CATIS: No Benefit of BP Reduction in Acute Phase of Stroke

Susan Jeffrey

November 17, 2013

DALLAS, Texas — A randomized trial finds no benefit of treating acute ischemic stroke patients with elevated blood pressure using antihypertensive medications in the first 48 hours after an event.

Results of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) trial showed that, compared with no antihypertensive treatment, treating patients to a target BP with antihypertensive medications did not reduce the risk for death or major disability at 14 days or hospital discharge; outcomes were virtually identical between groups.

Dr. Jiang He

"These findings suggest that unless a patient's systolic blood pressure [SBP] is 220 mm Hg or more or diastolic pressure is 120 mm Hg or more, the decision to lower blood pressure with antihypertensive treatment in patients with acute ischemic stroke does not improve or worsen outcome and therefore should be based on individual clinical judgment," the researchers, with lead author Jiang He, MD, PhD, from the department of epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, conclude.

Their findings were published online November 17 in the Journal of the American Medical Association to coincide with their presentation here at the American Heart Association (AHA) 2013 Scientific Sessions.

BP Elevations Common

Elevated BP in the setting of acute stroke is common, the researchers write; a study in 2007 using the US National Hospital Ambulatory Medical Survey showed 76.5% of patients arriving in the emergency department with acute stroke had systolic BPs of 140 mm Hg or greater.

Although the benefit of antihypertensive treatment in reducing the risk for stroke in both primary and secondary prevention is well established, the benefit of reducing BP in the acute phase of stroke is not clear. Observational studies have shown a decrease in BP within the first 48 hours to be associated with better, similar, and worse outcomes. "There are no published clinical trials with sufficient statistical power to address the question of whether lowering blood pressure reduces adverse clinical outcomes among patients with acute ischemic stroke," they write.

The CATIS trial was a single-blind, blinded end points, multicenter, randomized controlled trial looking at whether moderate BP reduction within 48 hours of stroke onset would reduce death and major disability, defined as a modified Rankin Scale (mRS) score of 3 or higher, at 14 days or hospital discharge. They also assessed the effect of antihypertensive treatment in the acute phase on 3-month mortality, major disability, and vascular events at a posttreatment follow-up visit.

Included were 4071 patients from 26 hospitals with acute ischemic stroke who were within 48 hours of symptom onset and had elevated BP. Patients who received thrombolytic therapy were excluded from this trial, they note. Although intravenous tissue plasminogen activator (tPA) is standard treatment for stroke, treatment rates remain low, at less than 6% in a recent US survey and around 2% in China, the authors say. "Therefore, our findings most likely are applicable for the majority of patients, who currently do not receive thrombolytic therapy."

Patients were randomized to receive antihypertensive therapy (n = 2038) with the aim of lowering systolic BP by 10% to 25% within 24 hours of randomization, achieving a level of less than 140 mm Hg by day 7, and maintaining it to that level during the entire hospitalization or to discontinue all hypertensive medications they'd been on prior to their stroke during their hospitalization (n = 2033). At hospital discharge, all patients were prescribed antihypertensive medications "according to clinical guidelines," the authors write.

"Our trial was designed to test a blood-pressure-reduction strategy rather than the efficacy of specific antihypertensive drugs," they point out. "As such, several antihypertensive agents, including intravenous angiotensin-converting enzyme inhibitors (enalapril, first line), calcium-channel blockers (second line), and diuretics (third line) could be used individually or in combination in the intervention group to achieve the targeted blood-pressure reduction according to a prespecified treatment algorithm."

Study physicians and nurses were not blinded to group assignment, but patients, investigators, and research staff collecting the outcome data were masked to treatment allocation, they note.

SBP reduction was achieved in both groups at both 24 hours and day 7, but as expected, was significantly lower in the treated group.

CATIS: Mean Systolic BP at 24 Hours by Treatment

End Point Antihypertensive Treatment No Treatment Relative Difference (%) Absolute Difference P
Baseline 24 h Baseline 24 h
Mean Systolic BP mm Hg (% difference) 166.7 144.7 (-12.7) 165.6 152.9 (-7.2) -5.5 - 9.1 mm Hg < .001

At 7 days, the SBP was lower still and still significantly different between groups.

CATIS: Mean Systolic BP at 7 Days by Treatment

End Point Antihypertensive Treatment No Treatment Absolute Difference, mm Hg (95% CI) P
Mean Systolic BP, mm Hg 137.3 146.5 -9.3 (-10.1 to -8.4) < .001

CI=confidence interval

However, the significant difference between SBP levels did not affect outcomes, either on the primary or the secondary composite end point.

CATIS: Primary and Secondary Outcomes

End Point Antihypertensive Treatment No Treatment Odds Ratio (95% CI) P
Death and Major Disability (mRS > 3) at d 14 or Hospital Discharge (Events) 683 681 1.00 (0.88 – 1.14) .98
Death and Major Disability at 3-mo Follow-up (Events) 500 502 0.99 (0.86 – 1.15) .93

CI=confidence interval

The authors point out that their study was conducted "exclusively in Chinese patients," so the management of acute stroke may differ from Western populations. For example, there was a high use of heparin among these study patients. "However, previous studies have demonstrated that the association between blood pressure and stroke is consistent between Chinese and Western populations," they note.

In 2011, investigators conducting the phase 3 Scandinavian Candesartan Acute Stroke Trial (SCAST) randomized 2029 patient with acute ischemic or hemorrhagic stroke to treatment with the angiotensin-receptor blocker candesartan (Atacand, AstraZeneca Pharmaceuticals LP) or placebo. They found the composite vascular end point didn't differ between the groups at 6 months, despite a significant difference in BP. "Furthermore, poorer functional outcomes were reported in the candesartan group," Dr. He and colleagues write.

CATIS differs from SCAST in that it tests an antihypertensive treatment strategy rather than a particular drug and achieved significantly greater BP reduction between groups, they note. "However, the findings from this trial indicate that antihypertensive treatment did not reduce or increase death or major disability in patients with acute ischemic stroke."

Two other preliminary trials including patients with both ischemic and hemorrhagic stroke have also failed to demonstrate a benefit with antihypertensive treatment in these patients, they add, the Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) trial, reported in 2009, and the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS), published in 2010.

Difficult Clinical Question

Dr. Cathy Sila

Invited discussant for this late breaking trial here was Cathy Sila, MD, George M. Humphrey II Professor of Neurology and director of the comprehensive stroke center at Case Western Reserve University in Cleveland. She pointed that CATIS is the largest study to date of active management of BP after ischemic stroke, with most other studies including only a few hundred patients, so it's "not surprising," she said, that current stroke guidelines "really say that the data are inconclusive and not convincing and that we're left up to our best devices on how to manage this very large population of patients."

Elevated BP is also very common in patients with acute stroke, Dr. Sila said, "and it's a very dynamic process. It declines over hours, days, or weeks, and it has prognostic significance. Patients with high blood pressure are more likely to suffer recurrent strokes and fatal strokes, and those with low blood pressure have a higher rate of cardiovascular mortality, with patients with admission pressures of 150 or 160 faring the best of all of these."

Successful reperfusion therapy with tPA often triggers an abrupt decline in blood pressure, she noted, "and this raises the question of how much the blood pressure is the cause or effect in the stroke and how do we use this information to help manage the patients."

There are factors arguing both for controlling and for maintaining elevated blood pressure in the setting of acute ischemic stroke, "and the story is really quite complicated," Dr. Sila pointed out. Hypertension after stroke increases the risk for cerebral edema due to the loss of autoregulation, for example, but depending on the stroke subtype, reducing blood flow to an infarct with a large penumbra of hypoperfused tissue could induce stroke progression.

In this study, Dr. He and colleagues conclude the decision to use antihypertensive treatment in this setting should be based on individual clinical judgment, Dr. Sila said. "As a vascular neurologist and hospitalist a large portion of the year, I really need more information, because we really need to know how to manage these patients.

 
I really need more information, because we really need to know how to manage these patients. Dr. Cathy Sila
 

"So my take on these data, if this is confirmed, is that this actually could substantially add to our clinical judgment, at least for a subset of patients with acute ischemic stroke, who are past the hyperacute phase, have mild stroke severity, and no major vessel occlusion," she said. "In this trial, active blood-pressure lowering of 12.7% within 24 hours to a goal blood pressure within the week didn't improve but it also didn't worsen a functional recovery of a median modified Rankin score of 2, which corresponds to a slight disability, where patients could have returned to all of their usual activity at the time of discharge."

The median length of stay of 13 days in this study in China is longer than would occur in the United States, she added, "but it's very reassuring that these patient were hospitalized during this vulnerable time, so that if they would have seen stroke progression precipitated by this treatment, they would have observed this in the study.

"So the relative safety of this approach could have significant implications for our patients in the US, where the mean length of stay would be 3 to 4 days, and blood-pressure control is really warranted before rehabilitation specialists would actually work with them."

Asked for comment on these findings, Ralph Sacco, MD, American Heart Association past president, Olemberg Family Chair in Neurological Diseases, Miller Professor of Neurology, Epidemiology and Public Health, Human Genetics, and Neurosurgery, and chair of the department of neurology at the Miller School of Medicine at the University of Miami, Florida, pointed out that current guidelines recommend aggressive treatment of BP in the acute phase of stroke only when the BP is markedly elevated.

"This study was a really select group of Chinese patients with moderate elevations of blood pressure and showed no benefit, although there are some hints that in the longer-term phase, there may be some benefits of blood-pressure reduction," Dr. Sacco told Medscape Medical News. "Right now, I think in the US, most of us would not abruptly lower blood pressure in the acute phase of stroke," he said. "However, we need to recall that once the acute phase is over, blood-pressure control is critical for preventing a recurrent stroke."

Further, none of these patients were treated with thrombolysis, and other exclusions included atrial fibrillation and even some heart disease, he added. "The American Stroke Association guidelines call for more aggressive management of blood pressure if you're going to use thrombolysis."

The study was supported by Tulane University and Collins C. Diboll Private Foundation, both in New Orleans; Soochow University, a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions, China, and the National Natural Science Foundation of China. The Changzhou Pharmaceutical Factory provided the study drug (enalapril). The authors report no relevant financial relationships.

JAMA . Published online November 17, 2013. Article

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