The findings, from the Scandinavian Candesartan Acute Stroke Trial (SCAST), indicated no benefit of treatment on the co-primary endpoints, which included a composite of vascular events at 6 months and functional outcome at 6 months. In fact, there was a nonsignificant trend toward worse outcomes with treatment.
"Our conclusion is that we find no indication for routine blood pressure lowering treatment in the acute phase of stroke," investigator Eivind Berge, MD, PhD, from the Trial Coordinating Center at Oslo University Hospital Ullevål in Oslo, Norway, said at a press conference here.
"There are other ongoing trials which may show us whether our result is generalizable, or whether there are subgroups or other approaches to blood pressure lowering treatment, which could confer benefit," he added.
The results were presented here at the American Stroke Association International Stroke Conference 2011 and published online simultaneously in The Lancet.
SCAST Results
Elevated blood pressure (BP) is common in the setting of acute stroke and is associated with poor short- and long-term outcomes, the authors write. "The optimum management of blood pressure in acute stroke is not known, and current practice is to accept high blood pressure in this situation," they note.
SCAST was a double-blind, placebo-controlled trial that randomly assigned 2029 patients with acute stroke, either ischemic or hemorrhagic, to receive candesartan or placebo for 7 days. Candesartan doses increased from 4 mg on day 1 to 16 mg on days 3 to 7. Patients were included if they had systolic BP above 140 mm Hg.
Two co-primary endpoints were a composite of vascular death, myocardial infarction (MI), or stroke in the first 6 months and functional outcome in the modified Rankin Scale (mRS) at 6 months.
Mean BP at baseline was 171/90 mm Hg. Over the 7-day treatment period, BP was significantly lower among patients receiving candesartan, with a mean BP of 147/82 mm Hg, vs 152/84 mm Hg in the placebo group (P < .001).
After 6 months, the risk for the composite vascular endpoint was not different between groups.
Table 1. Composite Vascular Outcome at 6 Months
| Endpoint | Candesartan | Placebo | Adjusted Hazard Ratio (95% CI) | P Value |
| Composite primary outcome (vascular death, MI or stroke) (n, %) | 120 (11.7) | 111 (11.3) | 1.09 (0.84 - 1.41) | .52 |
"For functional outcome…the distribution of mRS scores at 6 months were less favorable for patients treated with candesartan than for those on placebo, but the difference was not significant because the P value (.048) was greater than the threshold of 0.025 required to define significance when 2 co-primary effect variables are used," the authors write.
Table 2. Functional Outcome on mRS at 6 Months
| Endpoint | Adjusted Common Odds Ratio (95% CI) | P Value |
| Functional outcome | 1.17 (1.00 - 138) | .048* |
CI = confidence interval
For all secondary endpoints, including death from any cause, vascular death, ischemic stroke, hemorrhagic stroke, MI, stroke progression, symptomatic hypotension, and renal failure, as well as functional outcomes on the Scandinavian Stroke Scale and the Barthel Index, the researchers found a nonsignificant increased risk among patients treated with candesartan. For one of these, stroke progression, the difference was significant with a risk ratio of 1.47 (P = .04).
There was no evidence of a differential effect in any prespecified subgroups, irrespective of stroke subtype or systolic BP on admission.
"For the subgroup treated very early, we saw a benefit of candesartan; however, only for the composite endpoint and not for functional outcome," said co-investigator Else Charlotte Sandset, MD, also from the Trial Coordinating Center at Oslo University Hospital Ullevål, who presented the results here. "The interaction was nonsignificant."
Over follow-up, 9 (1%) patients receiving candesartan had symptomatic hypotension vs 5 (< 1%) of patients receiving placebo. Renal failure was seen in 18 (2%) patients in the candesartan group and 13 (1%) in the placebo group.
The researchers also performed a meta-analysis of randomized, controlled trials of BP-lowering treatment in acute stroke with more than 100 patients. "The SCAST data did not alter the result of previous trials, and we saw no beneficial effect on functional outcomes," Dr. Sandset said.
"Ongoing trials will help to clarify whether this finding is generalizable or whether there are subgroups of patients or different approaches to blood-pressure management for which a treatment benefit can be obtained," the authors conclude. "Until these trials have been completed, we see no place for routine blood pressure lowering treatment in the acute phase of stroke.
Alternate Strategies
In an accompanying commentary, Graeme J. Hankey, MBBS, MD, from the Department of Neurology at Royal Perth Hospital and School of Medicine and Pharmacology at the University of Western Australia, Perth, writes that the results of SCAST, when added to the results of 10 previous trials of lowering BP in acute stroke, increase the reliability of the evidence and suggest that pharmacologically lowering BP does not have a beneficial effect.
"Clinicians should therefore not be prescribing blood-pressure-lowering drugs within the first week of acute stroke in routine practice."
However, other BP-lowering strategies may still favorably affect outcomes, he adds. A pilot study called the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT) showed feasibility, safety, and effects on hematoma expansion of a BP-lowering protocol in patients with acute hemorrhagic stroke and high BP (Lancet Neurol. 2008;7:391-399).
On the basis of these results, a larger study, INTERACT 2, is investigating the effect of this strategy on functional outcome in 2800 patients.
Another trial, Efficacy of Nitric Oxide in Stroke (ENOS), will compare the effect on functional outcome of lowering BP with glyceryl trinitrate, and stopping or continuing antihypertensive drugs that patients were receiving before the stroke. Results of a recent trial, Continue or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS), showed no significant difference in death or dependency at 2 weeks by stopping or continuing previous antihypertensive treatment after a stroke (Lancet Neurol. 2010;9:767-775).
"The COSSACS trial was underpowered because of early termination, but the ENOS trial will hopefully reliably assess whether blood pressure-lowering drugs that have been prescribed before a stroke should be continued during the acute phase of stroke," Dr. Hankey concludes. While awaiting the outcome of the large ongoing trials, he writes, "SCAST’s results suggest that actively lowering blood pressure within the first week of acute stroke is not beneficial."
Philip B. Gorelick, MD, MPH, John S. Garvin Professor, head of the Department of Neurology and Rehabilitation, and director of stroke research at the University of Illinois College of Medicine, Chicago, pointed out that over time there has been reluctance to lower BP in acute ischemic stroke for fear that stroke deficits may worsen with loss of perfusion in patients with hypertensive regulatory curves that are shifted to the right.
The SCAST study ran for only 6 months, he noted, "and it may be that the benefit of blood pressure lowering is not appreciated until there is a longer follow-up period." In addition, the authors did not report on BP variability that has been postulated to be important to any beneficial effect of BP lowering.
"The practical message from this study is that blood pressure lowering with candesartan was not beneficial," Dr. Gorelick told Medscape Medical News. "Further study is needed to determine if this is a general effect associated with blood pressure lowering or if success may be related to the specific type of agent administered."
Larry Goldstein, MD, from Duke University Medical Center said whether or not to lower BP in this setting has been an area of some controversy.
"This study — and again this is a theme we're seeing here — was based on a smaller phase 2 trial that looked promising, but when studied in a large, prospective, randomized trial, there's nothing there," Dr. Goldstein said in an interview. "In fact, if anything, those patients did worse, so this is one that now provides additional data in support of our current guidelines recommendation."
The study was funded by the South-Eastern Norway Regional Health Authority, Oslo University Hospital Ullevål, AstraZeneca, and Takeda. Dr. Berge reports he has received payment for lectures from AstraZeneca and payment for board membership and expenses related to meetings from Bayer Healthcare. Disclosures for coauthors appear in the paper. Dr. Hankey discloses he is a member of the Data Safety and Monitoring Committee of the INTERACT trial; has received payment for consultancy work for the executive committee, ROCKET-AF trial, Johnson & Johnson; the Executive Committee, BOREALIS trial, Sanofi-Aventis; and the Steering Committee, TRA 2P TIMI 50 trial, Schering Plough. He is on the advisory board for Pradaxa (dabigatran) and has received payments for lectures and scientific symposia sponsored by Sanofi-Aventis and Pfizer.
Lancet. Published online February 11, 2011.
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