Two small trials added to the evidence that some
stroke patients could fare well going straight to mechanical
thrombectomy without IV thrombolysis, though the studies were confined
to Asian populations and non-inferiority was not shown in the strictest
sense.
For patients with acute ischemic stroke due to large vessel
occlusion, results were inconclusive (but somewhat favorable) for a
strategy of skipping the IV tissue plasminogen activator (tPA) usually
recommended prior to mechanical thrombectomy in the Japanese SKIP trial.
However, a similar strategy did prove to be non-inferior to combined thrombectomy and IV tPA in the Chinese DEVT trial.
IV thrombolysis is thought to benefit thrombectomy candidates by
increasing the chances of reperfusion. The trade-offs, however, include
an increased risk of bleeding complications, potential thrombus
fragmentation, and worsened distal perfusion, and extra cost and work
for the stroke team.
Both SKIP and DEVT were published online in JAMA.
SKIP: Thrombectomy Alone Neither Non-inferior Nor Inferior?
Thrombectomy alone did not meet non-inferiority criteria against the
standard of thrombectomy plus IV alteplase, but SKIP investigators
couldn't say it was inferior, either.
A good functional outcome, a modified Rankin Scale score 0-2 at 90
days, was similarly likely between stroke patients getting thrombectomy
alone and peers who had combined therapy (59.4% vs 57.3%), yet the
confidence interval around the effect estimate was wide and crossed the
non-inferiority margin of 0.74 (P=0.18 for non-inferiority).
"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," according to Kazumi
Kimura, MD, PhD, of Nippon Medical School in Tokyo, and colleagues.
Primary results were similar across subgroups and study sites.
There were no between-group differences in 90-day mortality (7.9% vs
8.7%). Intracerebral hemorrhage rates at 36 hours favored the group
receiving mechanical thrombectomy alone (33.7% vs 50.5%, P=0.02), but symptomatic intracerebral hemorrhage (sICH) did not favor either group (5.9% vs 7.7%).
SKIP was a noninferiority trial
conducted at 23 hospital networks in Japan. Participants were
randomized to mechanical thrombectomy with or without IV alteplase 0.6
mg/kg.
The SKIP cohort included 204 stroke patients (median age 74; 62.7%
men). All had acute stroke with internal carotid artery (ICA) or M1
occlusion.
Roughly 8 minutes separated lytic drug start and endovascular therapy start in those randomized to both treatments.
The
trial's open-label design was a major limitation, Kimura's group
acknowledged. Additionally, favorable outcomes were more frequent than
expected, potentially reducing the study's power.
SKIP's main findings were previously reported at the 2020 International Stroke Conference.
DEVT: Thrombectomy Alone Reaches Noninferiority
In the DEVT trial,
stroke patients randomized to mechanical thrombectomy alone had no
worse outcomes than controls, and investigators were able to show
non-inferiority.
Patients deemed functionally independent at 90 days (mRS 0-2) reached
54.3% of the thrombectomy alone group versus 46.6% of peers undergoing
combined IV tPA and thrombectomy, according to Qingwu Yang, MD, PhD, of
Xinqiao Hospital and The Second Affiliated Hospital, Army Medical
University in Chongqing, China, and colleagues.
Given that the lower boundary of the CI was -5.1% and fell within the
fairly generous noninferiority margin of -10%, the thrombectomy-only
strategy met non-inferiority (P=0.003 for non-inferiority).
Both groups experienced similar rates of sICH within 48 hours (6.1% vs 6.8%) and 90-day mortality (17.2% vs 17.8%).
A major caveat of DEVT
was that it had been terminated early because of efficacy, when 234 out
of a planned 970 patients were randomized, Yang's group noted.
DEVT participants were patients at 33 experienced stroke centers in
China (mean age 68; 43.6% women). The cohort was randomized to
endovascular thrombectomy alone or with IV alteplase.
Unlike SKIP, the DEVT trial had participants randomized to alteplase
receive the full dose of 0.9 mg/kg. Additionally, centers took longer,
approximately 40 minutes, between lytic drug start and thrombectomy
start.
Drawing Conclusions from Limited Evidence
Ultimately, the two trials are in line with prior retrospective studies and a recent randomized trial, DIRECT-MT,
which had suggested that outcomes after stroke were comparable whether
mechanical thrombectomy was or was not offered in tandem with IV
thrombolysis within 4.5 hours of symptom onset.
"With its higher drug dose and longer interlude for drug action, the
DEVT trial more strongly probed the ability of IV lytics to improve
outcome by quickly dissolving the target occlusion before EVT
[endovascular thrombectomy] can be performed," commented JAMA editor Jeffrey Saver, MD, of University of California Los Angeles, and Opeolu Adeoye, MD, of the University of Cincinnati.
"The
SKIP trial, in comparison, more fully explored the possibility that
lower-dose, shorter interlude IV lytics can improve outcome by
dissolving residual small thrombi in the distal vasculature after
incomplete endovascular reperfusion while minimizing the risk of
hemorrhagic transformation," they wrote in an accompanying editorial.
Yang and colleagues acknowledged that DEVT, SKIP, and DIRECT-MIT all
included Asian patients only, limiting the generalizability of their
findings given the higher prevalence of intracranial atherosclerotic
disease in Asian than in Western populations.
"Importantly, none of these three trials sought to demonstrate
noninferiority in the strongest sense of formally excluding the minimal
clinically important difference (MCID)," Saver and Adeoye added. They
noted that an MCID trial would need an "infeasibly large" sample size to
show "true indistinguishability" in the present setting.
"Nonetheless, taken together, the accumulated results from these
studies suggest that the simpler EVT alone strategy is broadly
noninferior to combined EVT and IVT [IV thrombolysis] and accordingly
may be reasonable to consider for patients who present directly to thrombectomy-capable centers," the editorialists said.
The duo offered two points of caution: that patients with
small-to-medium vessel occlusions are not eligible for endovascular
therapy, and that people with large vessel occlusions should only skip IV tPA if they are sure to receive thrombectomy quickly and reliably.
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Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow
Disclosures
SKIP was funded by the Japanese Society for Neuroendovascular Therapy.
Kimura
disclosed support from the 38th Mihara Cerebrovascular Disorder
Research Promotion Fund, Teijin Pharma, Medtronic, Pfizer Japan, Daiichi
Sankyo, and Nippon Boehringer Ingelheim, as well as relevant
relationships with Daiichi Sankyo, Bayer Healthcare, Nippon Boehringer
Ingelheim, and Bristol-Myers Squibb.
DEVT was funded by the National Natural Science Foundation of China.
Yang
disclosed no relevant relationships with industry. A co-author
disclosed relevant relationships with Anaconda, Biogen, Cerenovus,
Genentech, Imperative Care, Medtronic, Phenox, Prolong Pharmaceuticals,
Stryker Neurovascular, Astrocyte, Brainomix, Cerebrotech, Ceretrieve,
Corindus Vascular Robotics, Vesalio, Viz-AI, and Perfuze.
Saver
disclosed relevant relationships with Genentech, Medtronic, Stryker,
Cerenovus, BrainsGate, Boehringer Ingelheim, NONO, BrainQ, Abbott, Rapid
Medical, Johnson & Johnson, and Novo Nordisk. Adeoye disclosed
relevant relationships with Sense Diagnostics, the MOST trial, SIREN,
and Genentech.
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