Penumbra's FIRST Trial Presented at SNIS

August 1, 2013—The Society of NeuroInterventional Surgery (SNIS) announced that results from the FIRST trial, a prospective, multicenter study of intra-arterial (IA) treatment for acute ischemic stroke that is sponsored by Penumbra, Inc. (Alameda, CA), were presented at the SNIS 10th annual meeting in Miami Beach, Florida.

According the SNIS, multiple studies have been conducted during the past 5 to 10 years to assess the effectiveness of the evolving trend of IA treatment for acute ischemic stroke; however, the clinical outcomes of these treatments have never been compared to the outcomes of patients who were IA-eligible but not treated, thus the long-term benefits of these therapies have remained unclear.

Co-chair of the SNIS meeting, Don Frei, MD, noted that the FIRST trial provides an invaluable opportunity to gather real-world data that clearly show the natural evolution of ischemic stroke in patients who are not treated.

In the SNIS press release, Dr. Frei commented, “As all of our IA research to date has focused on single-study evaluation, or has compared treatments utilizing various devices, we have not had a valid control group comprised of ideal IA-eligible, but untreated, patients to provide the proper context for our work. FIRST fills that gap with meaningful data in our field's continuing assessment of IA stroke treatment and its impact.”

According to SNIS, the FIRST trial includes 62 patients to date, all of whom met the criteria for IA therapy, including presentation with large-vessel blockages in both the middle cerebral artery (MCA) and internal cerebral artery (ICA) within the standard 8-hour time window from the onset of stroke symptoms, but were not treated due to various reasons. These reasons include lack of access to a comprehensive stroke center. Results showed that only 10% of patients experienced restoration of blood flow in the affected brain vessel, and only 20.7% of patients were functionally independent 90 days after their stroke event. The remaining patients either died or were permanently disabled, experiencing a significant loss of quality of life.

Vallabh Janardhan, MD, who is Director of the Texas Stroke Institute, served as a Principal Investigator of the FIRST trial. Dr. Janardhan commented in the SNIS press release, “We have learned over the years that blocked blood vessels that result in heart attacks need to be reopened for patients to experience good outcomes from treatment. Our initial results show that blocked blood vessels that result in ‘brain attacks' can have devastating outcomes, with close to 80% of patients either dying or becoming severely disabled, if IA treatment options are not available within the required timeframe.”

As summarized in the SNIS announcement, differences in patient outcomes are notable when comparing FIRST results with previous studies designed to assess the effectiveness of IA therapy utilizing devices, including the Penumbra stroke system's safety and efficacy trial and the PICS (Penumbra Imaging Collaborative Study) trial.

In FIRST, blood flow was restored in more than 82% to 85% of patients treated with IA therapy as compared to 10% of the untreated patients in the trial. Additionally, the proportion of patients who achieved functional independence ranged from 37% to 44.7% in IA studies as compared to only 20.7% of FIRST trial patients. Treated patients also tended to have a much lower rate of mortality, with a range of 23.6% to 25.3%, than the untreated patients who had a mortality rate of 41.9%.

According to Dr. Frei, by providing a viable control population, the FIRST trial “may very well serve as a benchmark stroke study against which to compare current and future device trials.” A traditional benchmark for many neurointerventionists has been the PROACT II (Intra-Arterial Prourokinase for Acute Ischemic Stroke Trial) study comparing IA/prourokinase plus heparin versus heparin alone. However, as Dr. Frei noted, PROACT II included a control group (heparin-alone patients) that is not reflective of the current patient population that would be treated with IA therapy today. PROACT II was published in 1999 by Anthony Furlan, MD, et al in in the Journal of the American Medical Association (1999;282:2003–2011).

According to SNIS, in comparing FIRST and PROACT II, there were notable differences in entry criteria. FIRST patients presented to the hospital with MCA or ICA strokes within 8 hours, but PROACT II included only those patients with MCA strokes who arrived at the hospital within 6 hours. After treatment, when only comparing the outcomes of MCA strokes, FIRST patients showed notably worse results with restoration of blood flow in 8% of cases and a mortality rate of 36.6% as compared to 18% and 27.1%, respectively, in PROACT II.

At 7-day follow-up in FIRST, 21.4% of patients improved their National Institute of Health Stroke Scale (NIHSS) score by 50% or more. In PROACT II, 44% of patients achieved this measure at 90 days.

Dr. Janardhan commented, “As FIRST patients are representative of the stroke population that we consider for IA therapy today, and their results are considerably worse than those patients in PROACT II, the case can be more clearly made that eligible patients can indeed benefit from advanced therapy. With the addition of FIRST data to the growing research portfolio on IA therapy, the scientific community will benefit from the ability to measure future device trials against a viable control population.”

The FIRST trial is a prospective, multicenter, single-arm, natural history study with the specified inclusion criteria of large-vessel occlusion in the anterior circulation, presentation to hospital within 8 hours of symptom onset, a baseline NIHSS ≥ 10, patient ineligibility or refractory to lytic therapy, and eligibility for but untreated by intra-arterial therapy.

Of the 62 patients in FIRST, the mean age was 68 years (± 15.6), the median NIHSS score was 18, 100% of patients presented with TIMI (0–1), 98.4% of patients presented with TICI (0–1), and 52% of patients were refractory to intravenous recombinant tissue plasminogen activator. Other characteristics of the total study population included 59.7% women, 66% experienced MCA strokes, 31% experienced ICA strokes, and 3% had strokes in other locations.

Results showed that 20.7% of patients met the primary endpoint defined as a good functional outcome (modified Rankin Scale score of 0–2) at 90 days, and 14.5% of patients met the secondary endpoint defined as a NIHSS score of 0 to 1 at discharge or an improvement of 10+ points. The study reflected a 41.9% mortality rate, and an additional 37.4% of patients were permanently disabled with significant loss of quality of life. Adverse events occurred in 33.9% of patients, and symptomatic and asymptomatic intracranial hemorrhage occurred in 8.1% and 9.7%, respectively.