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For Your Patients-Stroke Risk

POST-TIA Stroke Risk Continues for 5 Years

Samson, Kurt

doi: 10.1097/01.NT.0000544501.78577.3c
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An analysis of data from a large international registry of patients who had a transient ischemic attack found that the risk of stroke continues up to five years later.

The risk of stroke after a transient ischemic attack (TIA) or minor stroke is known to be relatively high during the first year, but researchers have found new evidence that it may continue for up to five years.

The findings come from an analysis of data from a large international registry of TIA patients who were recruited after an initial TIA between 2009 and 2011 and followed for five years, including data on comorbid conditions and lifestyle factors. The study was published the June 7 print edition of the New England Journal of Medicine. One-year outcomes by the researchers were reported in the same journal in 2016.

The investigators used the TIA Stroke Registry of patients at moderate-to-high risk for stroke, with more than two thirds with an ABCD2 score of 4 or more at the time of their first stroke. The ABCD2 is a seven-point score for identifying TIA patients at the highest risk of stroke in the following two-days, but also to accurately predict stroke at seven and 90 days. It assigns points for a patient's age (60 years or older), blood pressure of 140/90, diabetes, as well as clinical features such as speech impairment and the duration of such symptoms.

Among the patients, 70.3 percent had hypertension, 8.9 percent were diabetic, and 70.4 had dyslipidemia.

Ipsilateral atherosclerotic stenosis, a major cause of embolism after atrial fibrillation, and small-vessel disease, were both predictors of stroke in the second through fifth year after. Composite risk outcomes included stroke, acute coronary syndrome, or death from cardiovascular causes. These rates were lower than historical cohorts of 22 percent and 17 percent, respectively, before aggressive risk-reduction measures for vascular disease were widely adopted, said corresponding author Pierre Amarenco, MD, director and chair of the department of neurology and Stroke Center at Bichat Hospital in Paris.

Cumulative incidence of the primary outcome and secondary outcomes, excluding deaths from any cause, were 12.9 percent at five years. The risk of stroke was 9.5 percent, approximately twice the rate of 6.2 percent and 5.1 percent, respectively, reported at one year.

“Until now, it was believed that the risk of TIA and minor ischemic stroke was very high within the first three months, but we now know from our data that the risk continues beyond one year with a steep curve,” Dr. Amarenco told Neurology Today. “The message for physicians and vascular neurologists is to continue to emphasize the importance of preventative measures beyond one year.”



Because half of the primary outcome events occurred during years two through five, it raises the question of whether better preventive strategies could decrease the risk of stroke after a TIA or a minor ischemic stroke beyond one year, he said.

“We need to address this long-term risk with new prevention strategies because these data were obtained under optimal control of blood pressure and lipid levels, as well as smoking cessation. We should try to reach unprecedented low levels of low density lipoprotein cholesterol, for example, and through clinical trials of new inhibitors of PCSK9, which plays a critical role in regulating blood cholesterol levels, as well as testing new peroxisome proliferator-activated receptors (PPAR alpha inhibitors).



PPAR inhibitors have shown promise as neuroprotective agents in cerebral ischemia and have demonstrated both preventive and acute neuroprotection, including both cerebral and vascular mechanisms, by decreasing neuronal death.

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Data from 21 countries with dedicated systems for patients with TIA were included, with care delivered by stroke specialists in Europe, Asia, and Latin America. These included emergency departments, stroke units, specialized day and outpatient clinics, all designed to evaluate patients on an urgent basis.

Among 61 sites that had participated in the one-year outcome study, the investigators selected 42 sites that had follow-up data on more than 50 percent of patients. Of these, 77 percent were evaluated by a stroke specialist within 24 hours of their initial hospital admittance.

Before being admitted, 27.7 percent were taking an antiplatelet agent, 87 percent were on aspirin, 10.2 percent were taking dual antiplatelet therapy, 5 percent were on some anticoagulant, 10 percent were being treated with hypertension meds, 92 percent were on a lipid-lowering agent, and 39 percent were taking an anticoagulant to address atrial fibrillation.



After the first stroke, 90.6 percent of patients were receiving antiplatelet therapy, but the rate fell to 71 percent at five years, while 16.2 percent were taking anticoagulant agents compared to 17 percent after five years. Dual antiplatelet therapy was being taken by 10.2 percent before admission, 16.1 percent after being admitted, and 6.6 percent by year five.

The study was supported by unrestricted grants from AstraZeneca, Sanofi, and Bristol-Myers Squibb.

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Elisabeth B. Marsh, MD, associate professor of neurology at the Johns Hopkins University School of Medicine, and director of the university's Bayview Comprehensive Stroke Center, in Baltimore, MD, told Neurology Today that while the study illustrates that the highest rate of stroke recurrence occurs in the year following the initial event, it also shows that individuals continue to have a steady and persistent long-term stroke risk and illustrates the need for continued aggressive risk factor modification.

“The fact that only two-thirds of these individuals were on a statin at five years, and two-thirds were on anticoagulation for atrial fibrillation, illustrates that we have potential room for improvement,” she said.

“The study also confirmed what we know about stroke etiology and risk: that those with atrial fibrillation and large vessel disease have the highest risk of stroke recurrence. It will be interesting to see how the use of dual antiplatelet therapy and high dose statins will impact future recurrence rates.”

S. Claiborne Johnston, MD, PhD, professor of neurology and dean of the Dell Medical School of University of Texas at Austin, agreed. “With further extension of follow-up now out to five years, the [] study shows that the risk of stroke remains high even after the first year of follow-up. We already knew that the risk was high in the first few days, and during the entire first year, but this tells us we need to continue to be vigilant about secondary prevention afterwards.”

Sean I. Savitz, MD, professor and Frank Yatsu chair in neurology and director of the Institute for Stroke and Cerebrovascular Disease at UTHealth in Houston, said there has been a tremendous amount of change in treating these patients in the decades since the study's initiation.

“This study was a major international undertaking that adds to our long-term understanding, and should help inform treatment decisions for such patients,” he told Neurology Today. But he added that the results might look better with today's technical and pharmacological options.

“We are now in what many of us would call a therapeutic era for stroke including selective use of dual antiplatelet treatment. I wonder what a study like this would look like if it were conducted today in light of how far we have come.”

Two clinical trials in particular — POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) and CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) — have recently confirmed that combining aspirin with the antiplatelet clopidogrel helped to reduce major ischemic events after TIA.

One of the challenges with TIA research is the difficulty in differentiating TIAs from other conditions that cause transient neurological symptoms, Dr. Savitz said, adding that that can make accurate diagnosis in an emergency setting difficult in some cases.

“In [these] cases it can be difficult to say for certain if a patient is experiencing a TIA or similar symptoms unrelated to ischemia. It is common in the literature to group TIAs with what are called ‘soft’ TIAs,' and some of these patients could in fact be experiencing a first seizure, a migraine, or other toxic-metabolic event,” he noted.

“The approach by many US hospitals is to assume that a patient with such symptoms is having a TIA,” he said. “In urgent care situations, ‘better to be safe than sorry’ tends to be the general rule, so this study provides us with important information. But I wish there could have been additional analyses to determine risk for subsequent events based on whether the diagnosis was a soft TIA. We have never had five-year outcome data from such a large series of patients, and when you look at the findings it is clear that the adoption of modern preventative stroke therapy has progressed quite a bit not only in the US but also elsewhere around the world.”

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Dr. Amarenco has received grants and/or speaking fees from AstraZeneca, Sanofi, and Bristol Myers-Squibb to fund the Dr. Marsh disclosed that at Johns Hopkins she receives salary support for participation in Medtronic's Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) trial and for Stryker's pipeline stenting trial. Dr. Johnston has received compensation for travel-related expenses from AstraZeneca.

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•. Amarenco P, Lavallée PC, Tavares LM, et al Five-year risk of stroke after TIA or minor ischemic stroke New Engl J Med 2018;378:2182–2190.
•. Amarenco P, Lavallée PC, Labreuche J, et al One-year risk of stroke after transient ischemic attack or minor ischemic stroke N Engl J Med 2016;374:1533–1542.
•. Johnston SC, Easton JD, Farrant M, et al Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA N Engl J Med 2018; Epub 2018 May 16.
    •. Wang Y, Wang Y, Zhao X, et al Clopidogrel with aspirin in acute minor stroke or transient ischemic attack N Engl J Med 2013;369:11–19.
    © 2018 American Academy of Neurology