Coagulation Markers Linked to Stroke Outcome in Hyperglycemia

Deborah Brauser

March 05, 2019

HONOLULU — Alterations in the blood coagulation pathway may help explain worse outcomes often seen after patients with hyperglycemia experience an acute ischemic stroke (AIS) — and glucose control could possibly play a part, new research suggests.

Dr Nina Gentile

The iSPOT study, which included data for 270 participants, was created to determine why patients with hyperglycemia "don't fare as well after stroke as patients who have normal blood glucose," lead author Nina T. Gentile, MD, professor and vice-chair for research at Temple University School of Medicine, Philadelphia, Pennsylvania, told Medscape Medical News.

Results showed that the tissue factor pathway of procoagulation for most of the markers measured was "overactivated" at baseline and then decreased 48 hours later, regardless of whether the patients received intensive glucose control treatment (targeted at 80 to 130 mg/dL) or standard of care (targeted up to 179 mg/dL).

Interestingly, the type of glucose control only affected outcomes in the patients who did not receive tissue plasminogen activator (tPA) therapy. In these patients, there was a greater reduction from baseline in mean level of FVIIa for those who received standard of care compared with those in the intensive glucose-control treatment group. However, favorable outcomes were associated with elevations in FVIIa.

Exploratory analyses showed that for the intensive glucose-control group, there was a significant link between favorable outcomes and increases in FVIIa, as well as reductions in tissue factor procoagulant activity (TF-PCA) and FVIII — but only for those who did not receive tPA.

For those who did receive tPA, there were no significant differences in glucose control treatment or in functional outcomes, suggesting that tPA itself may be affecting these biomarkers and "diluting" their effect, Gentile noted.

She presented the findings here at the International Stroke Conference (ISC) 2019.

Assessing Glucose Control on Blood Coagulation

Past research has shown an association between hyperglycemia in AIS and "elevated markers of tissue factor (TF) pathway activation of blood coagulation, and with worse functional outcomes," the investigators write.

However, the relationship between these markers and glucose control or with functional outcomes post stroke has been "unknown," they add.

iSPOT is an ancillary trial to the randomized SHINE trial, which, as reported by Medscape Medical News, was presented at the ISC 2019 meeting on February 6.

SHINE, which included 1100 hyperglycemic patients, showed that those who received up to 72 hours of continuous IV insulin infusion targeted to 80 to 130 mg/dL did not have greater functional improvement scores on the modified Rankin Scale 90 days post stroke compared with those who received subcutaneous insulin targeted to 80 to 179 mg/dL.

"This isn't a substudy of SHINE. We have our own infrastructure, and it was funded separately," Gentile said. "The reason why it's linked is because to duplicate the clinical trial just for the purposes of collecting the blood for the biomarkers is crazy. So we used the opportunity that SHINE provided us. It's not a subanalysis of data, it's additional data."

For iSPOT, the investigators assessed 270 patients from SHINE. Half of these participants received the intensive glucose control protocol, and the other half received standard glucose control.

"iSPOT has been working alongside the SHINE trial in order to better understand both studies' results," Gentile explained. "SHINE showed that intensive control of blood glucose does not improve stroke outcome. For our trial, we tried to determine the effects of intensive glucose control on blood coagulation and their relationship to stroke outcomes."

Eight Markers Measured

Eligibility criteria included treatment less than 12 hours after AIS onset, a score of 3 to 22 on the National Institutes of Health Stroke Scale, and a blood glucose level higher than 110 mg/dL if the patient had a history of diabetes or a level of 150 mg/dL or higher if the patient had no history of diabetes. Exclusion criteria were a history of a thrombotic or hypercoaguable condition.

At time of randomization and again 48 hours later, blood samples were collected to measure levels of eight markers: FVII, FVIIa, FVIII, TF-PCA, tissue factor pathway inhibitor, thrombin antithrombin, plasminogen activator inhibitor–1, and D-dimer.

In the intensive group, 30 patients had favorable functional outcomes, and 102 patients had unfavorable outcomes. In the standard-treatment group, 20 patients had favorable outcomes, and 112 had unfavorable outcomes.

Among patients in the intensive group, for those with favorable outcomes, the initial mean blood glucose level was 167 mg/dL; at the 48-hour assessment, it was 98 mg/dL. For those with unfavorable outcomes, the mean levels were 163 mg/dL and 106.5 mg/dL, respectively.

In the standard-treatment group, the glucose levels were 177 and 150 mg/dL, respectively, for those with favorable outcomes, and were 184 and 187 mg/dL for those with unfavorable outcomes.

"The key characteristics were similar between treatment groups with the exception of an expected difference between the intensive and standard arms at 48-hour blood glucose measurement," Gentile told meeting attendees. "Our patients were also similar in terms of whether they had a favorable or unfavorable outcome in each arm."

Critical Impact?

Results showed that "with few exceptions, biomarker levels after stroke were extremely elevated at baseline and then fell over 48 hours in both tPA- and non-tPA-treated patients," Gentile said. In addition, "there was very little change in factor levels by [glucose] treatment group."

The one exception was for FVIIa. Among patients not treated with tPA, those in the intensive glucose-control group showed "very little difference" in levels of FVIIa from baseline to 48 hours, said Gentile, whereas those in the standard group showed a significant reduction in levels (P < .05).

This potential marker was significantly associated with functional outcome but, again, only in those not treated with tPA. In this group, significant elevations in FVIIa levels were found in those with favorable vs unfavorable outcomes (P < .01).

In those with favorable outcomes, there were also trends for greater reductions in levels of TF-PCA and FVIII, "both of which are strong markers of coagulation," and for a rise in FVII (for all, P < .1), Gentile noted.

Exploratory analyses assessed possible interactions between factor levels, functional outcome, and treatment. In the non-TPA-treated patients in the intensive glucose-control group, a favorable outcome was significantly associated with greater reductions from baseline in TF-PCA (P < .01) and FVIII (P < .05) and with elevations in FVIIa (P < .05) in comparison with nonfavorable outcomes.

However, among the non-tPA-treated patients who received standard glucose-control therapy, there was only an association between favorable outcomes and increases in FVII (P < .01).

Overall, "intensive blood glucose treatment makes a critical impact on an important marker of blood coagulation," Gentile said.

However, "further study is needed to understand these findings, particularly in context of the SHINE overall primary results," she added.

Gentile later told Medscape Medical News that "there's probably something there, but were we able to see something that was more sensitive than an overall clinical outcome in these patients? We were diving pretty deep and looking at things that don't have as many variabilities.

"I think we were able to find a signal that may be diluted by so many other factors that impact on clinical outcome, but this opens up a number of hypotheses. Are there subsets of SHINE patients that have a stronger signal? Perhaps those are people that may actually benefit from intensive blood glucose control more than others, which is exciting. It opens up the possibility that we could really target and be very specific about therapies for these people," said Gentile.

"Future Almost Upon Us"

After the presentation, session co-moderator Peter Panagos, MD, professor of emergency medicine and neurology at Washington University, St. Louis, Missouri, told Medscape Medical News that the results from iSPOT, as well as those from SHINE, "will add a lot" to the field's knowledge base.

Dr Peter Panagos

"Even if doesn't change practice immediately, using this kind of analysis I think is going to lead to long-term benefits and how we understand this group," Panagos said.

He added that the study's take-away message is that AIS is a complicated process, "and we're just beginning to understand the overall ideology and causes of it. Looking at inflammation and atrial fibrillation and hypertensive management are all extremely important. Any bit of knowledge that we can achieve from a certain subgroup population is going to add to the overall specialty of stroke care," he said.

"Serum biomarkers at the point of care and imaging biomarkers that are quick, accessible, and easy to interpret are all going to allow us to move towards a more precision approach to how we manage stroke patients — instead of treating all patients the same way," said Panagos.

"I think serum biomarkers combined with imaging biomarkers are the future, and the future is almost right upon us at this point. So it's an exciting time in this specialty," he said.

The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS). Gentile reports having received a research grant from the National Institutes of Health–NINDS. Panagos has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2019: Abstract LB9. Presented February 7, 2019.

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