Six months after receiving the angiotensin-receptor blocker candesartan to acutely lower blood pressure following either ischemic or hemorrhagic stroke, the only detectable result was a trend toward harm that fell short of statistical significance, a large multicenter European trial has found. An accompanying meta-analysis reached the same negative conclusion.
Neurologists in the US who specialize in the treatment of stroke said that while questions remain, the study and meta-analysis should prompt strong reservations about lowering blood pressure in the first 36 hours following stroke, at least outside the critical three-hour window when intravenous medications can be delivered.
The Scandinavian Candesartan for Treatment of Acute Stroke Trial (SCAST) randomized 2,029 patients with acute stroke and systolic blood pressure of 140 mm Hg or higher within 30 hours of symptom onset. Participants received either candesartan or placebo for seven days, with doses increasing from 4 mg on day one to 16 mg on days three to seven. The composite endpoint was vascular death, myocardial infarction, or stroke during the first six months, with functional outcome measured by the modified Rankin Scale.
The treatment modestly but significantly lowered blood pressure during the seven-day treatment period (mean 147/82 mm Hg in the candesartan group on day seven vs. 152/84 mm Hg in the placebo group; p<0.0001). But six months later, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs. placebo, 111 events; adjusted hazard ratio 1.09, 95% CI 0.84 to 1.41; p=0.52).
Analysis of functional outcome suggested a trend toward higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1.17, 95% CI 1.00 to 1.38; p=0.048 [not significant at p≤0.025 level]). The researchers found no evidence of a differential effect in any of the pre-specified subgroups.
Included in the study published in the Lancet was a meta-analysis of 11 prior trials, which likewise showed no benefit of acutely lowering blood pressure following stroke, and a trend toward risk. Eivind Berge, MD, PhD, and Else Charlotte Sandset, MD, of the Trial Coordinating Centre at Oslo University Hospital Ulleval in Norway, led the investigators.
“It's an important study,” said Sean Savitz, MD, associate professor of neurology and co-director of the stroke program at the University of Texas Medical School at Houston. “This tells us that perhaps we really need to think twice before we give an antihypertensive agent in the first 36 hours after stroke. It lends support to some of the guidelines and old teachings handed down through the decades about not lowering the blood pressure in the acute setting of an ischemic stroke.”
But he and other neurologists agreed that with other trials continuing, and with the great variability of stroke pathophysiology, neurologists may continue to attempt to lower blood pressure in selected patients.
DR. SEAN SAVITZ: “This tells us that perhaps we really need to think twice before we give an antihypertensive agent in the first 36 hours after stroke. It lends support to some of the guidelines and old teachings handed down through the decades about not lowering the blood pressure in the acute setting of an ischemic stroke.”
“It's still an individual decision about whether to treat blood pressure or not,” Dr. Savitz said. “No stroke patient is the same. The decision to treat blood pressure depends on where stroke is, on where exactly the vessel is blocked or whether there is bleeding.”
The six-month follow-up in the study makes interpreting the results of SCAST “tricky,” said Mitchell S.V. Elkind, MD, associate chairman of neurology for clinical research and training at Columbia University.
“It's meant to be a study of acute treatment of blood pressure following stroke,” he said, “but the outcomes were at six months. A lot can go on in those six months, so what happens in the first week may not be as relevant. To draw the conclusion of how soon we need to lower blood pressure, we need to have the outcomes measured in a much shorter period of time.”
Those caveats aside, Dr. Elkind said, “Our practice here, and what the guidelines say, is not to lower blood pressure in the acute setting. Once the patient is stabilized and ready for discharge, that's when blood pressure control becomes paramount.”
At least three other large trials of lowering blood pressure acutely following stroke are continuing. The Efficacy of Nitric Oxide in Stroke (ENOS) trial is testing the use of transdermal nitrous oxide beginning within 48 hours following ischemic or hemorrhagic stroke and continuing for seven days. Its estimated enrollment of 5,000 patients is expected to be completed this October.
Two other trials are using intravenous medications to lower blood pressure in the first hours following a hemorrhagic stroke: the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) and the Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT 2).
“The benefit of lowering blood pressure in intracerebral hemorrhage is very time dependent,” said Adnan I. Qureshi MD, executive director of the Minnesota Stroke Initiative and professor of neurology, neurosurgery and radiology at the Zeenat Qureshi Stroke Research Center at the University of Minnesota. “It has to be done intravenously, in the first three hours or so. The fact that SCAST found no benefit from lowering it after that is what I would have predicted, at least for hemorrhagic stroke.”
For ischemic stroke, Dr. Savitz noted, guidelines for treatment with intravenous tissue plaminogen activator (TPA) require that blood pressure be below 185/110, and that TPA not be administered unless blood pressure can be brought below that level with intravenous medication.
DR. MITCHELL S.V. ELKIND said the six-month follow-up in the study makes interpreting the results of the analysis “tricky,” noting “…a lot can go on in those six months, so what happens in the first week may not be as relevant. To draw the conclusion of how soon we need to lower blood pressure, we need to have the outcomes measured in a much shorter period of time.”
“In that case you would have to lower it,” Dr. Savitz said. “That's a totally different ballgame.”
The 2007 guidelines on stroke care from the American Heart Association/American Stroke Association offer evidence-based guidelines for management of blood pressure in patients not eligible for treatment with recombinant tissue plasminogen activator (rtPA) or other acute reperfusion intervention (excerpted below):
* Data to guide recommendations for treatment are inconclusive or conflicting. Many patients have spontaneous declines in blood pressure during the first 24 hours after onset of stroke. Until more definitive data are available, it is generally agreed that a cautious approach to the treatment of arterial hypertension should be recommended (Class I, Level C Evidence). Patients who have other medical indications for aggressive treatment of blood pressure should be treated.
* It is generally agreed that patients with markedly elevated blood pressure may have their blood pressure lowered. A reasonable goal would be to lower blood pressure by about 15 percent during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus exists that medications should be withheld unless the systolic blood pressure is >220 mm Hg or the diastolic blood pressure is >120 mm Hg (Class I, Level C Evidence).
Recommendations for managing blood pressure for intracerebral hemorrhage (ICH) can be found in the ICH guidelines (Stroke 2007;38:2001-23).
Source: Stroke 2007;38;1655-1711.
Adams HP, Zoppo del G, Wijdicks EFM, et al. Guidelines for the early management of adults with ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Counsel, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. 2007;38;1655–1711.