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Aspirin + Clopidogrel
Why Two Treatments May Not Be Better Than One for Lacunar Stroke


A new study found that evidence did not support long-term use of dual antiplatelet therapy (aspirin and clopidogrel) over aspirin therapy alone in a group of patients who had recently experienced a lacunar stroke while on aspirin therapy.

Although aspirin (acetylsalicylic acid, or ASA) is often prescribed as a preventative treatment for individuals who have already had — or are at high risk for — a heart attack or stroke, a significant number of these patients still go on to have events while taking ASA. In these cases, clinicians may replace or combine a different antiplatelet agent with the aspirin therapy, but does this provide a significant benefit?

A Neurology study, published online first on Jan. 2, set out to answer this question within a specific subgroup of patients. Investigators used data from the Secondary Prevention of Small Subcortical Strokes (SPS3) study to identify a cohort of patients who had experienced a lacunar stroke while on ASA. They then compared the long-term patient outcomes of adding clopidogrel to ASA versus ASA alone to see if using two treatments was in fact better than one.

[The SPS3 study is a randomized, multicenter clinical trial sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), which was conducted in seven countries and designed to define ways to reduce stroke recurrence, cognitive decline, and major vascular events in patients with symptomatic small subcortical strokes.]

Robert Côté, MD, professor in the department of neurology, neurosurgery, and medicine at McGill University and senior physician at Montreal General Hospital, who led the study, said that “although many clinicians switch to or add a different antiplatelet agent when a patient presents with new cerebral ischemic symptoms while on ASA therapy, this practice has never been validated and thus is not specifically recommended in present stroke prevention guidelines.”

From their analysis, Dr. Côté and colleagues found that evidence did not support long-term use of dual antiplatelet therapy “in patients with a recent lacunar stroke while on ASA therapy (patients judged clinically as ASA failures),” because it resulted in more side effects with no significant additional benefit.


This NINDS-funded subgroup analysis included 838 individuals from the SPS3 study who had experienced a lacunar stroke despite taking aspirin therapy. These patients were randomized to aspirin (325 mg/day) and clopidogrel (75mg/day) or placebo (same dose) and were followed for an average of 3.5 years. Adherence was measured by pill counts at follow-up visits.

This cohort had “failed” ASA therapy, and had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n=2,151) in SPS3 (p=0.03), according to Dr. Côté and colleagues. Participants were 65.6 years old on average, and a majority (65 percent) were men. The study's primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage), and the main safety outcome was major extracranial hemorrhage.

The patients taking both ASA and clopidogrel did not have a significant reduction in recurrent stroke — 3.1 percent per year compared with 3.3 percent per year in the aspirin only group. But the side effect profiles — particularly gastrointestinal hemorrhage — were greater in the patients taking both therapies. (The site of bleeding was determined by an investigator at the local study center.) The risk of gastrointestinal bleeding in the dual therapy group was 1.03 percent per year versus 0.38 percent per year in the monotherapy group (HR, 2.7; 95% CI, 1.1-6.9). For ischemic stroke, there was no significant difference between the two groups (HR, 0.90; 95% CI, 0.59-1.38), the authors wrote. And although the risk of gastrointestinal bleeding was higher in the dual antiplatelet group (p=0.04), the risk of intracranial hemorrhage did not differ (p=0.55).

“Our study found no significant benefits to combining aspirin with clopidogrel in the long term for patients with a recent lacunar stroke,” Dr. Côté said. He noted that “there was an increased risk of gastrointestinal bleeding and higher overall mortality” in the dual therapy group.

However, he pointed out, because the report was based on a post-hoc analysis, “we cannot exclude the potential influence of unknown confounders. Also, the results can only apply to lacunar strokes.” Another limitation, he said, was that the size of the cohort was relatively small. Additionally, the “study did not address the potential benefit of this dual antiplatelet combination selectively in the acute setting (for example, during the first hours or days after the initial ischemic event).”

Several questions remain unanswered, including whether these conclusions will also apply to other subtypes of ischemic stroke. Future research should explore “newer and more potent antiplatelet/antithrombotic approaches” (such as ticagrelor) in these higher risk patients, he said. Citing the Chinese trial — CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) — and the ongoing US POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke) study, Dr. Côté added this dual antiplatelet approach in ASA failure subgroups should be evaluated “specifically in the acute setting, that is, at the start of treatment within hours with a short follow-up period such as three months.” [See Neurology Today's coverage of the CHANCE study:]


Stroke neurologists agreed that this study was an important addition to the discussion on antiplatelet therapies for stroke prevention, but they also raised questions about what the findings may actually mean in practice.

This study provides objective evidence, at least for this subgroup of patients with lacunar strokes, that “the ‘two is better than one’ approach is not a winning strategy and that there are downsides to combining two antiplatelet agents — particularly hemorrhage,” said Gregory Albers, MD, director of the Stanford Stroke Center and professor of neurology and neurological sciences at the Stanford University Medical Center. A major strength of this analysis is the well-defined patient subgroup, he said, contrasted with many older studies where “different stroke subtypes are rolled together, and you're not quite sure if the results of the study apply to your patient.”

In an accompanying editorial also published in the Jan. 2 online edition of Neurology, Luis Castilla-Guerra, MD, PhD, of the department of internal medicine at Hospital de la Merced in Seville, Spain, and Ralph Sacco, MD, of the University of Miami Miller School of Medicine, commended the study for its well-characterized infarct subtype, and “outstanding methodology and statistical analysis” addressing an important clinical question. The study was also in concordance with results from WARSS (Warfarin-Aspirin Recurrent Stroke Study), which they noted, “adds to the validity of the findings.”

The study suggests that “dual antiplatelet therapy is not likely to be helpful in patients with lacunar strokes, due to occlusion of small blood vessels deep in the brain,” said Seemant Chaturvedi, MD, professor of neurology and stroke program director at Wayne State University, who was a local site principal investigator in the SPS3 study. But it did not address “whether switching to another antiplatelet strategy such as clopidogrel monotherapy or aspirin plus dipyridamole would be clinically effective.”

Although this was a “nice subgroup analysis,” said S. Claiborne Johnston, MD, PhD, director of the Clinical and Translational Science Institute and associate vice chancellor of research at the University of California–San Francisco, the cohort size was not large enough to “rule out an effect of clopidogrel in these patients; in fact, the confidence intervals include a 30 percent hazards reduction with clopidogrel-aspirin.” [Dr. Johnston is a senior author of the Chinese CHANCE study, and a principal investigator of the POINT study in the US.]

Another limitation, the editorialists said, was characterizing “ASA failure” patients as those who experienced a new ischemic event while taking ASA, as opposed to the more common approach of defining failure based on a laboratory test measuring the antiplatelet effects of aspirin. Unfortunately, said Dr. Albers, none of the currently available antiplatelet agents have perfect efficacy in terms of preventing events — most have about a 30 percent relative risk reduction. That means that aspirin will prevent less than half of all recurrent strokes so “failure is not unexpected,” he added.

Dr. Albers found it particularly interesting “that in these patients, who had a stroke while taking aspirin, and are already known to be a high risk subgroup, we would think they would be more likely to respond to a different agent — yet they did not,” he said. But one concern for clinicians is that such patients may be reluctant to stay on aspirin therapy because they think a new and different therapy offers more hope, he continued. “Combination therapies clearly involve more risk, so they should not be used unless there is clear benefit to outweigh the risk.” In addition, “people often don't take aspirin very seriously because it's not an expensive prescription medicine, and so compliance may be an issue.”

Agreeing, Dr. Johnston said that if this belief “affects their adherence, combining clopidogrel or dipyridamole with aspirin could still be the right choice even without evidence that efficacy is greater. Drugs that aren't taken have no efficacy.”

Certainly, in terms of cost-effectiveness, aspirin is still the best antiplatelet option for preventing stroke, noted Dr. Albers, and this study was a “good vote” for its use in specific patients. The bottom line, he said, is “we don't have an antiplatelet combination that's more effective for these patients. We need to either study new agents or focus our attention on other risk factors that present in these patients, instead of trying to create our own combination that we think may be more effective because combinations may be more likely to cause hemorrhages than prevent more strokes.”

There are currently ongoing studies of laboratory tests which would be able to predict the effectiveness of various antiplatelet therapies in different patients with the hope that treatments may be individualized in the future, he said.

For now, Dr. Albers and the editorialists agreed that in light of these recent findings, increased emphasis should be placed on controlling known risk factors — lowering blood pressure, getting proper exercise, not smoking, lowering cholesterol — in these patients who are already identified as being at an elevated cardiovascular risk.


•. Côté R, Zhang Y, Hart RG, et al. Does the combination ASA/clopidogrel confer better long-term vascular protection. Neurology 2014; E-pub 2014 Jan. 2.
    •. Castilla-Guerra L, Sacco RL. Editorial: Treating lacunar strokes occurring on aspirin. Adding clopidogrel is not the simple solution. Neurology 2014: E-pub 2014 Jan. 2.
      •. More about the SPS3 Study:
        •. More about the US POINT trial: