Mechanical Thrombectomy Fails to Show Noninferiority to Combined Intravenous Thrombolysis Approach

Kentaro Suzuki, MD, PhD

Mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding functional outcome in patients with acute large vessel occlusion (LVO) stroke in the SKIP randomized clinical trial (UMIN000021488). Although, wide confidence intervals surrounding the effect estimate did not allow for a conclusion of inferiority.¹

The study, led by Kentaro Suzuki, MD, PhD, department of neurology, Nippon Medical School, Japan, and colleagues observed favorable outcome in 60 of the 101 patients (59.4%) in the mechanical thrombectomy alone group compared to 59 of 103 (57.3%) in the combined group (difference, 2.1% [1-sided 97.5% CI, –11.4 to ¥]; odds ratio [OR], 1.09 [1-sided 97.5% CI, 0.63 to ¥]). Noninferiority was also proven in a separate per-protocol analysis.

Overall, the median age of the enrollment group was 74 years, 128 (62.7%) were men, and the median NIHSS score was 18 (interquartile range [IQR], 12–23). Favorable outcome, the primary outcome of the study, was defined as a modified Rankin Scale (mRS) score of 0 to 2 at 90 days (range, 0 [no symptoms] to 6 [death]), with noninferiority margin ORs of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI).

"Although this study hypothesis could not be proved, the point estimates of treatment effect for mechanical thrombectomy alone was nominally slightly better, not worse, compared with combined therapy. Accordingly, a larger trial or meta-analysis of trials is needed to conclusively assess noninferiority,” Suzuki et al concluded.

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Secondary outcomes showed that mechanical thrombectomy alone was not associated with a favorable shift in the distribution of the mRS score at 90 days (OR, 0.97; 1-sided 97.5% CI, 0.60 to ¥; noninferiority, P = .27) without any violation of the proportional odds assumption (Brant test P = .90). At 90 days after onset, there were 8 deaths (7.9%) in the mechanical thrombectomy alone group and 9 (8.7%) in the combined group (difference, –0.8% [95% CI, –9.5 to 7.8]; OR, 0.90 [95% CI, 0.33 to 2.43]; P >.99).

Among the 7 secondary efficacy end points and 4 safety end points, 10 were not statistically significantly different, including the aforementioned mortality at 90 days.

Suzuki and colleagues did not observe any significantly different rates of successful reperfusion after mechanical thrombectomy, defined as expanded Thrombolysis in Cerebral Infarction (eTICI) grade of 2b or greater between the mechanical thrombectomy alone and combined groups (91 [90.1%] vs 96 [93.2%]; difference, –3.1% [95% CI, –11.8 to 5.6]; OR, 0.66 [95% CI, 0.24 to 1.82]; P = .46).

Intracerebral hemorrhage was assessed by only computed tomography (CT) at 36 hours from onset and identified in 86 patients, 16 of which showed parenchymal hematoma. At 36 hours from onset, the rate of any intracerebral hemorrhage was lower in the mechanical thrombectomy alone group compared with the combined group (34 [33.7%] vs 52 [50.5%]; difference, –16.8% [95% CI, –32.1 to –1.6]; OR, 0.50 [95% CI, 0.28 to 0.88]; P = .02).

The study authors noted that this rate was not statistically significant between the 2 groups based on the National Institute of Neurological Disorders and Stroke (NINDS) criteria (8 [7.9%] vs 12 [11.7%]; difference, –3.7% [95% CI, –13.0 to 5.6]; OR, 0.65 [95% CI, 0.25 to 1.67]; P = .48) and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria (6 [5.9%] vs 8 [7.8%]; difference, –1.8% [95% CI, –9.7 to 6.1]; OR, 0.75 [95% CI, 0.25 to 2.24]; P = .78).

Favorable outcomes were less frequent in patients with any intracerebral hemorrhage (symptomatic [n = 14] and asymptomatic [n = 72]) than those without intracerebral hemorrhage (41.9% [36 of 86] vs 70.3% [83 of 118]; P <.001).

The incidence of other hemorrhagic events was not significantly different (1 of 101 [1%] and 4 of 101 [4%]; P = .37; difference, –2.9% [95% CI, –0.08 to 0.02]; OR, 0.25 [95% CI, 0.03 to 2.25]; P = .37) between the 2 groups.

"Together, the trial findings demonstrate that the treatment strategies of EVT alone and of IVT before EVT (when performed soon after one another at thrombectomy-capable stroke centers) yield numerically similar results for patients with AIS-LVO," Jeffrey L. Saver, MD, neurologist, University of California, wrote in a related editorial. "The findings from these studies reinforce and extend the results of another recently published study, the DIRECT-MT trial,² which enrolled 656 Chinese patients with AIS-LVO."

He added, "In that trial, EVT alone was noninferior to EVT plus IVT (alteplase, 0.9 mg/kg) with regard to functional outcome at 90 days based on the between-group difference in the distribution of the modified Rankin Scale scores (adjusted common odds ratio, 1.07 [95% CI, 0.81-1.40]), with noninferiority defined as the lower bound of the 95% CI of the adjusted odds ratio equal to or larger than 0.8.”³ 

The SKIP study results add to the growing list of literature assessing the overall and specific utility of mechanical thrombectomy to treat patients with stroke. With a number of these studies suggesting its effectiveness in treating the condition, there has been an ongoing global initiative from the Society of Vascular and Interventional Neurology (SVIN) to increase access to the procedure.

In December 2020, Dileep Yavagal, MD, professor of clinical neurology at the University of Miami, past president of SVIN, and chair of the initiative (aptly named Mechanical Thrombectomy 2020+), noted to NeurologyLive that the procedure “is effective up to 24 hours after stroke symptoms, so it has to be accessed very urgently. In the early period, it’s very time sensitive. The earlier you get this treatment, the better the outcomes.” Although, he noted that the time-sensitive nature of mechanical thrombectomy is “putting 2 types of burden on accessing this care. It has to be available widely, but also in a geographically distributed manner so that patients can get it quickly. It’s not a therapy that affords itself to being centralized.”

Yavagal spoke with NeurologyLive in detail to discuss the need to expand its use, and what work the society is conducting to ensure that more hospitals and treatment centers can get that access.

REFERENCE

1. Suzuki K, Matsumaru Y, Takeuchi M, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: the SKIP randomized clinical trial. JAMA Neurol. published online January 19, 2021. doi: 10.1001/jama.2020.23522

2. Saver JL, Adeoye O. Intravenous thrombolysis before endovascular thrombectomy for acute ischemic stroke. JAMA. Published online January 19, 2021. doi: 10.1001/jama.2020.22388