Highlights From the American Heart Association's International Stroke Conference 2007, San Francisco, California, February 7-9, 2007

Tolerability to aspirin/dipyridamole may be improved by starting with once-daily dosing together with an additional 81-mg dose of aspirin. After 1 week, standard twice-daily dosing of aspirin/dipyridamole can begin with a lower likelihood of adverse events, according to Andre G. Douen, MD.

Start with once daily aspirin/dipyridamole to improve tolerance

“We have traditionally used aspirin for stroke prevention, but studies show that it only provides about a 20% reduction in vascular events. More recently, there have been studies with combined aspirin and extended-release dipyridamole, showing that it will extend the risk reduction to 37% or so,” he said.

The studies to which he referred are the Second European Stroke Prevention Study (ESPS-2) and the European/ Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), which enrolled high-risk patients with stroke or transient ischemic attack (TIA). A significant number of patients started on aspirin/dipyridamole, however, are unable to tolerate this therapy, largely due to headaches, said Dr Douen, adjunct professor of neurology at the University of Ottawa, Ontario, Canada.

About one third of patients enrolled in ESPS-2 and ESPRIT discontinued aspirin/dipyridamole, compared with less than one fifth of patients randomized to aspirin. Headaches and gastrointestinal symptoms were the leading cause of aspirin/dipyridamole discontinuation, and accounted for 33% of the adverse events in ESPS-2 and 26% in ESPRIT.

“Within the first day or 2 of starting aspirin/dipyridamole, you’re going to know if you get headache,” said Dr Douen. “The headaches tend to attenuate and go away after a week. The patients may be uncomfortable with headache and don’t want to use it, particularly if they’ve had a stroke or TIA.”

In an attempt to overcome headache and improve tolerance, Douen and colleagues studied 100 patients with stroke or TIA in an outpatient stroke prevention clinic, starting them on 1 tablet daily of aspirin/dipyridamole (25/200 mg) for 1 week together with 81 mg/day of aspirin. Patients were then continued on the standard twice-daily dose of aspirin/ dipyridamole after 1 week.

Eighty-six patients continued the use of aspirin/dipyridamole without complications. Therapy was discontinued or switched in 14 others for adverse events or medical reasons. Only 6 of the 14 stopped for problems related to aspirin/dipyridamole; 5 of whom reported nausea plus headache. “Nausea seemed to be the more prominent reason for discontinuing,” said Dr Douen. One patient had severe headache without nausea.

Of the remaining 8 patients who discontinued, 5 were switched for medical reasons and 3 were switched to aspirin alone by the family physician.

After switching to twice-daily dosing of aspirin/dipyridamole after about a week, “you can either maintain the 81 mg of aspirin if you wish or you can remove it,” he said. “A lot of stroke patients also have some cardiac risk factors or prior heart disease; the cardiologists like these patients to be on 75 mg or more of aspirin per day and they often say that there’s not enough aspirin in the aspirin/dipyridamole formulation. Maintaining an extra dose of 81 mg of aspirin helps to cover that.”

A surge in the incidence of stroke occurs about a decade earlier in women than in men. Further, when women do suffer a stroke, their presenting symptoms are more often atypical compared with men.

Stroke surge hits women earlier; presentation may be different in women vs men

An analysis of data from the National Health and Nutrition Examination Surveys (NHANES) over 3 time periods (1999-2000, 2001-2002, and 2003-2004) reveals that women 45-to-54 years old are more than twice as likely to have a stroke than men in this age group, said Amytis Towfighi, MD. This elevation in stroke risk is accompanied by an elevation in certain biomarkers during this period in their lives.

Among 17,061 adults who took part of the NHANES from 1999 to 2004, 15,309 answered questions about stroke, and 606 (4%) of them had suffered a stroke.

The prevalence of stroke was equal among men and women aged 35 to 44 years. In the earliest survey (1999), stroke prevalence was also equal among men and women 45 to 54 years old, but in 2004, women aged 45 to 54 were 4 times as likely to have had a stroke than men aged 45 to 54.

In the 45 to 54 age group, independent predictors of stroke in women were coronary artery disease (CAD), which increased the risk of stroke by almost 13 times, and an increase in waist circumference, which increased the risk of stroke by 54%.

Women aged 45 to 54 had 4 times the odds of having CAD compared with women 35 to 44 years old, and had almost twice the odds of having hypertension than women 55 to 64 years old.

“CAD is generally more prevalent in men than women, but in the age group of 45 to 54, it was higher in women. Women’s risk of CAD increased 4-fold from before age 45 to after age 45,” said Dr Towfighi, a neurovascular fellow at the University of California Los Angeles Stroke Center.

The risk factors for stroke increased at a much higher rate in women than they did in men, she said.

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Women had a sharper rise in blood pressure, total cholesterol, and glycohemoglobin at age 45 to 54 compared with similarly aged men. Starting at age 35, systolic blood pressure increased by 8 to 10 mm Hg in each succeeding decade among women and by 4 mm Hg among men. The mean total cholesterol level was higher in men vs women aged 35 to 44 (207 mg/dL vs 198 mg/dL; = .001), but by age 55, it was higher in women compared with men (221 mg/dL vs 212 mg/dL; = .003).

Similarly, while men aged 35 to 44 had higher glycohemoglobin, women’s levels increased at a higher rate than did men’s levels, so that glycohemoglobin levels were the same by age 55.

Other data presented here reveal that classic stroke symptoms are often absent in women.

Chief complaints were analyzed from 1724 ED patients who were ultimately confirmed to have a stroke. The chief complaints consistent with the American Stroke Association’s warning signs are numbness/weakness, confusion/trouble speaking, trouble seeing, trouble walking and/or dizziness, and headache.

“The big difference is that 10% of males and 15% of females had none of the 5 warning signs, at least as they described in their chief complaint,” said lead investigator Julia Gargano, MS.

After adjusting for other factors, women were 40% less likely to report difficulty with walking/balance or coordination/dizziness, were 20% less likely to report trouble seeing, and 33% less likely to report any of the 5 warning signs.

The most common complaints among the patients without any of the warning signs were loss of consciousness or syncope, respiratory complaints, falls or accidents, pain, and seizure. Each of these complaints was more common among women than men.

“Our research group is currently trying to understand the role of the presenting symptoms on delays in evaluation observed in our Michigan stroke registry data,” said Ms. Gargano, PhD candidate in the department of epidemiology at Michigan State University, East Lansing, Mich. These data show that 59% of men but only 44% of women ultimately confirmed to have stroke (but who arrive <2 hours after symptom onset) receive brain imaging within 60 minutes of ED arrival.

Risk factors associated with diabetes are not well controlled among patients with acute stroke, reported Lee Schwamm, MD. These patients are therefore at risk for recurrent stroke and cardiovascular and microvascular complications.

Control of diabetes and associated risk factors is suboptimal in stroke patients

Patients with diabetes that went undiagnosed until their admission for stroke had more poorly controlled risk factors at both admission and discharge.

For this study, data were obtained on 159,338 patients who suffered an ischemic stroke or transient ischemic attack (TIA). Of these, 46,436 had known diabetes at the time of their admission for stroke and 2630 were newly diagnosed with diabetes at stroke admission. Adherence to a subset of evidence-based interventions relevant to diabetes care was analyzed.

Compared with patients with known diabetes prior to their index stroke or TIA, those with newly diagnosed diabetes had a higher percentage of ischemic stroke (88.7% vs 77.7%), a higher mean low-density lipoprotein (LDL) cholesterol (117.6 mg/dL vs 106.1 mg/dL), a higher hemoglobin A1c (A1c) level (8.18% vs 7.87%), a greater prevalence of atrial fibrillation (13.0% vs 10.2%), and a greater prevalence of smoking (19.9% vs 13.7%). More patients with known diabetes met the criteria for a diagnosis of obesity (31.2% vs 27.2%).

Those newly diagnosed with diabetes also had fewer vascular risk factors documented in their medical history prior to admission, and were more likely to have their A1c or LDL cholesterol measured while in the hospital.

Forty-one percent of those known to have diabetes had no cholesterol measurement performed in the hospital. Of those with LDL cholesterol measured, 29% were above the goal of 100 mg/dL for patients with diabetes.

Those with newly diagnosed diabetes were less likely to be discharged on cholesterol-reducing therapy (81% of known diabetics vs 77% of newly diagnosed diabetics).

“What’s really startling is that 66% of the patients who were known to be diabetic had no measure of long-term diabetic control while in the hospital, which tells you that the diabetes is simply not being addressed effectively in the in-patient setting. They’re in for their stroke and they’re out,” said Dr Schwamm, vice chairman of neurology and director of acute stroke services, Massachusetts General Hospital, Boston.

Of the patients that had A1c measurements in the hospital, 18% with known diabetes and 36% with newly diagnosed diabetes had levels greater than 7%, indicating lack of control.

These findings on LDL cholesterol and A1c were the most disconcerting findings of this analysis, said Dr Schwamm. “If you’re recognized as having diabetes, lipid control becomes a very important intervention,” he said. “The failure to detect diabetes means that they’re less likely to have lipid control introduced, and control of the diabetes itself was obviously less good in the patients who weren’t known to have diabetes because they’re walking around with essentially unmanaged diabetes.”

Aggressive lipid management should be an important part of management in patients with diabetes, especially one who just had an atherosclerotic event, he said.