Direct to Thrombectomy.

Abstract

HomeStrokeVol. 52, No. 7Direct to Thrombectomy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBDirect to Thrombectomy Kyriakos Lobotesis, MBBS Brian H. BuckMD Kyriakos LobotesisKyriakos Lobotesis Correspondence to: Kyriakos Lobotesis, MBBS, Imaging Department, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5093-9751 Imaging Department, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, United Kingdom (K.L.). Search for more papers by this author and Brian H. BuckBrian H. Buck https://orcid.org/0000-0002-7984-6062 Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada (B.H.B.). Search for more papers by this author Originally published11 Jun 2021https://doi.org/10.1161/STROKEAHA.121.034423Stroke. 2021;52:2442–2444Recently, stroke clinicians have found themselves asking similar questions to cardiologists a decade ago on how to best combine pharmacological thrombolysis and endovascular therapies into pathways that best optimize early reperfusion. This is subsequent to a growing body of observational data suggesting that a strategy of direct mechanical thrombectomy (MT) may be similar in efficacy and safety to the combination of intravenous thrombolysis (IVT) and MT in patients presenting with large vessel occlusion (LVO).1 Hence, the recent publication of 3 randomized clinical trials assessing the noninferiority of direct MT versus combination therapy with MT and IVT is a welcomed first step in addressing these questions.2–4The 3 reported studies were multicenter trials that included adult patients presenting with an LVO in the internal carotid artery or M1 arteries within 4.5 hours of symptom onset and were eligible for IVT (Table). DIRECT-MT also included patients with proximal M2 occlusions.2 The primary outcome measure for the trials was a good functional outcome defined as a modified Rankin Scale score of 0 to 2. Secondary outcome measures including expanded treatment in cerebral infarction score, symptomatic hemorrhage, and death were also analyzed. There were no statistically significant differences in the secondary outcome measures. However, in the DEVT trial, there was a statistically significant difference in the rate of asymptomatic hemorrhage, with fewer in the MT group (15.7% versus 25.6%).3 Asymptomatic hemorrhage is associated with poorer clinical outcomes. Two of the trials demonstrated statistical noninferiority of direct MT when compared with combination therapy.2,3 Suzuki et al4 showed very similar rates of good functional outcome, but this did not meet the pretest specified statistical significance for noninferiority. An important limitation of these studies is that they all used noninferiority margins that exceeded thresholds based on the 5% minimal clinical difference acceptable to the stroke community.5 Overall, these results could have profound implications for the future treatment of acute ischemic stroke, but there are some additional caveats and questions that remain unanswered.Table. Summary of Randomized Trials Comparing MT Alone Versus Intravenous Alteplase Plus MTTrial nameSetting (number enrolled)IVT dosing in control armStudy populationPrimary outcomeNoninferiority marginMain result (MT vs MT + IVT)Imaging outcome (for MT vs MT+IVT)ConclusionDIRECT-MT541 stroke centers in China (n=656)0.9 mg/kgMedian age 69, median NIHSS score 17, ICA occlusion 35%Between group difference in distribution of 90-d mRSAdjusted OR≥0.80Adjusted common OR, 1.07 (95% CI, 0.81–1.40)Recanalization before MT 2.4% vs 7.0% eTICI≥2b 79.4% vs 84.5%MT alone noninferiorDEVT633 stroke centers in China (n=234), stopped early for efficacy0.9 mg/kgMedian age 70, median NIHSS score 16, ICA occlusion 15.5% and 14.4% (for MT and MT+IVT)Proportion of favorable outcome (mRS score 0–2) between groups at 90 d≥−10% difference7.7% difference (97.5% 1 sided CI, −5.1% to ∞)Recanalization before MT 1.7% vs 2.6% eTICI≥2b 88.5% vs 87.2%MT alone met threshold for noninferioritySKIP723 hospital network in Japan (n=204)0.6 mg/kgMedian age 74, median NIHSS score 18, ICA occlusion 37.7%Favorable outcome (mRS score 0–2) between groups at 90 dOR≥0.74OR, 0.90 (97.5% 1 sided CI, 0.63 to ∞)Recanalization before MT 0% vs 1.0% eTICI≥2b 90.1% vs 93.2%Failed to demonstrate noninferiorityeTICI indicates expanded Treatment in Cerebral Infarction; ICA, internal carotid artery; IVT, intravenous alteplase; mRS, modified Rankin Scale; MT, mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; and OR, odds ratio.One important caveat is the speed of IVT administration in the trials. For example, in the 2 trials completed in China,2,3 the authors highlight that patients often travel by personal vehicle to hospital and informed written consent is required before IVT. This usually involves a discussion with family members. In addition, patients in China are required to pay for IVT, a decision that can delay administration of the drug. These factors reduced the speed of thrombolysis delivery in the trials when compared with other health care systems with more advanced prehospital stroke pathways and without the consent requirement. The SKIP trial completed in Japan did not suffer from this limitation, however, the dose of alteplase administered was lower (0.6 mg/kg). In this trial,4 noninferiority was not found to be statistically significant. Additionally, the workflow of these trials required a computed tomography angiogram LVO identification before randomization and IVT initiation. This delay meant that, for example, in the SKIP trial around 20% of patients had procedural groin puncture before the initiation of the IVT. In contrast, many stroke centers focus on fast IVT delivery and the bolus of IVT is given at an earlier time point, typically after review of the noncontrast computed tomography and before confirmation of LVO. This raises the question with regards to the strength of the conclusions one can draw from these studies and whether more rapid delivery of IVT may have provided an additional benefit in the combination therapy group. The efficacy of IVT in terms of recanalization decreases with time from stroke onset and as the clot burden increases.6There were patients who recanalized after thrombolysis and before the thrombectomy procedure in all studies. In the largest, DIRECT-MT, the rates of recanalization before the procedure were 2.4% in the direct MT group compared with 7% in the combined thrombolysis group (odds ratio, 0.33 [0.14–0.74])—an absolute difference of 4.6%. In these trials, there was little delay between thrombolysis and thrombectomy, especially when compared with drip and ship models of stroke treatment. In patients with a longer delay from thrombolysis to thrombectomy, outside of the trial setting, thrombolysis will have longer to be efficacious. This could result in even higher rates of preprocedure recanalization. In most patients in these trials, the thrombolysis was still being infused during the thrombectomy—something that would not necessarily occur in most interhospital transfer patients. In the HERMES meta-analysis (where >80% of patients were thrombolysed using standard alteplase dose of 0.9 mg/kg), the rate of clinical improvement or no target occlusion seen on diagnostic catheter angiography was 6.8%.7 Other studies have reported recanalization rates as high as 13% within 60 minutes of standard-dose alteplase for patients with internal carotid artery or M1 segment thrombus.8 Additionally, their result may be improved further with the earlier administration of thrombolytics such as tenecteplase which is more fibrin specific, longer activity and has higher rates of early recanalization and reperfusion.9 In the EXTEND-IA TNK study, patients treated with tenecteplase before MT had higher rates of recanalization before thrombectomy compared with those treated with alteplase (22% versus 10%, respectively) and better functional outcomes.9 Similar rates of reperfusion (19.3%) with tenecteplase in patients with LVO were seen in the EXTEND-IA TNK part 2 study.10Overall, the quality of these studies should be considered excellent, and the work is to be commended. As it stands, thrombolysis should continue to be the gold standard of care in patients with stroke who are eligible. However, it is equally reassuring that in the direct thrombectomy group, rates of good functional outcome were not inferior and appeared to be very similar. In specific patient groups, it may be reasonable to consider not administering thrombolysis: for example, in patients who present to a thrombectomy center with an LVO, a larger clot burden and higher bleeding risks. Patients clearly should be considered on a case-by-case basis but given these recent findings, it would seem direct MT to be a reasonable and safe approach.It is important to also review these findings from a service delivery perspective. They raise a very important question with regards to what to do with patients with suspected LVO. In large sparsely populated geographic regions, for patients presenting to primary stroke centers with long transport times to comprehensive stroke centers, there remains a clear role for IVT. If transfer times for patients screened for LVO were comparable between primary stroke centers (able to perform only IVT) and comprehensive stroke centers (able to perform both IVT and MT), the results of these trials tip the balance in favor of transferring directly to comprehensive stroke centers, bypassing the primary stroke centers. However, in most countries, this is usually not the case, with a large proportion of our patients with suspected LVOs still presenting to primary stroke centers. Subsequently, this translates to longer transfer times and poorer outcomes. We are bound by the way our services historically evolved and were applied. MT did not develop in parallel with IVT and was implemented on the foundations of the already existing extensive IVT networks. Hence, we perhaps should reexamine the logistics of our acute stroke systems and look to streamline care and access to centers that can perform MT, patients with suspected LVO. Of course, this emphasizes the importance for the development and advancement of early and efficient prehospital patient triaging.Looking forward, the role of IVT in acute stroke treatment will likely evolve from a blanket strategy of thrombolysis for all eligible under 4.5 hours to a more personalized approach. Decisions about the optimal reperfusion strategy for a given patient will likely incorporate a multitude of factors such prehospital transport time, estimation of clot burden and likelihood of technically successful MT. There are other ongoing trials investigating this same clinical question (MR-CLEAN NO-IV, SWIFT DIRECT, DIRECT-SAFE) and we eagerly await those results11–13.Nonstandard Abbreviations and AcronymsIVTintravenous thrombolysisLVOlarge vessel occlusionMTmechanical thrombectomySources of FundingNone.Disclosures Dr Buck is a coprincipal investigator on the Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT) study funded by the Canadian Institute of Health Research, has grants from Alberta Innovates, and nonfinancial support from Medtronic outside the submitted work. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 2444.Correspondence to: Kyriakos Lobotesis, MBBS, Imaging Department, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, United Kingdom. Email k.[email protected]net