Adding Third Antiplatelet Did Not Prevent Strokes and Increased Bleeding Risks, Researchers Report
By Ed Susman
April 6, 2017
ARTICLE IN BRIEF
The use of a three-drug antiplatelet combination did not significantly reduce the risk of stroke or transient ischemic attack, according to the TARDIS study investigators.
HOUSTON — The addition of a third antiplatelet drug did nothing to prevent strokes, but it did increase bleeding risks, according to a new report presented here in February at the 2017 International Stroke Conference sponsored by the American Heart Association/American Stroke Association.
Intensive therapy with aspirin, clopidogrel, and dipyridamole had similar outcomes as less intensive therapy at 90 days in terms of stroke or transient ischemic attack (TIA) recurrence and severity on the modified Rankin Scale, said the study leader Philip Bath, MBBS, MD, head of clinical neuroscience at the University of Nottingham in the United Kingdom (UK).
When compared with UK guideline recommendations for one or two antiplatelets, the use of a three-drug combination did not significantly reduce the risk of stroke or transient ischemic attacks (adjusted hazard ratio 0.90 [95% CI 0.69-1.19], p=0.47).
The TARDIS (Triple Antiplatelets for Reducing Dependency in Ischaemic Stroke) study — an international, prospective, randomized open-label blinded-endpoint controlled trial — randomized patients with acute non-cardioembolic ischemic stroke or TIA to intensive antiplatelet therapy (combined aspirin, clopidogrel and dipyridamole) or guideline-recommended antiplatelets (clopidogrel alone, or combined aspirin and dipyridamole) for one month. The primary outcome was stroke and TIA recurrence, and their severity (as measured by the modified Rankin Scale) at three months.
The study protocol required oral aspirin with a loading dose of 300 mg a day and then 75 mg a day for 30 days. There were also provisions for delivering aspirin crushed and by a rectal route. Clopidogrel was delivered with a loading dose of 300 mg, followed by 75 mg a day orally or in a crushed version. Dipyramidole was administered in 200 mg twice a day through day 28 or 150 mg three times a day delivered on all 30 days of the trial.
The trial was limited to patients 50 years old or older who were treated within 48 hours of the onset of stroke symptoms. The patients' symptoms included motor weakness or other signs of stroke, isolated dysphasia, and isolated hemianopia. The trial allowed for relatives or caregivers to consent to enroll in the study if the patient lacked the capacity to do so.
“This was a very inclusive trial,” Dr. Bath said.
Of the 3,096 patents included in the trial, 62.8 percent were men, and the average age of the cohort was 69 years. The average time to randomization from onset of symptoms was 29.3 hours, but those with TIAs had a time of 24.2 hours from onset of symptoms to randomization. Patients who had a stroke were randomized an average of 32.1 hours post-stroke symptom onset.
Dr. Bath said 11.3 percent of the patients in the study had experienced a previous stroke, and 13 percent had previously been diagnosed with ischemic heart disease; 26.4 percent of them had previously been on aspirin therapy, but only 5.2 percent had been on previous clopidogrel, and just 2.7 percent of patients had been on an aspirin plus dipyridamole therapy.
Dr. Bath said the researchers scrutinized outcomes of myriad subgroups and found the triple drug combination showed no benefit consistently over the guideline-recommended treatment strategy.
But when bleeding episodes were analyzed on an ordinal basis — that is, severity of the incidents was calculated — there was a strong significance that indicated intensive therapy caused more bleeding (OR 2.49 [95% CI 2.00-3.10], p<0.001), Dr. Bath reported.
“Any serious adverse events were also similar in both the guideline-driven treatment and the intensive treatment patients, but there were more severe bleeding episodes with intensified therapy,” Dr. Bath said. The risk of bleeding was more than two times greater if the patients were on the intensified therapy rather than on the guideline-driven treatment (p<0.001). Fatal bleeding was also greater numerically, but was low overall. There were seven fatal bleeding episodes in the intensive group and four in the guideline-driven treatment.
“Any tendency for less recurrent cerebral ischemic events was offset by increases in major bleeding with more intensive treatment,” Dr. Bath said.
The TARDIS study will not change clinical practice, he said. “Intensive antiplatelet therapy is not recommended. Clinicians should use the guideline therapy of either clopidogrel or aspirin plus dipyridamole.”
Amytis Towfighi, MD, director of neurological services and innovation for the Los Angeles County Department of Health Services, who moderated the session, said that an ongoing trial in the United States is studying the same treatment choices and may provide a definitive word on whether added therapies are beneficial or not.
“Only one trial in the US has shown a benefit for dual antiplatelet therapy, and that is why we are waiting for the results of the POINT [Platelet-Oriented Inhibition in New TIA] trial,” Dr. Towfighi said. “That is [also] why the US guidelines now recommend single antiplatelet therapy to prevent recurrent stroke. Aspirin and dipyridamole are packaged together in one pill, so it is two drugs in one pill, and we count it as one pill.”
Because there have been trials using dual antiplatelet treatment in people with stents, which showed an anti-stroke benefit, “the stroke community thinks that two is better than one for stroke prevention,” she said. “But that trial has never been done.”
“We really don't know if two [antiplatelets] are better than one [for stroke prevention],” she said. “Considering the TARDIS results, however, we should not be looking at three drugs.”
“This trial asks an important question,” said Mark Alberts, MD, vice chair of clinical affairs in neurology and neurotherapeutics at the University of Texas Southwestern Medical School at Dallas. “And we have gotten a fairly definitive answer which is, more is not better.
“We have seen this with numerous other studies with antiplatelet therapy in both ischemic stroke and coronary artery disease: The more antiplatelet agents you add on and the longer the treatment, the greater the increased risk of hemorrhagic bleeding complications that occur — not just in the brain but elsewhere in the body, such as gastrointestinal hemorrhage.
“We are all looking for a ‘sweet spot’ in terms of identifying that subgroup of patients who are at very high risk for recurrent ischemic events and figuring out how long or how short they need to be treated with more intensive therapy,” Dr. Alberts said.
He also suggested that the outcomes of the POINT study might narrow that sweet spot.
Dr. Bath said that TARDIS was designed to build upon successes of other trials that showed that treatment with antiplatelet agents – first the use of aspirin – appeared to reduce the early recurrence of events after ischemic stroke or TIA. Then researchers added dipyridamole to the aspirin regimen and found better results; and when clopidogrel was added to aspirin [in the subgroup with intracranial stenosis], there were also better results than just treating with aspirin alone. Hence, the researchers wanted to determine if the addition of a third agent would improve outcomes further – but TARDIS did not show that result, he said.