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NINDS Halts the Aspirin-Clopidogrel Arm of Stroke Trial

Samson, Kurt

doi: 10.1097/01.NT.0000407791.46431.57


Just three months into a large multicenter clinical trial evaluating combining aspirin and the antiplatelet drug clopidogrel to prevent secondary small vessel subcortical strokes, the NINDS has stopped all but the blood pressure reduction arm of the study.

In a clinical advisory announcement, the NINDS said its decision to halt the antiplatelet component of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial was prompted by a higher than acceptable number of bleeding events and deaths from all causes, as well as a lack of evidence that the combination offered any greater benefit than using either drug alone.

SPS3 is the first study to evaluate the combination specifically in patients with a recent subcortical stroke confirmed by MRI. Recruitment ended in April with the enrollment of 3,200 patients in North America, Latin America, and Spain. The subjects were randomized to receive 325 mg of enteric-coated aspirin each day and either 75 mg of clopidogrel or a placebo.

The researchers are also searching for an ideal target for reducing blood pressure to prevent secondary stroke, and tracking cognitive decline in the patients.

The study's data and safety monitoring board recommended ending the antiplatelet phase of the study after 6.5 percent of patients taking both drugs experienced bleeding events by mid-June — 5.5 percent of whom suffered a non-CNS hemorrhage, compared to 3.3 percent of patients taking aspirin alone. The mortality rate in the combination arm was also greater: 5.8 percent versus 4.1 percent in the aspirin-placebo group.

“These results support current guidelines that recommend against the use of the combination of clopidogrel plus aspirin for secondary stroke prevention, and now extend this advice to those with recent small subcortical strokes, or lacunar infarcts, that have been confirmed by MRI,” the NINDS advisory notice stated.

The risk of bleeding events has been reported in a number of prior trials of aspirin and clopidogrel, noted NINDS Deputy Director Walter J. Koroshetz, MD, but unlike SPS3, earlier trials did not focus exclusively on small vessel obstruction in patients with a recent MRI-confirmed subcortical stroke.



“We had hoped that the stroke prevention effects of dual antiplatelet treatment would overwhelm the known risk of bleeding in patients with small vessel disease who have very high secondary stroke risk, but it did not turn out that way,” he told Neurology Today in a telephone interview. “The safety monitoring board advised the NINDS that continuing the drug arm would be futile, but that the blood pressure study arm should continue.”

Participating physicians and subjects have been notified to halt dual treatment, but to continue working to meet blood pressure reduction goals of less than 130 mmHg or between 130-149 mmHg. The hypertension arm of the study will continue until April 2012, with patients continuing to take aspirin and blood pressure medication.

Unlike most major strokes that damage surface areas of the brain and are caused by a blockage or rupture of a major blood vessel, subcortical strokes, or lacunar strokes, are smaller and injure deep structures within the brain. Blood is supplied to these areas through much smaller blood vessels than those in the surface regions of the brain and because of this, hypertension can lead to impaired blood flow and stroke.

Although subcortical strokes involve only a small part of the brain, they can cause serious impairment, including sudden weakness, numbness, and paralysis, as well as loss of motor control resulting in severe problems with walking and speech. Because the symptoms can initially be subtle, many patients are not aware that they have suffered a subcortical stroke, however secondary strokes are common.

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“It's back to the drawing board” in the search for an effective drug therapy for preventing secondary small vessel subcortical strokes, said Dr. Koroshetz. “We need to know more about the biology that causes these tiny vessels to become diseased and then to occlude or rupture.”

He noted that the 2004 MATCH trial also found no cardiovascular benefit in using aspirin and clopidogrel over clopidogrel alone, and patients in the dual antiplatelet treatment arm had significantly more bleeding events than those on clopidogrel alone. Moreover, a 2008 study found that while combined use of clopidogrel and aspirin for stroke prevention was common prior to publication of the MATCH results, rates fell dramatically afterward.

The CHARISMA trial, completed in 2006, also found no significant benefit with combining aspirin with clopidogrel in patients with stable cardiovascular disease or multiple cardiovascular risk factors, but also found combination therapy to be associated with increased bleeding risk and greater mortality.



Nonetheless, controlling hypertension remains an extremely important investigative target of SPS3, according to Dr. Koroshetz.

“Hypertension is the major risk factor, so it is important to know how to best control blood pressure in preventing small vessel stroke and its link to cognitive impairment.”

Results from a major study published in 2010, the ACCORD trial, found little improvement in overall cardiovascular outcomes among type 2 diabetics when blood pressure was reduced to below the standard 140/80mmHg levels, however there were fewer strokes, Dr. Koroshetz noted.

“This hints that aggressive blood pressure lowering might be a real game changer for patients with small vessel stroke. Because of the commitment of the investigators and patients, the final results of SPS3 should have a high impact for neurologic practice.”

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Oscar Benavente, MD, professor of neurology and research director of stroke at the University of British Columbia in Vancouver, said that despite the disappointing results from the antiplatelet component of SPS3, the study still offers an opportunity to study other aspects of small subcortical stroke.

“A very unique feature of this trial is having MRI confirmation of a recent lacunar stroke and the exclusion of other stroke subtypes, so we have a very well defined population to study,” he told Neurology Today in a telephone interview.

The researchers will also be able to closely track cognitive decline because each subject underwent baseline cognitive testing at the trial's outset, with follow-up testing at predetermined periods.

“Now the idea is to try to identify which level of blood pressure control works better,” said Dr. Benavente, the principal investigator of SPS3.

Specific targets for post-stroke blood pressure control have yet to be established, and until the ACCORD trial, the accepted standard, at least for preventing cardiovascular events in diabetic patients, was “the lower the better,” he said. But ACCORD found no evidence of any benefit when systolic blood pressure was reduced to below 120 mmHg.

“The imbalance in bleeding complications in the SPS3 subjects is also interesting,” he said. “Most were systemic hemorrhages rather than CNS-related bleeds, and if you look at the incidence of intracerebral hemorrhages, there was no significant difference between patients taking both drugs or aspirin alone, but we will need to see the final results, including data about effects on ischemic events, to fully understand how dual antiplatelet therapy actually performed in the study population.”

The reason for excess mortality in the combination arm is also unclear, he continued. “Most deaths were classified as ‘uncertain’ rather than due to vascular causes as one would expect if they were related to the combination therapy.”

“We have yet another well-designed study demonstrating a higher rate of systemic bleeding when aspirin and clopidogrel are used together for long periods, although the risk of intracerebral bleeding was low,” Sheryl Martin-Schild, MD, PhD, assistant professor of neurology and director of the stroke program at Tulane University Medical Center in New Orleans, told Neurology Today in a telephone interview.

However, brief exposure to both drugs in acute settings carries little bleeding risk for stroke patients who are ineligible for tissue plasminogen activator, according to adverse event data collected at Tulane's Stroke Center, she said.

“We load patients with aspirin and clopidogrel and continue both during the acute admission and have not found higher adverse bleeding rates than patients treated with either drug alone, even in patients with large territory strokes. We give them the combination until their stroke has stabilized. We rarely discharge patients on both drugs.”

There are exceptions, though, she continued. “For certain patients, such as those with recent stents or atrial fibrillation deemed ineligible for anticoagulation, I prescribe the combination indefinitely. Some patients have such severe intracranial vascular disease that I am more concerned about the risk of ischemic stroke than systemic bleeding and I recommend continuation of aspirin and clopidogrel. In this case, I inform patients of the risks and that there is no evidence supporting continued dual antiplatelet use.”

Dr. Martin-Schild said she is looking forward to seeing the actual data from the combination arm, as well as the results of the blood pressure and cognitive decline components. “I think this trial will be closely dissected for any potential utility of dual antiplatelets in these patients and may determine if more intensive blood pressure control confers better protection from recurrent stroke and cognitive decline in patients with subcortical strokes.”

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• Diener HC, Bogousslavsky J, Brass LM, et al., on behalf of the MATCH investigators, Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial. Lancet 2004;364:331–337.
    • Cushman WC, Evans GW, Byington RP, et al., on behalf of the ACCORD Study Group: Effects of intensive blood-pressure control in Type 2 diabetes mellitus. N Engl J Med 2010;362:1575–1585.
      • Hills NK, Johnston SC. Trends in usage of alternative antiplatelet therapy after stroke and transient ischemic attack. Stroke 2008;39:1228–1232.
        • Bhatt DL, Fox KAA, Hacke W, et al., for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–1717.
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