit or harm with regard to short-term or longer-term SBP levels after a recent non-cardioembolic ischemic stroke, and imply that clinicians regularly caring for stroke patients in the outpatient setting may need to be vigilant about how low a given patient’s BP is within the normal range to promote favourable outcomes," the researchers, with lead author Bruce Ovbiagele, MD, Department of Neurosciences, University of California, San Diego, conclude.
They caution, though, that these data should be considered hypothesis-generating, and the notion that aggressively and consistently lowering BP to within the normal range after an ischemic stroke is not beneficial, "remains unproven, and will require the conduct of dedicated clinical trials comparing intensive with usual BP reduction in the stable follow up period after a stroke."
In the meantime, the results support aiming for consistent systolic BP of less than 140 mm Hg and diastolic less than 90 mm Hg in patients with a recent stroke, they conclude.
In an interview, Dr. Ovbiagele said that on the basis of this new information, he wouldn’t actually attempt to increase BP in those with very low SBPs but rather would try to optimize their overall vascular risk profile.
But for patients in the high normal range below 140 mm Hg, he told Medscape Medical News, "based on this study I wouldn’t try to keep them below 120 mm Hg as the guidelines call for; again I would keep them where they are and optimize overall vascular risk reduction.
PROFESS Trial
Current secondary stroke prevention guidelines suggest maintaining a normal BP, defined as SBP less than 120 mm Hg and diastolic BP less than 80 mm Hg in a patient with a prior stroke, the authors note. However, there are limited data on BP within the normal range for risk reduction after a stroke.
Last year, analyses from 2 large BP trials showed evidence of a J-shaped curve, with no benefit of more aggressive SBP targets less than 120 mm Hg in high-risk patients with diabetes in the ACCORD study, and perhaps even harm from SBP targets below 130 mg Hg and diastolic BP less than 85 mm Hg in patients with diabetes and heart disease in the INVEST trial.
In the wake of these findings, Dr. Ovbiagele and coauthors write, "there is mounting interest in exploring the existence and nature of the J-shaped link of BP with outcome in various patient groups at high risk for vascular events. For stroke, the vascular disease entity most highly correlated with BP, it is generally perceived that a J-shaped association between BP and outcome may not exist."
In this analysis, they used data from the PROFESS trial, a 2-by-2 factorial trial comparing 4 regimens: a combination of aspirin and extended-release dipyridamole compared with clopidogrel and telmisartan compared with placebo. All patients also received antihypertensive medications at the discretion of the investigator for BP control. In all, 20,330 patients from 695 centers in 35 countries were randomly assigned within about 30 days of having a noncardioembolic ischemic stroke.
The main results of the trial showed no significant difference between these treatments, the authors note, so all patients were combined for this study.
Patients were categorized by their mean SBP over follow-up as very low-normal (<120 mm Hg), low-normal (120 to <130 mm Hg), high-normal (130 to <140 mm Hg), high (140 to <150 mm Hg), and very high (>150 mm Hg).
The primary outcome was first recurrence of stroke of any type, and the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular disease.
They found that, with use of high-normal SBP as a reference, rates of both primary and secondary outcomes were increased in the high and very high SBP ranges, but also in the very low-normal range.
Table. Stroke Rates and Risk for Primary and Secondary Outcomes by SBP
CI = confidence interval; MI = myocardial infarction.
Timing may be important, they speculate. The J-shaped association of SBP with recurrent vascular risk after stroke was most pronounced in the first 90 to 180 days after the qualifying event.
"As you can see from our analysis, even though there seem to be this higher risk of stroke, MI [myocardial infarction], vascular death and all-cause mortality in those who were less than 120 mm Hg over the 2 years of follow up in PROFESS, most of that risk was up front," Dr. Ovbiagele told Medscape Medical News. "When we analyzed them by time point, we found that the really big difference of the J-curve was mostly in the first 6 months after the stroke."
Thereafter, there was little difference between the various groups based on SBP, he added. "What that tells me is that within 6 months after the stroke, one has to be careful about how low the blood pressure is; beyond that you probably can go ahead and lower blood pressure."
This may also explain some divergence of their findings from other trials, which included patients with both ischemic and hemorrhagic stroke and showed benefit at much lower BPs, as well as patients randomly assigned out to 5 years after their index event, he noted.
What to do about BP after an acute stroke has always been an issue for stroke neurologists, with competing concerns about preventing recurrence vs reducing brain perfusion in these patients.
An earlier trial suggested that lowering BP acutely might be beneficial, but more recent results from the Scandinavian Candesartan Acute Stroke Trial (SCAST) showed no benefit and some indication of harm in the acute setting, Dr. Ovbiagele noted. Results from SCAST were presented in February at the International Stroke Conference 2011 and published in The Lancet.
"So we’re now we’re going back again to thinking it might be harmful in the acute setting, but of course this now extends beyond the acute setting and into the subacute setting," he concludes.
Ongoing trials may shed further light on the relationship, the authors add. The Prevention of Decline in Cognition After Stroke Trial (PODCAST) is looking at the effect of achieving low-normal SBP on cognition after a recent ischemic or hemorrhagic stroke, and the Secondary Prevention of Small Subcortical Strokes (SPS3) is evaluating a subset of patients with ischemic stroke (those eligible for magnetic resonance imaging with small-vessel disease strokes) within 6 months with higher BP cutoffs of less than 150 mm Hg vs 130 mm Hg.
Another trial, called the Systolic Blood Pressure Intervention Trial (SPRINT) and funded by the National Institutes of Health, is looking at the general population, comparing SBP lowering to below 120 mm Hg to a target of 140 mm Hg in reducing the risk for cardiovascular and kidney disease, as well as age-related cognitive decline.
Moderation in All Things
Philip B. Gorelick, MD, MPH, John S. Garvin Professor and head of the Department of Neurology and Rehabilitation at the University of Illinois College of Medicine, Chicago, and director of the Center for Stroke Research, was a member of the steering committee for the PROFESS trial.
Asked for comment on these findings, Dr. Gorelick pointed out that elevated BP is the most important modifiable risk factor for stroke, and reduction of BP usually results in a considerable lessening of stroke risk.
Analyses of some clinical trial data have suggested that the brain will tolerate more substantial BP lowering than will the heart, and this may be attributed to the autoregulatory capacity of these respective organs, Dr. Gorelick told Medscape Medical News.
"In this hypothesis-generating study among recent noncardioembolic ischemic stroke patients, patients with systolic blood pressure less than 120 mm Hg, 140 to less than 150 mm Hg, and 150 mm Hg or higher were at increased risk of recurrent stroke," he pointed out.
"The message here is that those at the more extreme tails of the blood pressure distribution are at higher risk of stroke, whereas those with more moderate blood pressure levels may be more protected from recurrent cerebral ischemia," Dr. Gorelick said.
"Until we know more, the usual target blood pressure goal of < 140 mm Hg in uncomplicated hypertensives is a reasonable one to aim for," he concludes. "Like alcohol consumption for those who imbibe, moderation of even blood pressure control may be the way to go. This study suggests, that yes, there may be a J-shaped curve in relation to blood pressure and stroke occurrence."
Boehringer Ingelheim provided grant monies and materials to execute the PROFESS trial. Dr. Ovbiagele reported he was paid as a consultant by Avanir Pharmaceuticals for 1-time participation in an experts advisory meeting held in June 2011. Disclosures for coauthors appear in the paper.
JAMA. 2011;306:2137-2144. Abstract
The study, a post hoc analysis of data from the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, is published online in the November 16 issue of the Journal of American Medical Association. The new issue, a cardiovascular disease theme issue, was released early to coincide with the American Heart Association Scientific Sessions 2011.
"Our results indicate that there may indeed be thresholds of benefit or harm with regard to short-term or longer-term SBP levels after a recent non-cardioembolic ischemic stroke, and imply that clinicians regularly caring for stroke patients in the outpatient setting may need to be vigilant about how low a given patient’s BP is within the normal range to promote favourable outcomes," the researchers, with lead author Bruce Ovbiagele, MD, Department of Neurosciences, University of California, San Diego, conclude.
They caution, though, that these data should be considered hypothesis-generating, and the notion that aggressively and consistently lowering BP to within the normal range after an ischemic stroke is not beneficial, "remains unproven, and will require the conduct of dedicated clinical trials comparing intensive with usual BP reduction in the stable follow up period after a stroke."
In the meantime, the results support aiming for consistent systolic BP of less than 140 mm Hg and diastolic less than 90 mm Hg in patients with a recent stroke, they conclude.
In an interview, Dr. Ovbiagele said that on the basis of this new information, he wouldn’t actually attempt to increase BP in those with very low SBPs but rather would try to optimize their overall vascular risk profile.
But for patients in the high normal range below 140 mm Hg, he told Medscape Medical News, "based on this study I wouldn’t try to keep them below 120 mm Hg as the guidelines call for; again I would keep them where they are and optimize overall vascular risk reduction.
PROFESS Trial
Current secondary stroke prevention guidelines suggest maintaining a normal BP, defined as SBP less than 120 mm Hg and diastolic BP less than 80 mm Hg in a patient with a prior stroke, the authors note. However, there are limited data on BP within the normal range for risk reduction after a stroke.
Last year, analyses from 2 large BP trials showed evidence of a J-shaped curve, with no benefit of more aggressive SBP targets less than 120 mm Hg in high-risk patients with diabetes in the ACCORD study, and perhaps even harm from SBP targets below 130 mg Hg and diastolic BP less than 85 mm Hg in patients with diabetes and heart disease in the INVEST trial.
In the wake of these findings, Dr. Ovbiagele and coauthors write, "there is mounting interest in exploring the existence and nature of the J-shaped link of BP with outcome in various patient groups at high risk for vascular events. For stroke, the vascular disease entity most highly correlated with BP, it is generally perceived that a J-shaped association between BP and outcome may not exist."
In this analysis, they used data from the PROFESS trial, a 2-by-2 factorial trial comparing 4 regimens: a combination of aspirin and extended-release dipyridamole compared with clopidogrel and telmisartan compared with placebo. All patients also received antihypertensive medications at the discretion of the investigator for BP control. In all, 20,330 patients from 695 centers in 35 countries were randomly assigned within about 30 days of having a noncardioembolic ischemic stroke.
The main results of the trial showed no significant difference between these treatments, the authors note, so all patients were combined for this study.
Patients were categorized by their mean SBP over follow-up as very low-normal (<120 mm Hg), low-normal (120 to <130 mm Hg), high-normal (130 to <140 mm Hg), high (140 to <150 mm Hg), and very high (>150 mm Hg).
The primary outcome was first recurrence of stroke of any type, and the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular disease.
They found that, with use of high-normal SBP as a reference, rates of both primary and secondary outcomes were increased in the high and very high SBP ranges, but also in the very low-normal range.
Table. Stroke Rates and Risk for Primary and Secondary Outcomes by SBP
| SBP | Recurrent Stroke Rates (95% CI) (%) | Adjusted Hazard Ratio for First Stroke Recurrence (95% CI) | Adjusted Hazard Ratio for Stroke, MI, or Vascular Death (95% CI) |
| Very low-normal | 8.0 (6.8 - 9.2) | 1.29 (1.07 - 1.56) | 1.31 (1.13 - 1.52) |
| Low-normal | 7.2 (6.4 - 8.0) | 1.10 (0.95 - 1.28) | 1.16 (1.03 - 1.31) |
| High-normal | 6.8 (6.1 - 7.4) | Reference | Reference |
| High | 8.7 (7.9 - 9.5) | 1.23 (1.07 - 1.41) | 1.24 (1.11 - 1.39) |
| Very high | 14.1 (13.0 - 15.2) | 2.08 (1.83 - 2.37) | 1.94 (1.74 - 2.16) |
Timing may be important, they speculate. The J-shaped association of SBP with recurrent vascular risk after stroke was most pronounced in the first 90 to 180 days after the qualifying event.
"As you can see from our analysis, even though there seem to be this higher risk of stroke, MI [myocardial infarction], vascular death and all-cause mortality in those who were less than 120 mm Hg over the 2 years of follow up in PROFESS, most of that risk was up front," Dr. Ovbiagele told Medscape Medical News. "When we analyzed them by time point, we found that the really big difference of the J-curve was mostly in the first 6 months after the stroke."
Thereafter, there was little difference between the various groups based on SBP, he added. "What that tells me is that within 6 months after the stroke, one has to be careful about how low the blood pressure is; beyond that you probably can go ahead and lower blood pressure."
This may also explain some divergence of their findings from other trials, which included patients with both ischemic and hemorrhagic stroke and showed benefit at much lower BPs, as well as patients randomly assigned out to 5 years after their index event, he noted.
What to do about BP after an acute stroke has always been an issue for stroke neurologists, with competing concerns about preventing recurrence vs reducing brain perfusion in these patients.
An earlier trial suggested that lowering BP acutely might be beneficial, but more recent results from the Scandinavian Candesartan Acute Stroke Trial (SCAST) showed no benefit and some indication of harm in the acute setting, Dr. Ovbiagele noted. Results from SCAST were presented in February at the International Stroke Conference 2011 and published in The Lancet.
"So we’re now we’re going back again to thinking it might be harmful in the acute setting, but of course this now extends beyond the acute setting and into the subacute setting," he concludes.
Ongoing trials may shed further light on the relationship, the authors add. The Prevention of Decline in Cognition After Stroke Trial (PODCAST) is looking at the effect of achieving low-normal SBP on cognition after a recent ischemic or hemorrhagic stroke, and the Secondary Prevention of Small Subcortical Strokes (SPS3) is evaluating a subset of patients with ischemic stroke (those eligible for magnetic resonance imaging with small-vessel disease strokes) within 6 months with higher BP cutoffs of less than 150 mm Hg vs 130 mm Hg.
Another trial, called the Systolic Blood Pressure Intervention Trial (SPRINT) and funded by the National Institutes of Health, is looking at the general population, comparing SBP lowering to below 120 mm Hg to a target of 140 mm Hg in reducing the risk for cardiovascular and kidney disease, as well as age-related cognitive decline.
Moderation in All Things
Philip B. Gorelick, MD, MPH, John S. Garvin Professor and head of the Department of Neurology and Rehabilitation at the University of Illinois College of Medicine, Chicago, and director of the Center for Stroke Research, was a member of the steering committee for the PROFESS trial.
Asked for comment on these findings, Dr. Gorelick pointed out that elevated BP is the most important modifiable risk factor for stroke, and reduction of BP usually results in a considerable lessening of stroke risk.
Analyses of some clinical trial data have suggested that the brain will tolerate more substantial BP lowering than will the heart, and this may be attributed to the autoregulatory capacity of these respective organs, Dr. Gorelick told Medscape Medical News.
"In this hypothesis-generating study among recent noncardioembolic ischemic stroke patients, patients with systolic blood pressure less than 120 mm Hg, 140 to less than 150 mm Hg, and 150 mm Hg or higher were at increased risk of recurrent stroke," he pointed out.
"The message here is that those at the more extreme tails of the blood pressure distribution are at higher risk of stroke, whereas those with more moderate blood pressure levels may be more protected from recurrent cerebral ischemia," Dr. Gorelick said.
"Until we know more, the usual target blood pressure goal of < 140 mm Hg in uncomplicated hypertensives is a reasonable one to aim for," he concludes. "Like alcohol consumption for those who imbibe, moderation of even blood pressure control may be the way to go. This study suggests, that yes, there may be a J-shaped curve in relation to blood pressure and stroke occurrence."
Boehringer Ingelheim provided grant monies and materials to execute the PROFESS trial. Dr. Ovbiagele reported he was paid as a consultant by Avanir Pharmaceuticals for 1-time participation in an experts advisory meeting held in June 2011. Disclosures for coauthors appear in the paper.
JAMA. 2011;306:2137-2144. Abstract
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