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CADISS: No difference in treatment with antiplatelets, anticoagulants after cervical artery dissection
NASHVILLE, Tenn. — For prevention of stroke, major bleeding or death, it did not matter whether patients with cervical artery dissection were treated with antiplatelet drugs or anticoagulants, according to findings from the CADISS study.
Hugh S. Markus, BA, BM Bch, DM, FRCP, and colleagues enrolled 250 patients diagnosed with cervical artery dissection (118, carotid dissection; 132, vertebral dissection) at local hospitals in the United Kingdom and Australia.
Carotid and vertebral dissection accounts for 10% to 25% of stroke in young and middle-aged patients and is associated with risk for recurrent stroke, Markus, from the Stroke Research Group of the department of neurology at the University of Cambridge, said during a presentation. “This has led people to widely use anticoagulants and antiplatelet agents in an attempt to reduce risk of embolization. But there is really no evidence for either approach, and physicians use different approaches, often believing one approach is particularly good for little reason at all. There are also no [randomized controlled trial] data to govern this choice.”
Furthermore, he said, previous research has estimated that the rate of early recurrent stroke in this population is as low as 1% and as high as 15%, “so we are a bit uncertain as to how high this recurrent stroke risk is, and how intensively we need to treat these patients.”
Patients were randomly assigned antiplatelet agents — aspirin, dipyridamole or clopidogrel alone or in dual combination, as determined by the treating physician — or anticoagulation in the form of low–molecular-weight heparin followed by warfarin. The primary endpoint was ipsilateral stroke and death at 3 months.
Four cases of ipsilateral stroke occurred: three in the antiplatelet group, one in the anticoagulant group. There was one case of major bleeding, a subarachnoid hemorrhage in the anticoagulant group. No deaths were reported during the study period.
The groups did not differ in the incidence of the primary endpoint in the intention-to-treat population (OR = 0.335; 95% CI, 0.006-4.233). The low rate of events is “very reassuring,” Markus said.
A central review of imaging failed to confirm dissection in 52 patients, Markus said. Therefore, the researchers conducted a per-protocol analysis of patients whose dissection was confirmed and also found no difference between the groups in the primary endpoint (OR = 0.346; 95% CI, 0.006-4.39), he said.
Failure to confirm dissection was generally due to poor image quality or to other pathologies such as atherosclerosis being found, according to Markus. “This means that some patients may not be getting the appropriate diagnosis, and dissection has a rather different long-term prognosis than other forms of stroke,” he said.
The researchers determined that, based on the per-protocol endpoint of stroke, death or major bleeding with a power of 0.8 and a significance level of 0.05, it would take a sample size of 9,752 patients to show a difference between the two treatments, Markus said. – by Erik Swain
References:
CADISS trial investigators. Lancet Neurol. 2015;doi:10.1016/S1474-4422(15)70018-9.
Markus HS, et al. Plenary Session II: LB3. Presented at: International Stroke Conference; Feb. 11-13, 2015; Nashville, Tenn.
Disclosure: Markus reports receiving a grant from the Stroke Association for this study.
Perspective
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Cervical (carotid or vertebral) artery dissection is a common cause of stroke in young adults; however, there is limited awareness of this syndrome outside of the field of neurology, and no consensus exists regarding its management. There is significant difference between the pathophysiology of cervical artery vs. systemic (eg, aortic) dissection, former being mostly the result of mechanical trauma to the neck, such as the shearing force of chiropractic manipulation; a sudden, forceful movement of neck during explosive vomiting; or persistent, repetitive trauma of chronic coughing. This unique mechanism and its propensity for associated thromboembolism associated with cervical artery dissection mandates medical therapy that is entirely different from that used, for example, in aortic dissection.
For years, the body of knowledge regarding cervical artery dissection management demonstrated minimal, if any, utility of surgical intervention. In fact, most sources agree that surgical intervention in cervical artery dissection is linked to worse outcomes, including mortality. On the other hand, use of an antithrombotic agent for prevention of thromboembolic stroke became a standard of practice; however, the dilemma of using anticoagulation vs. antiplatelet agents has persisted in literature for decades. Despite being responsible, by some reports, for up to 25% of ischemic strokes in adults younger than 60 years of age, the overall contribution of cervical artery dissection to etiologic stroke subtypes is probably less than 5%. Thus, this relatively small number of cervical artery dissection-associated strokes provided a limited experience for developing management guidelines in the field. In fact, no randomized controlled data regarding safety and efficacy of antiplatelet vs. anticoagulant agents for stroke prevention in cervical artery dissection existed until the CADISS study.
In the CADISS trial, as a result of collaboration between 46 stroke centers, 250 patients with cervical artery dissection (118 carotid, 132 vertebral artery) were randomized to antiplatelet vs. anticoagulant treatment within 7 days of the diagnosis. Individual choice of agents and vascular imaging techniques to confirm the diagnosis were at the discretion of local investigators. At 3 months, death and ipsilateral stroke were assessed by investigators blinded to treatment.
In an intention-to-treat analysis, there was no difference in outcome between the treatment arms, further reinforcing the equipoise of antithrombotic use in cervical artery dissection for prevention of stroke. However, there are several important observations that emerged from this trial that enhanced our understanding of this disease as a whole.
First, rates of recurrent stroke associated with cervical artery dissection are low (1.6%), and all of them occurred ipsilateral to the site of injured vessel. In fact, there were no stroke events identified in cervical artery dissection that manifested with local syndrome (headache, neck pain, or Horner syndrome; n=26). This also points to the fact that cervical artery dissection is likely underdiagnosed in general population, unless it manifests with stroke.
Secondly, CADISS demonstrated that previously accepted radiographic criteria of cervical artery dissection were not confirmed in approximately 20% of diagnoses upon central review. These data highlight the persistent challenge of clinical trial enrollment in stroke and the need for strict diagnosis criteria as well as training and quality control in defining neuroimaging parameters.
Finally, this trial highlights the fact that anticoagulation is equally safe in this patient population (despite a single major bleeding event in anticoagulation group vs. none in antiplatelets), while antiplatelets are generally as effective (despite three ipsilateral stroke events in antiplatelet arm vs. one event in anticoagulant arm). The apparent lack of difference between the two treatment arms may in part be driven by the low event rates in this disease, with estimated sample size needed to demonstrate the difference of nearly 10,000. For now, the decision regarding the choice of antithrombotic will remain at the discretion of treating neurologist, accounting for the specifics of each individual case.