No recurrent stroke prevention seen with clopidogrel plus aspirin

Pauline Anderson

February 03, 2012

New Orleans, LA - Adding clopidogrel to aspirin is no more effective in preventing recurrent stroke than taking aspirin alone in patients with subcortical stroke and increases the risk of major bleeds and total mortality, including nonvascular mortality, results of a new study show [1].

The increased risk of death in study patients taking this dual therapy was unexpected and unexplained, said lead author Dr Oscar Benavente (University of British Columbia, Vancouver).

Results of the double-blind antiplatelet portion of the Secondary Prevention of Small Subcortical Strokes (SP3) study, a randomized, multicenter international trial of patients with lacunar strokes, were released during the International Stroke Conference 2012.

This arm of the trial was stopped in October 2011 when a scheduled data review showed an increased risk of bleeding with combination therapy, and futility analysis showed little likelihood of benefit.

All-cause mortality

The study included 3020 subjects who were randomized to receive 325 mg of aspirin plus placebo (n=1503) or 325 mg of aspirin plus 75 mg of clopidogrel (n=1517). After a mean follow-up of 3.5 years, there was about an equal distribution of recurrent ischemic and hemorrhagic strokes between the two groups (HR 0.92, 95% CI 0.73-1.2; p=0.52).

But investigators uncovered a significant difference in all-cause mortality; there were 77 total deaths in the aspirin group compared with 113 in the aspirin/clopidogrel group (HR 1.5, 95% CI; 1.1-2.0; p=0.005). There were more vascular deaths (26 vs 19), probable vascular deaths (19 vs six), and nonvascular deaths (41 vs 32) in the aspirin group compared with the combination group.

As well, there were more major hemorrhages in the combination group, with 105 vs 56 events with aspirin, for a rate of 2.1% vs 1.1% per patient-year, respectively.

While the combination therapy wasn't effective in preventing secondary strokes long term, there are still ongoing investigations into this therapy's efficacy in the shorter term—within 90 days. "That question still needs to be answered," said Benavente.

Lacunar strokes are a common condition of vascular disease and are especially prevalent among some minorities, including Hispanics, said Benavente. In this study population, 30% were Hispanic, half were non-Hispanic whites, and 20% were African American. Benavente said racial differences as well as geographical differences are topics for future study.

Benavente stressed that this comparison is only part of the SPS3 study; patients were separately randomized to blood-pressure management with a systolic blood pressure target of either 130 to 149 mm Hg or <130 mm Hg to look at effects on stroke and cognition, and that arm continues.

He noted that they found no interaction between the blood-pressure and antiplatelet treatment, he said. Results of this part of the study will be presented later this year.

The study raises the question of how to treat these stroke patients. Benavente said there is need for further investigation into possible new agents for this group.

Confirm guidelines

Asked to comment, Dr Ralph Sacco (Miller School of Medicine, University of Miami, FL) said that the risk of bleeding with clopidogrel plus aspirin in stroke patients has been documented.

"There have been other trials including high-risk stroke patients where we've looked at clopidogrel and aspirin vs clopidogrel and found increased risk of bleeding, so I think our guidelines have said that we shouldn't be using clopidogrel plus aspirin in all comers with stroke."

The increased risk of mortality in patients on combination therapy in this study is harder to explain, especially since so many of the deaths were nonvascular, and remains unclear, said Sacco. "Here is another signal, beyond that of bleeding, and so now we have potentially mortality that we need to take into consideration as reasons that we shouldn't be using clopidogrel and aspirin in most stroke patients."

He stressed, however, that if stroke patients also have heart disease or a stent, there is still a good indication for using this combination therapy.

Be navente reports research support from National Institute of Neurological Disorders and Stroke and other research support from Sanofi/Bristol-Myers Squibb.


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