Multiple studies have been conducted over the past five to ten years to assess the effectiveness of an evolving trend in acute ischaemic stroke treatment—performing intra-arterial treatment or a minimally invasive surgery using special devices to snare or dissolve clots that are blocking blood flow within a vessel of the brain. However, because the clinical outcomes from these treatments have never been compared to the outcomes of patients who were intra-arterial treatment eligible but not treated, the long-term benefits of these therapies have remained unclear.
According to Don Frei, a neurointerventionist who specialises in intra-arterial treatment and co-chair of the Society of Neurointerventional Surgery (SNIS) 10th Annual Meeting where the study results were reported this week, the trial provides an invaluable opportunity to gather real-world data that clearly shows the natural evolution of ischaemic stroke in patients who are not treated. “As all of our intra-arterial treatment research to date has focused on single study evaluation, or has compared treatments utilising various devices, we have not had a valid control group comprised of ideal intra-arterial treatment-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 intra-arterial treatment stroke treatment and its impact.”
The FIRST Trial includes 62 patients to date, all of whom met the criteria for intra-arterial therapy, including presenting with large vessel blockages in both the middle cerebral artery and internal cerebral artery within the standard eight-hour time window from the onset of stroke symptoms, but were not treated due to various reasons including lack of access to a comprehensive stroke centre. Results showed that only 10% of patients experienced a restoration of blood flow in the affected brain vessel and only 20.7% of patients were functionally independent at 90 days after their stroke event. The remaining patients either died or were permanently disabled, suffering a signficant loss of quality of life.
Vallabh Janardhan, director of the Texas Stroke Institute, USA, and a principal investigator of the FIRST trial said:“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 intra-arterial treatment options are not available within the required timeframe.”
When comparing FIRST results with previous studies designed to assess the effectiveness of intra-arterial therapy utilising devices, the differences in patient outcome are notable. Blood flow was restored in over 82% to 85% of patients treated with intra-arterial therapy as compared to 10% of the untreated patients in the FIRST trial. Additionally, the proportion of patients who achieved functional independence was in the range of 37% to 44.7% in intra-arterial treatment studies as compared to only 20.7% of FIRST trial patients. Treated patients also tended to have a much lower rate of mortality than the untreated patients, with a range of 23.6% to 25.3% compared with 41.9%, respectively.
In providing a viable control population, the FIRST Trial, Frei says “may very well serve as a benchmark stroke study against which to compare current and future device trials.” Traditionally, many practitioners in the neurointerventional field have looked to the intra-arterial PROACT II (Prourokinase for acute ischemic stroke) trial, a study comparing intra-arterial therapy/prourokinase plus heparin versus heparin alone, to fill that role. Published in the Journal of the American Medical Association in 1999, PROACT II included a control group (heparin alone patients) that is not reflective of the current patient population that would be treated with intra-arterial therapy today, says Frei.
When assessing FIRST and PROACT II side by side, differences in entry criteria are notable. FIRST patients presented to the hospital with middle cerebral artery or internal cerebral artery strokes within eight hours as opposed to PROACT II which included only those patients with middle cerebral artery strokes who arrived at the hospital within six hours. Following treatment, when comparing only outcomes of middle cerebral artery strokes, FIRST patients reflected 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. Additionally, when measuring what percentage of patients improved their follow-up National Institute of Health Stroke Scale (NIHSS) score by 50% or more, FIRST patients recorded 21.4% at seven-day follow-up while 44% of PROACT II patients achieved this measure at 90 days.
“As FIRST patients are representative of the stroke population that we consider for intra-arterial 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,” says Janardhan. “With the addition of FIRST data to the growing research portfolio on intra-arterial 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, multicentre, single-arm natural history study. Patients with a large vessel occlusion in the anterior circulation, who presented to hospital within eight hours of symptom onset, with a baseline NIHSS score equal to or over 10 were included in the study. The cohort had to be ineligible or refractory to lytic therapy and eligible for, but untreated by intra-arterial therapy.
Of 62 study participants, the mean age was 68 years (±15.6); the median NIHSS score was 18; All patients were TIMI (0–1); 98.4% of patients were TICI (0–1) on presentation; and the percentage of patients refractory to intravenous tissue plasminogen activator was 52%. Of the total study population, 59.7% were female; 66% suffered middle cerebral artery strokes; 31% suffered from internal cerebral artery strokes; and 3% suffered strokes in other locations. Results showed that 20.7% of patients met the primary endpoint defined as a good functional outcome (modified Rankin Scale of 0–2) at 90 days, and 14.5% of patients met the secondary endpoint defined as a NIHSS score of 0–1 at discharge, or an improvement of ten plus 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 haemmorhage occurred in 8.1% and 9.7% respectively.