More Evidence That 'Time Is Brain' in Stroke

Pauline Anderson

December 21, 2015

A new analysis from the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) again highlights the importance of time in treating patients with ischemic stroke.

Primary results of MR CLEAN first found that intra-arterial treatment (IAT) improves functional outcomes in patients with ischemic stroke; now, in a paper published online December 21 in JAMA Neurology, they showed that this intervention has better outcomes the earlier it's done.

For every hour of delay to reperfusion, there was a 6% absolute risk difference for a good outcome, defined as a modified Rankin Scale (mRS) score of 0 to 2.

"We now have firm evidence to make benchmarks" and to recommend investigation of a blockage following a stroke and for immediate removal if one is found, said study author Diederik WJ Dippel, MD, PhD, Department of Neurology, Erasmus WC University Medical Center, Rotterdam, the Netherlands.

Dr Diederik WJ Dippel

"Every patient who comes to the emergency room with a stroke needs neuroimaging immediately, including vessel imaging to see if there's a clot obstructing the vessel, and then they need to go to an intervention center as quickly as possible," he said.

These results were first presented at the International Stroke Conference in February 2015 and reported by Medscape Medical News at that time.

The MR CLEAN trial investigated the use of IAT — in almost every case using a retrievable stent — in patients with a confirmed intracranial occlusion in the anterior cerebral circulation who could be treated within 6 hours of stroke onset.

The study was conducted in 16 hospitals in the Netherlands and included 500 patients; the median age was about 66 years and the median National Institutes of Health Stroke Scale score was 17.

Of the 500 patients, 233 were assigned to the intervention group and 267 to the control group (ie, no IAT). All patients received usual treatment, including intravenous tissue plasminogen activator (tPA) treatment if indicated.

The study found that functional outcomes on the mRS were better for patients receiving IAT than for those not receiving IAT: The rate of an mRS score of 0 to 2 was 19.1% for those getting the intervention vs 32.6% for those not getting it. These results were published online December 17, 2014, in the New England Journal of Medicine.

The 7-point mRS ranges from 0 (no symptoms) to 6 (death). A score of 2 or less indicates functional independence and is considered a good outcome.

"A good outcome is being independent with minor deficits, going home and living your life again," although not all stroke patients achieving this outcome will return to work, said Dr Dippel.

In the setting of IAT, delay to reperfusion has been shown to have a negative effect on the likelihood of a good outcome. However, no evidence supported the hypothesis that delays also influence the size of the treatment effect, the researchers say.

Time to Reperfusion

In this new analysis, the median time to groin puncture (TOG), defined as the time from stroke onset to placement of the catheter in the groin, was 256 minutes. Median time to reperfusion (TOR), defined as the time from stroke onset to reperfusion or end of the procedure, was 333 minutes. Reperfusion was defined as a modified Thrombolysis In Cerebral Infarction score of 2b or 3.

Among the 233 patients in the intervention group of MR CLEAN, 7.3% didn't reach the intervention room, the authors note. Treatment was started within 3 hours in 10.7%, at 3 to 4.5 hours in 41.2%, and at more than 4.5 hours in 40.8%. In 8.2% of the patients, treatment started more than 6 hours after stroke onset (these patients were also included in the analysis).

The primary outcome was the mRS score at 90 days.

The study uncovered a statistically significant interaction between TOR and treatment (P = .04) but not between TOG and treatment (P = .26). The association with TOG may not have reached significance because of the varying duration of the intervention (from 46 to 94 minutes), said the authors.

TOR might be a better indicator than TOG of the mechanism of treatment effect modification, said Dr Dippel. "Reperfusion is the key."

After adjustment for age, National Institutes of Health Stroke Scale score, history of stroke, atrial fibrillation, diabetes, and intracranial arterial terminus occlusion, the risk difference (on reaching independence) was 25.9% (95% confidence interval [CI], 8.3% - 44.4%) when reperfusion was reached at 3 hours, 18.8% (95% CI, 6.6% - 32.6%) at 4 hours, and 6.7% (95% CI, 0.4% - 14.5%) at 6 hours.

"There was a 6% per hour less chance of a good outcome; that's very steep," commented Dr Dippel.

"We showed before that this intervention worked, and now we showed that from 0 to 6 hours — actually between 2 and 6 hours as nobody got treated before 2 hours — the treatment effect itself (the difference between treatment and no treatment) diminishes quickly with time, and that's important."

Dr Dippel acknowledged that "we were rather slow" in treating patients, but said this was because the intervention was experimental and so wasn't routinely available at all participating hospitals, and patients had to consent to being randomly assigned, all of which took time.

Bigger Effect

The relationship between time and treatment effect for reperfusion uncovered by the study is greater than that seen with tPA treatment, such as with alteplase, according to Dr Dippel. Intravenous alteplase administered within 4 to 5 hours of stroke onset has been proven to be effective, with the size of the treatment effect diminishing over time.

While time is of the essence when it comes to reperfusion, Dr Dippel stressed that stroke patients treated after 5 hours may still benefit. "It doesn't mean that you should not treat patients after 5 hours," although the benefit is less.

A limitation of the study was the small number of patients treated at the beginning and end of the 6-hour time window, so the 95% CI in the interaction models were wide. Effect estimates from these areas should be interpreted with caution, said the authors.

Asked to comment on the findings, Ralph L. Sacco, MD, professor and chair, neurology, Miller School of Medicine, University of Miami, Florida, noted that the study shows that the concept of "time is brain" applies to intra-arterial treatments.  

Just as door-to-needle time is an important determinant of good outcomes with intravenous tPA, time from stroke onset to reperfusion is a critical determinant of outcomes with intra-arterial interventional therapy for acute ischemic stroke, said Dr Sacco.

"The faster you can restore blood flow in a blocked cerebral artery, the greater the chance of a meaningful recovery," he told Medscape Medical News. "The evidence is strong that the intervention works when used within 6 hours of onset, but the sooner the better."

Researchers are investigating whether the time window can be extended beyond 6 hours under certain circumstances, said Dr Sacco. "But for now, we need to get patients treated as quickly as possible."

Paul M. Katz, MD, director of the Stroke Program at Temple University Hospital, Philadelphia, Pennsylvania, also commented on the study. He said it's "important" that studies like this one that will stimulate stroke centers to organize and put systems into place for the rapid evaluation and treatment of stroke patients.

He noted that many such systems are already in place at his own institution.

This study was supported in part by the Dutch Heart Foundation and unrestricted grants from AngioCare BV, Covidien/EV3, MEDAC GmbH/LAMEPRO, Penumbra, Inc, and Stryker. Dr Dippel reported that his institution receives fees for his role as consultant for Stryker (speakers' bureau/lecture fees).

JAMA Neurol. Published online December 21, 2015. Abstract


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