POINT: Success at Last for Dual Antiplatelet After Stroke, TIA

May 17, 2018

GOTHENBURG, Sweden — A combination of clopidogrel plus aspirin reduced major ischemic events, including ischemic stroke, myocardial infarction, or death from ischemic vascular causes, compared with aspirin alone in patients with minor ischemic stroke or high-risk transient ischemic attack (TIA) in the POINT trial.

Although the dual antiplatelet therapy was associated with an increased bleeding risk, the authors say the benefits outweigh the risk.

Results show that for every 1000 patients who are treated with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent approximately 15 major ischemic events and would cause five major hemorrhages.

Presenting the long-awaited trial here at the 4th European Stroke Organisation Conference (ESOC) 2018, Clay Johnston, MD, University of Texas at Austin, noted that while all the benefit occurred in the first month of treatment, bleeding risk continued over the 90-day treatment period, so stopping clopidogrel after 30 days would make sense.

Dr Clay Johnston

"If dual antiplatelet therapy is given for just 30 days, then this results in 19 major ischemic events being prevented per 1000 patients treated at the cost of two extra major bleeds," he reported.

 "My guess is that people will use dual therapy for the 30 days. It wasn't the primary endpoint but it was a prespecified endpoint, and the results are very compelling and fit with the biology," Johnston told Medscape Medical News.

"In addition, we didn't see any increase in fatal or intracranial bleeding. The additional bleeds were systemic — mainly gastrointestinal, which we can treat — and most were reversible," he added. 

On the risk-benefit ratio, Johnston said, "We are preventing many more ischemic events than bleeds caused. And the ischemic events prevented were mainly ischemic strokes, which usually leave permanent damage, whereas the increased bleeds were systemic and mainly reversible. To me, the trade-off is clear."

The trial was published online in the New England Journal of Medicine to coincide with its presentation at the ESOC meeting.

The POINT trial builds on the previous Chinese CHANCE trial, which also showed a reduced ischemic event rate without an increased bleeding risk with 21 days of dual antiplatelet therapy. But the restricted ethnic population of the CHANCE trial and different patterns of stroke care in China have limited the generalizability of the results, Johnston explained.

"The POINT trial provides the confirmation we have been waiting for and broaden the results of the CHANCE trial to more diverse populations and care settings," he said.

The trial was greeted with great enthusiasm by experts at the ESOC meeting, and applause broke out upon presentation of the results at the opening plenary session.

ESOC past president, Kennedy Lees, MD, University of Glasgow, United Kingdom, called POINT "a fantastic trial."

"I am one of those who believed the CHANCE results and so am already doing this, but now routine practice will change," Lees told Medscape Medical News.

"I would say it also confirms that the bleeding risk is there constantly over 3 months, but if the treatment period is restricted to the first 3 or 4 weeks you get the treatment benefit without such a large risk."   

"To my mind, this trial has replicated CHANCE and reinforced its results," Lees said. "As soon as people read the POINT paper they will start using dual antiplatelet therapy — this is something that will happen straight away —  these drugs are already available. It is a safe and very reasonable approach."

Jeffrey Saver, MD, University of California Los Angeles, also said the trial has been "long awaited and much anticipated. It is wonderful to see confirmed positive results. It will have an immediate impact, and I expect that giving dual antiplatelet therapy for 3 to 4 weeks will now become the new approach to care."

ESOC president elect, Bart Van de Worp, MD, University Medical Center, Utrecht, the Netherlands, said, "Before the presentation I was concerned that dual antiplatelet therapy might lead to more intracranial hemorrhages, but while there was a slight increase in bleeding, this was bleeding was outside the brain, which we can treat."

The POINT trial randomly assigned 4881 patients with a minor ischemic stroke or high-risk TIA to receive clopidogrel (600 mg loading dose then 75 mg per day) plus aspirin (50 to 325 mg per day) or the same range of aspirin doses alone for 90 days. The dose of aspirin in each group was selected by the site investigator.

The trial was halted early at 84% of planned enrolment because both the efficacy and safety boundaries were crossed.

Results showed that at 90 days, major ischemic events (stroke, myocardial infarction, cardiovascular death) occurred in 121 of 2432 patients (5.0%) receiving dual therapy and in 160 of 2449 patients (6.5%) receiving aspirin alone (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 - 0.95; P = .02).

Most events occurred during the first week after the initial event, and most of the prevented events were ischemic strokes.

Subgroup analysis showed no benefit in lower-risk TIA patients (those with ABCD scores < 5) because these patients had very low event rates. Johnston said this group would have been more likely to include TIA mimics who wouldn't have had an increased stroke risk.

Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin alone (hazard ratio, 2.32; 95% CI, 1.10 - 4.87; P = .02).

19 Years in the Making

Johnston told Medscape Medical News that the POINT trial is truly long awaited.

"This trial has taken 19 years to complete. It was first proposed in 1999, but people weren't sure we had enough data to launch it back then," he said. "A trial was later funded by industry but that got cancelled for complicated reasons, and so it went back and eventually got funded from the US National Institute of Neurological Disorders and Stroke. But it takes a long time to recruit this many people into a publicly funded trial, which doesn't pay as much as a drug company–sponsored trial on a per-patient basis."

In an accompanying editorial, James C. Grotta, MD,  Memorial Hermann Hospital, Houston, Texas, says it is important to emphasize which patients were not included in this trial.  

He notes that the POINT trial excluded patients with a cardiac source of symptoms, such as atrial fibrillation, most of whom receive anticoagulation; those with severe extracranial carotid disease, who might benefit from endarterectomy or stenting; and those with severe intracranial atherosclerosis, who are typically treated with dual antiplatelet therapy for 3 months or longer after the SAMMPRIS trial. The POINT trial included many of the remaining patients with TIA or stroke.

"Although these patients are certainly at risk for subsequent ischemic events, the risk in this population is low, as shown by the need to increase the sample size midway through the trial," Grotta adds.

"The trial results seem valid and generalizable, given that the trial was conducted in 10 countries, with only 4% of patients being lost to follow-up," he added. "The only procedural blemish is that approximately 29% of the patients discontinued the trial medication before 90 days, but the results were similar in both the intention-to-treat and as-treated analyses."

Grotta concludes that his take-home message from the SAMMPRIS, CHANCE, and POINT trials "is that the combination of aspirin plus clopidogrel reduces the chance of recurrent ischemic stroke during the high-risk period in the first few weeks after a TIA or noncardioembolic ischemic stroke. However, to conform to the results of the POINT trial, if dual therapy is used, it should be confined to the first 3 weeks after a TIA or minor stroke and then transitioned to monotherapy."

If patient follow-up and adherence to therapy are not reliable, then dual therapy perhaps should not be considered, he said. Dual therapy may also not be advisable in patients with an uncertain diagnosis of TIA, who either would have been excluded from the trial or did not benefit.

"Finally, patients who are at increased risk for bleeding, such as those with cerebral microbleeding or a history of brain or systemic bleeding, were excluded from this trial and may not be appropriate candidates for such dual therapy," Grotta said. "The POINT trial has provided useful data to help us further personalize our efforts in preventing recurrent stroke."

 The POINT trial was supported by grants from the National Institute of Neurological Disorders and Stroke. Sanofi provided clopidogrel and placebo for 75% of the patients in the trial.

4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018. 

N Engl J Med. Published online May 16, 2018. Abstract,  Editorial

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