No Benefit of BP Lowering With Candesartan in Acute Stroke

Daniel M. Keller, PhD

June 16, 2011

June 15, 2011 (Hamburg, Germany) — In a new subanalysis of a placebo-controlled trial of the angiotensin receptor blocker candesartan in patients with elevated blood pressure (BP) soon after stroke, a large decrease or an increase in systolic BP from baseline to day 2 was associated with an increased risk for early adverse events, whether patients received drug or placebo.

However, a large reduction in systolic BP was not associated with an increased risk for poor functional outcomes at 6 months.

Presenting these results from a subanalysis of the Scandinavian Candesartan Acute Stroke Trial (SCAST) at the 20th European Stroke Conference, Else Charlotte Sandset, MD, from the Department of Internal Medicine and Hematology and the Trial Coordinating Center at Oslo University Hospital Ullevål in Oslo, Norway, concluded that the investigators found "no indication for routine blood pressure lowering in patients with acute stroke and elevated blood pressure."

No Trials to Guide Practice

Although 75% of patients have a systolic BP of 140 mm Hg or greater after acute stroke and although elevated BP in the early post-stroke period has been associated with poor short- and long-term outcomes, no large-scale clinical trials had been available to guide practice. Therefore, SCAST was undertaken at 146 centers in 9 European countries to study the effect of BP lowering with candesartan in patients with acute stroke and elevated BP.

The double-blind trial randomly assigned patients with acute ischemic or hemorrhagic stroke and systolic BP of 140 mm Hg or greater to receive candesartan or placebo for 7 days. Candesartan doses were escalated from 4 mg on day 1 up to 16 mg for days 3 to 7. Patients were eligible if treatment could be started within 30 hours of symptom onset. Follow-up continued for 180 days, and treatment during the follow-up period was left to the discretion of the treating clinicians.

Earlier results from SCAST presented in February at the American Stroke Association International Stroke Conference 2011 and published in The Lancet showed no benefit and some suggestion of harm for the 2 co-primary effect variables of composite vascular end point and of functional outcome at 6 months when BP was lowered with candesartan during the acute phase of stroke.

There was no difference in the rate of recurrent stroke, and a subgroup analysis revealed no subgroup that was harmed by or benefited from candesartan administration in terms of the composite end point or functional outcome. The exception was a statistically significant benefit for the composite end point favoring candesartan for patients treated within 6 hours of symptom onset.

For the secondary end point of stroke progression, the use of candesartan was associated with an elevated risk, with a relative risk of 1.47 (95% confidence interval [CI], 1.01 - 2.13; P = .04). At the time of the original presentation, the investigators questioned whether any subgroup of patients may benefit from a BP-lowering treatment in the immediate post-stroke period.

For the present analysis, they asked whether patients who experience a large reduction in BP after acute stroke are at higher risk for early adverse events and poor long-term functional outcome compared with other patients.

Patients in the study were categorized according to their absolute difference in systolic BP at baseline and on day 2, forming 4 nearly equal-sized groups: increase or no change (n = 265), small decrease (0-15 mm Hg; n = 242), moderate decrease (15- 28.5 mm Hg; n = 241), and large decrease ( > 28.5 mm Hg; n = 248).

Early adverse events were defined as the combined end point of stroke recurrence, stroke progression, and symptomatic hypotension occurring within 7 days of randomization. Functional outcome at 6 months was measured by the modified Rankin Scale.

Baseline characteristics among the groups did not differ by age (range of means, 70.5-71.3 years), sex (38%-42% women), qualifying event (81%-88% ischemic stroke; 10%-18% hemorrhagic stroke), or medical history.

The only baseline characteristics that significantly differed for the 4 groups were BP, symptom duration, and Scandinavian Stroke Scale score, where a high score reflects mild symptoms.

Baseline Characteristics

Characteristic Increase/Unchanged (n = 265) Small Decrease (n = 242) Moderate Decrease (n = 241) Large Decrease (n = 248) P Value
Mean systolic BP (mm Hg) 164.4 167.9 171.7 181.2 < .001
Mean diastolic BP (mm Hg) 86.5 89.7 91.5 93.8 < .001
Symptom duration (h) 19.1 18.2 17.7 15.7 < .001
Median SSS score 41 44 42 45 .001

SSS = Scandinavian Stroke Scale

Combined End Point

The risk for the combined end point of stroke progression, stroke recurrence, and symptomatic hypotension was nearly the same for the candesartan group, the placebo group, or when the 2 groups were combined for each of the magnitudes and directions of changes (small or large increase or decrease) in systolic BP from baseline to day 2.

For an increase or no change in systolic BP, the risk of achieving the end point increased for the candesartan group, the placebo group, and when the 2 were combined. However, only the combined data showed a statistically significant difference above an odds ratio of 1.0, with an odds ratio of approximately 1.9.

A moderate decrease in systolic BP was associated with a trend toward higher odds ratios only for the placebo and combined data groups. With a large decrease in systolic BP, the combined data group had an odds ratio for reaching the end point of approximately 2.0, which was statistically different from an odds ratio of 1.0.

Small decreases in systolic BP had no effect on the odds of reaching the combined end point for any of the groups.

In summary, Dr. Sandset said, "A large decrease or an increase in systolic blood pressure from baseline to day 2 was associated with an increased risk of early adverse events."

However, a large reduction in systolic BP was not associated with an increased risk for poor outcome at 6 months, where the odds ratio was 1.17 (95% CI, 1.00 - 1.38). In this case the P value was .048, which was not statistically significant because it was not less than the threshold of .025, as required when 2 co-primary effect variables are used, the authors explained.

Dr. Sandset cautioned that this study was a post hoc analysis of data from SCAST and that the data should be interpreted with caution. She concluded that these results do not give any indication for routine use of treatments to lower BP in patients with acute stroke and elevated BP.

The ongoing Efficacy of Nitric Oxide in Stroke (ENOS; www.ist3.com) trial and the Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) may help to clarify whether there are subgroups of patients who may benefit from BP-lowering therapies or whether different approaches to lowering BP may offer some benefit.

Questions Remain

Werner Hacke, MD, PhD, professor and chairman of the Department of Neurology at the University of Heidelberg in Germany, commented that he still has questions about what to do about BP in the acute phase after a stroke.

"This is not a trial that looks at early modification of blood pressure," he said. "It looks at modification during the first couple of days but not in the decisive time where we really want to know what's going on, and that has not been tested." He suggested that a better test of an effect would be "to randomize quite early, that is, in the first few hours after stroke onset."

He said such a trial would have to incorporate very rigid safety monitoring. Because one wants to maintain brain perfusion, "I would fear that we would see negative consequences, and all guidelines usually say don't lower blood pressure in the first hours after stroke," he stressed.

"There is no evidence whatsoever what to do with blood pressure, and people have made up their mind and their decisions and now it's in the guidelines [that] you should not touch [blood pressure]," Dr. Hacke said, noting that he himself was in large part responsible for the European guidelines.

He said he doubted that the results seen in SCAST were specific to candesartan or to the angiotensin receptor blocker class of antihypertensive drugs. "I believe it has to do with the speed in which you lower [blood pressure], how closely you monitor it, [and] how well this monitoring is done," he said.

The trial was funded by the South-Eastern Norway Regional Health Authority and Oslo University Hospital Ullevål and by limited, unrestricted grants from AstraZeneca and Takeda. AstraZeneca provided study drug. Some of the authors have previously received payment from pharmaceutical companies, but all of the activities involved were unrelated to this work. Dr. Sandset has disclosed no relevant financial relationships. Dr. Hacke, who had no role in SCAST, is a speaker for Bayer-Schering and Boehringer Ingelheim.

20th European Stroke Conference, Hamburg, Germany. Large Clinical Trials 3. Presented Wednesday May 25, 2011.

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