CADISS: Antiplatelet, Anticoagulant Equal in Cervical Dissection

Susan Jeffrey

February 17, 2015

NASHVILLE, TENNESSEE — A new study finds no difference between antiplatelet and anticoagulant treatment for patients with cervical artery dissection in preventing stroke or death.

However, endpoint events were rare: Only 2% of patients had recurrent stroke at 3 months, lower than rates reported in previous studies, the researchers note. Twenty percent of dissections weren't confirmed after a central review of imaging, "suggesting criteria for diagnosis are not correctly applied in all cases," they report.

"The results of our study, to our knowledge the first randomized trial of antiplatelet treatment compared with anticoagulant treatment for extracranial carotid and vertebral artery dissection, show that recurrent stroke at three months is rare, with no significant difference between the two treatments," the researchers, with first author Hugh S. Markus, University of Cambridge, United Kingdom, conclude.

Dr Hugh S. Markus

"Although more strokes occurred in the antiplatelet group than in the anticoagulant group, this difference was counterbalanced by one major subarachnoid hemorrhage in the anticoagulant group," they note.

Dr Markus told Medscape Medical News that, on the basis of these data, either approach is "reasonable, but antiplatelets are easier, so I would tend to use these now," specifically clopidogrel, he noted. "If anticoagulants are given, then a short course of perhaps a couple of weeks or a month would be a reasonable option, followed by an antiplatelet."

Results of the Cervical Artery Dissection in Stroke Study (CADISS) were presented here at the International Stroke Conference (ISC) 2015, with simultaneous publication online February 12 in Lancet Neurology.

Antiplatelet vs Anticoagulant

Extracranial carotid and vertebral artery dissection is an important cause of stroke, accounting for about 1% of all strokes but about 25% of strokes in young people, Dr Markus said.

In some observational studies it has been associated with a high risk for recurrent stroke, he noted. "This worries us, and we believe this is primarily embolic. This is suggested by the pattern of infarcts we see and also the fact that we can detect emboli using transcranial Doppler distal to the dissection."

Both antiplatelet drugs and anticoagulant drugs are used to reduce this risk for embolization, but whether one treatment strategy is more effective is not known. There is currently no evidence for either approach, and physicians use very different approaches, "often believing one approach is particularly good for very little reason at all," Dr Markus said. "And there's no RCT [randomized clinical trial] data to govern this choice."

Also unclear is how high the actual risk for stroke is and how intensive treatment needs to be, he added.

CADISS was set up as an initial phase 2 feasibility trial in 250 patients, "to allow us to power a larger definitive study if that was the appropriate thing to do next," he said, and to better define the actual risk for recurrent stroke.

CADISS included 250 patients with carotid (n = 118) and vertebral (n = 132) dissection with symptom onset within the last 7 days from hospitals with specialized stroke and neurology services in the United Kingdom and Australia.

Patients were randomly assigned to receive antiplatelet drugs or anticoagulant drugs for 3 months, with local clinicians choosing the specific treatment. Antiplatelets included aspirin, clopidogrel, or both; anticoagulants consisted of low-molecular-weight heparin, followed by warfarin.

Patients and clinicians were not masked to allocation, but there was blinded assessment of endpoints by an adjudication committee.

Diagnosis was made by the local center using MRI; Doppler imaging was not considered adequate to diagnose dissection, Dr Markus noted. Images were then collected and reassessed centrally.

The primary endpoint was ipsilateral stroke or death in the intention-to-treat population at 3 months.

"This was quite a challenging study to recruit to," Dr Markus noted. "We started off, but then we were hit by the European Clinical Trials directive, [revision of clinical trials guidelines in the European Union] and rather overinterpretation perhaps of some of the directives that came out of that. Recruitment was temporarily stopped, but then we managed to pick up again, and we were lucky to be joined by Australia for the last few years of the study and we managed to recruit all 250 patients," with complete follow-up.

Mean time to randomization was 3.65 days (standard deviation, 1.91); about 10% of patients had received thrombolysis. The major presenting symptoms were stroke or transient ischemic attack in about 80% (n = 224) and local symptoms (headache, neck pain, or Horner's syndrome; n = 26) in the remainder.

"The first striking this is how few endpoints there were in these patients," Dr Markus said. "So there were only four strokes, they were all ipsilateral." Strokes were seen only among the majority of patients who first presented with a stroke, he noted; none were seen among those presenting with exclusively local symptoms.

"So this gives us a recurrent stroke rate of 1.6%, or if you look at only those patients presenting with stroke, it was 2.1%," he said.

No patients died, but one major bleeding event (subarachnoid hemorrhage) occurred in the anticoagulant group.

"If one looks at analysis by treatment, not surprisingly there are no significant differences between these groups," he said.

Table 1. CADISS: Ipsilateral Stroke or Death by Treatment Group (Intention-to-Treat)

Endpoint Antiplatelet Treatment (n = 126), n (%) Anticoagulant Treatment (n = 124), n (%) Odds Ratio (95% Confidence Interval) P Value
Ipsilateral stroke or death at 3 mo 3 (2) 1 (1) 0.335 (0.006 - 4.233) .63

 

Central review of imaging failed to confirm dissection in 52 patients. Much of the imaging for these cases was of poor quality, so although a dissection might have been present, it couldn't be confirmed on the scans provided, he said. In other cases, alternative abnormalities were found, including atherosclerosis, atretic rather than vertebral artery, and narrowed artery without definite evidence of dissection.

Preplanned per protocol analysis excluding these patients retained all the endpoints seen in the intention-to-treat analysis but again showed no significant treatment difference.

Table 2. CADISS: Ipsilateral Stroke or Death by Treatment Group (Per Protocol)

Endpoint Antiplatelet Treatment (n = 101), n (%) Anticoagulant Treatment (n = 96), n (%) Odds Ratio (95% Confidence Interval) P Value
Ipsilateral stroke or death at 3 mo n (%) 3 (3) 1 (1) 0.346 (0.006 - 4.390) .66

 

Power calculations for a definitive phase 3 trial to answer this question based on these recurrence rates showed that approximately 9972 patients would be required to show a difference between the two treatments, "which I think in a condition like dissection will be a great challenge," Dr Markus concluded, although he cautioned that confidence intervals were wide because of the small number of events.

"In conclusion, I think CADISS has shown in a perhaps more rigorous sampling frame that the recurrent stroke rate in these patients is low; 1.6% in the intention-to-treat and 2.0% in the per protocol analysis," he said. "This is lower than has been reported in some observational studies, and I think this is very reassuring for us and for our patients."

There was no difference between treatments, but this is based on few endpoints, he noted.

Review did not confirm diagnosis of dissection in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice. "This really does suggest that the diagnostic criteria for dissection are not always appropriately implemented in practice," Dr Markus said. "This has quite big implications because this means that the patients may not be getting the appropriate diagnosis, and dissection, as we all know, has a rather different long-term prognosis to other forms of stroke, so it is important to make accurate diagnosis."

Treatment Controversial

In an editorial accompanying the publication, Scott E. Kasner, MD, Department of Neurology, University of Pennsylvania, Philadelphia, points out that the CADISS investigators estimated that a future trial with a similar design would require 10,000 patients to detect a 1% difference in ipsilateral stroke or death between treatments.

"If the population could be restricted to those who present with stroke, are correctly and rapidly diagnosed, and are then enrolled and treated early, maybe only half or even a quarter as many participants would be needed. Testing of newer oral anticoagulants, which are probably safer and easier to manage than warfarin, should also be considered," Dr Kasner notes.

However, despite "outstanding sites" in the United Kingdom and Australia, recruitment in CADISS occurred at an average of one participant per center per year. A study of even 5000 patients might take 500 sites and 10 years to complete recruitment, he points out.

"The primary objective of CADISS was to establish the feasibility of a definitive clinical trial comparing antiplatelet treatment with anticoagulation for patients with cervical artery dissection," Dr Kasner writes. "The investigators achieved their objective—that pivotal trial is not feasible at present."

"Antiplatelet treatment seems to be the safer, more convenient, and less costly default treatment for now, but efforts should continue to understand the pathophysiology of dissection and to identify and characterise the rare patients who remain at risk for subsequent stroke," Dr Kasner concludes.

Dr Kyra Becker

Asked for perspective on these findings, Kyra Becker, MD, ISC chair, professor of neurology, joint professor of neurological surgery, University of Washington School of Medicine, Seattle, said the findings are important.

"I think CADISS was very important given that the treatment of dissection has been so controversial," Dr Becker told Medscape Medical News.  

These data suggest that the risk for stroke or recurrent stroke "is very small and does not appear to be affected by which antithrombotic is used, she noted. "I suspect the findings will change practice in that there seems to be no clear benefit/indication for anticoagulation."

Larry B. Goldstein, MD, professor of medicine, Division of Neurology and director of the Duke Stroke Center at Duke University Medical Center, Durham, North Carolina, cautioned that although the trial was "terribly underpowered," it is nevertheless "probably going to be as close as we're going to get" to an answer given the high numbers calculated to power a phase 3 study, at about 10,000 patients.

Dr Larry B. Goldstein

"That's never going to happen," Dr Goldstein told Medscape Medical News. "It's completely unfeasible."

While some characteristics might argue for anticoagulant treatment in individual patients for at least a period of time, he said, "it seems, at least from these data, that there is no reason to do it in many patients — with all those caveats."

For his part, Dr Goldstein anticipates being less aggressive with using anticoagulants than before. "My own practice in patients who had stroke related to a dissection was anticoagulating for 3 months, with the idea that in general it's fairly safe over a short period of time and because of the uncertainty of the data and the trends in the data suggest possible benefit."

These are often very young people, so they generally do well with anticoagulants in any case, Dr Goldstein said. "Having better data, I think now that risk-benefit may switch the other way since we don't know of there being definite benefit and certainly there's always risk of anticoagulants. There's risk of aspirin also but I would tend to be less sure about using an anticoagulant than I was before," he concluded.

The study was funded by the UK Stroke Association. The researchers have disclosed no relevant financial relationships. Dr Kasner reports he has received personal fees from Bayer, Boehringer Ingelheim, and Daiichi Sankyo, potentially related to this comment.

International Stroke Conference (ISC) 2015. Abstract LB3. Presented February 12, 2015.

Lancet Neurol. Published online February 12, 2015. Abstract Editorial

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