Women With Stroke Still Less Likely to Receive Thrombolysis, but Gap Is Narrowing

Erik Greb

June 12, 2020

Women who experience acute stroke are still less likely to receive intravenous (IV) thrombolysis compared to men, new research suggests. However, this gender gap appears to have narrowed significantly over time.

Results of a systematic review and meta-analysis show that among all patients with acute ischemic stroke, women were 13% less likely to receive IV thrombolysis.

However, in studies in which data were provided on the subgroup of patients eligible to receive IV recombinant tissue plasminogen activator (rtPA), the difference in treatment rate among women was reduced to 5%, and the rate was not statistically different from that of men.

"All our analyses showed high levels of between-study variation, indicating that the specific findings are very much study specific," Mathew Reeves, PhD, professor of epidemiology and biostatistics at Michigan State University in East Lansing, told Medscape Medical News.

"The continued presence of this sex difference calls for further studies designed to explain its origins, as well as ongoing surveillance to monitor the magnitude and changes over time," the investigators write.

The study was published online June 10 in Neurology.

Evidence-Based Treatment

IV thrombolysis is among a small number of evidence-based medical treatments for acute ischemic stroke. A previous meta-analysis by these investigators, which included 18 studies published between 2000 and 2008, showed that women were 30% less likely to receive IV rtPA compared with men.

Sex differences in care and outcomes following stroke could reflect differences in access to, or delivery of, medical care. Differences in eligibility for treatment are another potential explanation of the sex-based discrepancy in treatment, the researchers note. For example, severe hypertension on presentation, which is more common in women, has been considered a contraindication for IV thrombolysis.

For this new report, the investigators conducted a systematic review and meta-analysis to determine whether the administration of IV thrombolysis still differed by sex.

Using the same search terms as in the previous review, they searched the MEDLINE, EMBASE, and ISI Web of Science databases for articles published between April 2008 and December 2018 that included information about sex-specific treatment rates of IV thrombolysis for acute ischemic stroke in hospital settings.

The primary outcome measure was the unadjusted odds ratio (OR) comparing the IV rtPA treatment rate in women with that of men among all admissions for ischemic stroke.

The investigators identified 1097 studies, of which 31 met eligibility criteria. They excluded seven studies that used the same data source from a similar time as another publication. Twenty-four studies were analyzed in the final systematic review. The studies had a broad range of sample sizes and treatment rates.

When Reeves and colleagues analyzed the 17 studies with data on the unadjusted sex differences among all patients with ischemic stroke, they calculated a random effects summary unadjusted OR of 0.87 for treatment among women compared with men. However, here was significant heterogeneity among these studies.

Ten studies provided data on the adjusted OR for the sex difference in treatment. Factors for which the data were adjusted included age, comorbidities, stroke severity, and race. The summary adjusted OR was 0.95, but there was also significant heterogeniety between these studies.

For the seven studies that provided data on the subgroup of patients who were eligible to receive rtPA, the summary unadjusted OR was 0.95 (95% confidence interval, 0.88 –1.02). These studies were less heterogeneous, and the difference in treatment rate by sex was not statistically significant.

Recent systematic reviews have suggested that differences in the clinical presentation of stroke might explain the lower likelihood that women would receive thrombolysis, the investigators note.

Sex differences in patient preference could also be an influential factor. A Canadian study of case scenarios indicated that women were less likely to accept thrombolysis compared with men.

Significant Limitations

Commenting on these findings for Medscape Medical News, Louis R. Caplan, MD, professor of neurology at Harvard Medical School in Boston, Massachusetts, said a lack of relevant data significantly limits the conclusions that can be drawn from the study.

"We do not know the reason for excluding treatment, nor do we know the protocols at the centers from which the data were collected," he said.

In addition, the study does not report whether National Institutes of Health Stroke Scale (NIHSS) scores for women or men were available, nor does it describe whether NIHSS scores were used to select candidates for treatment, said Caplan, who was not involved in the study.

In most of the studies, the investigators adjusted for age, comorbidities, and severity, "but it would have been nice if studies had data on other factors, such as socioeconomic status and living alone," Reeves acknowledged.

"The best approach to understanding these differences is to do two analyses," Reeves said. "First, examine sex differences within the subpopulation of stroke cases who are known to be eligible (they arrived within 4.5 hours and had no contraindications).

"Second, follow this up with a careful accounting of all the reasons that a patient was deemed ineligible, including delayed arrival, presence of contraindications, inability to clarify critical clinical information, other detailed clinical aspects of the lesion itself," Reeves added. "However, these latter data points are hard to come by in large studies."

Caplan noted that clinical practice in many academic hospital centers and advanced stroke centers changed during the study period.

"Now, more centers do more vascular imaging and perfusion imaging than during the early years of the data collection," he said.

"Since women have more embolic infarcts and fewer large-artery lesions, this imaging may identify fewer situations in which the benefit vs the risk of thrombolysis or mechanical embolectomy does not favor treatment," he added.

Reeves countered that he is "not aware of any data showing whether and how these newer imaging methods would affect the assessment of eligibility for tPA ― and critically, whether this is different between men and women. This [information] will probably be more relevant to the assessment of endovascular therapy–based treatments," said Reeves.

"People are going to look at [the study by Reeves and colleagues] and say, 'Women are undertreated,' " Caplan added. "That's a wrong conclusion. We don't know. It might be a good thing that they were not treated. They may not have had vascular lesions for which the benefit-risk ratio would favor treatment.

"To make sense of it, you need to collect a lot more data," he concluded.

The investigators and Caplan report no relevant financial relationships.

Neurology. Published online June 10, 2020. Abstract

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