In patients with small subcortical strokes, there is no benefit to be had from combination therapy using clopidogrel plus aspirin, interim results from the SPS3 (Secondary prevention of small subcortical strokes) study revealed.
Oscar Benavente, University of British Columbia, Vancouver, Canada, presented the results of the antiplatelet intervention aspect from SPS3 at the International Stroke Conference 2012. He said that small subcortical strokes account for more than 25% of brain infarcts and are the most common cause of vascular dementia. Despite their frequency and importance, no clinical trial has focused on this stroke subtype.
The SPS3 trial is a randomised, multicentre, clinical trial conducted in eight countries, aimed to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. SPS3 enrolled patients who have experienced a small subcortical stroke (also known as a lacunar stroke). The main goal of this study is to learn more about preventing secondary stroke in people who have already had a subcortical stroke. The investigators also designed the study to learn how to prevent problems with thinking and memory decline which could happen after a stroke. Both aspirin and clopidogrel are widely-used for blood clotting and stroke prevention. Investigators intended to find out if using the drugs together is more effective in preventing another stroke than using aspirin alone. This study is also seeking information about the best level of blood pressure control after a stroke. Lacunar strokes prevalent among some minorities including hispanics, and in the SPS3 study population, 30% were Hispanic, half were non-Hispanic whites, and 20% were black.
The investigators completed recruitment of 3020 patients with symptomatic small, subcortical strokes verified by MRI, within 180 days and without carotid stenosis or major cardiac sources of embolism. These patients were randomly assigned to receive aspirin plus placebo (n=1503) or 325mg of aspirin plus 75mg of clopidogrel (n=1517).
After a mean follow-up of three and a half years, recurrent ischaemic and haemorrhagic strokes in the two groups was near equal (p=0.52). However, there was a significant difference in all-cause mortality with 77 deaths in the aspirin group vs. 113 in the aspirin plus clopidogrel group (p=0.005).
The aspirin plus placebo group had more vascular deaths (26 vs. 19), probable vascular deaths (19 vs. 6), and nonvascular deaths (41 vs. 32) than the combination group. The combination group had more major haemorrhages than the aspirin plus placebo group (105 vs. 56 events, respectively), for a rate of 2.1% vs. 1.1% per patient-year, respectively.
The increased risk for death in study patients taking combination therapy was “unexpected and unexplained”, said Benavente.
In October 2011, the antiplatelet intervention was prematurely stopped based on the recommendation made by the Data Safety Monitoring Board due to the following reasons: 1) A suggested increased risk of bleeding and death among subjects assigned to combination therapy of aspirin plus clopidogrel; and 2) A futility analysis showing that, given the current observed data, there was a small probability of showing a benefit in favour of combination therapy over aspirin alone, if this part of the trial continued to the planned end.
While the results of SPS3 showed that combination therapy was not effective in preventing secondary strokes over the long term, its efficacy within 90 days is still being studied.
“These results do not support the use of combination clopidogrel plus aspirin for secondary stroke prevention in patients with small subcortical strokes. The blood pressure intervention continues and is anticipated to be completed in May 2012,” said Benavente.
The National Institutes of Health (NIH) in Washington DC is sponsoring this study.