Bridging therapy vs. direct thrombus removal: a comprehensive overview of the five hot spots; five controversies are broken down one by one

*Only for medical professionals to read and refer to 5 hotspots + 5 controversies + guide recommendations
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Five major studies in 2015 showed that intravenous thrombolysis is the basis for the benefits of thrombectomy.
In the past two years, four recent studies comparing direct thrombectomy and bridging therapy have become the focus of attention in the field of stroke treatment
.

Faced with the advent of the era of endovascular treatment, can you bypass intravenous thrombolysis and directly remove the thrombus? Research progress and controversy coexist.
This article takes you in-depth analysis of the focus of attention on endovascular treatment of stroke
.

1.
Will bridging treatment delay the patient's endovascular treatment time? The key to acute ischemic stroke (AIS) treatment is to open the blocked blood vessel as soon as possible and save the ischemic penumbra.
Intravenous thrombolysis (IVT) and endovascular therapy (EVT) are time-dependent.
The key to EVT treatment is to start as soon as possible.
Endovascular treatment shortens the time from admission to puncture (DTP)
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So will IVT extend DTP? The SKIP study in Japan [1] showed that there was no statistically significant difference in the random puncture time between the direct embolectomy and bridging embolectomy groups
.

Similarly, the DEVT study conducted in China [2] showed that there was no statistical difference in the time from random to puncture
.

Table 1: The effect of direct embolectomy and bridging therapy on puncture time in different studies A meta-analysis of 38 observational studies [3] [11,798 patients with large vessel occlusion (LVO), 56% receiving bridging therapy] The results also showed that there was no significant difference in the time of intravascular reperfusion therapy between the two groups [standardized mean difference (SMD) = 0.
05, 95% CI = -0.
08, 0.
17]
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2.
Is there a difference in benefit between direct embolectomy and bridging therapy? Among the four recent randomized controlled trials (RCT) studies, only DIRECT-MT[4] and DEVT confirmed that the prognostic outcome of the modified Rankin Scale (mRS) score function of direct thrombus removal at 90 days is not inferior to bridging therapy, SKIP and MR CLEAN -NO IV [5] did not confirm that direct thrombectomy is not inferior to bridging therapy, so skipping intravenous thrombolysis and direct thrombectomy still needs more solid evidence-based support
.

The three RCT studies of SKIP, DIRECT-MT and DEVT are all based on non-inferiority statistical design, and the pre-set non-inferiority values ​​are 0.
74, 0.
80, and -10%, respectively
.

The DIRECT-MT and DEVT studies have concluded that the prognostic outcome of the mRS score function of direct thrombus removal at 90 days is not inferior to bridging therapy, while the SKIP study failed to prove that direct thrombectomy is not inferior to bridging therapy in terms of efficacy [1,2,4]
.

With the publication of 3 large-scale RCT studies in Asia, the Dutch similar clinical trial MR CLEAN-NO IV study [5] released the results at the International Stroke Conference (ISC) in 2021.
The main purpose of this study is to evaluate the superiority of direct thrombus removal.
The secondary objective is to evaluate the non-inferiority of direct thrombus removal
.

The results showed that there was no significant difference in the 90-day mRS scores between the bridging and direct thrombectomy treatment groups; acOR did not reach the preset non-inferiority threshold of 0.
80, non-inferiority was not established, that is, the efficacy of direct thrombectomy was not superior or non-inferior.
For bridging therapy
.

Figure 1: The proportion of patients with mRS scores at 90 days in the MR CLEAN-NO IV study.
The current international mainstream view is that intravenous thrombolysis should not be skipped for direct thrombectomy
.

Direct thrombus removal still needs more research to confirm
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3.
Is there a difference in bleeding risk between direct embolectomy and bridging therapy? Receiving IVT before thrombus removal does not cause the time delay of EVT, and can improve the patient's good prognosis, but there is still concern that IVT increases the risk of intracranial hemorrhage
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SKIP, DIRECT-MT, DEVT and MR CLEAN-NO IV 4 RCT studies confirmed that bridging therapy does not increase the incidence of spontaneous intracerebral hemorrhage (sICH) [1,2,4,5]
.

Table 2: The sICH incidence results of the 4 RCT studies.
Except for the standard design RCT, there is no difference between bridging treatment and direct thrombus removal.
In the real world, the meta-analysis of the above 38 observational studies [3] also confirmed Bridging treatment did not increase the risk of sICH, and there was no significant difference in the risk of sICH between the two groups (corrected OR = 0.
87, 95% CI = 0.
61-1.
25)
.

Figure 2: Results of the incidence of sICH in the meta-analysis study 4.
Is there a difference in the risk of death between direct thrombus removal and bridging therapy? SKIP, DIRECT-MT and DEVT studies show that there is no significant difference in mortality between direct embolectomy and bridging treatment [1,2,4]
.

Table 3: Mortality results of the SKIP, DIRECT-MT and DEVT studies.
In addition, a meta-analysis of the above 38 observational studies [3] also showed that bridging treatment significantly reduced the 3-month mortality of LVO patients compared with direct thrombus removal (OR=0.
80 after correction, 95% CI 0.
66-0.
97)
.

Another real-world study [6] showed that compared with direct thrombus removal, IVT pretreatment was independently associated with a reduction in mortality at 3 months (OR 0.
50; 95% CI 0.
26-0.
96)
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5.
Are there other benefits of bridging therapy? ■ The successful reperfusion rate of the bridging treatment group is higher than that of the direct thrombus removal group.
Can thrombolytic therapy before intra-arterial treatment achieve a higher vascular recanalization rate? A retrospective study[7] included 93 patients with middle cerebral artery occlusion, and showed that bridging therapy is more common than direct thrombectomy for femoral artery puncture until the final recanalization time is ≤1 hour (bridging therapy group vs.
direct thrombectomy =65% vs 41%), and the successful recanalization rate (defined as mTICI ≥2b) in the bridging treatment group increased significantly (bridging treatment group vs direct thrombus removal = 89% vs 66%, P=0.
01)
.

Figure 3: Results of recanalization time and recanalization rate of a retrospective study ■ Bridging therapy is more direct than thrombus removal, and significantly reduces the risk of new infarction.
The DIRECT-MT study [4] shows that bridging therapy is more direct than thrombus removal to cause new infarctions There are fewer incidents
.

ESCAPE postmortem analysis [8] showed that bridging therapy significantly reduced the risk of new infarction after direct embolectomy (bridging therapy vs direct embolectomy = 3.
0% vs 9.
1%, OR = 0.
32, 95% CI 0.
11-0.
96)
.

■ Bridging therapy significantly reduces the number of thrombectomy times compared with direct thrombectomy.
IVT improves the thrombectomy speed and successful reperfusion rate, reduces the number of thrombectomy stents, and reduces the possibility of vascular microthrombosis
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A study of 57 patients with middle cerebral artery M1 occlusion who underwent thrombectomy [9] showed that compared with direct thrombectomy, bridging therapy usually requires only 2 or less thrombectomy times to achieve recanalization
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The five major controversies brought about by the limitations of the latest RCT The most recent non-inferiority RCT research results have aroused heated discussions, and their limitations have also brought controversy
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Controversy 1: Too wide non-inferiority cutoffs The non-inferiority cutoffs for SKIP, DIRECT-MT, and DEVT studies are 0.
74, 0.
80, and -10%, respectively
.

DIREC-MT pre-determined a non-inferiority threshold of 0.
80 based on previous research data
.

The SKIP study pre-determined a non-inferiority threshold of 0.
74
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The non-inferiority limit (-10%) used in the DEVT study was not selected using the smallest clinically meaningful difference or fixed threshold method, and the non-lower limit of 10% was very wide, and there was no consensus in the clinical community.
This can lead to concerns about the robustness of research results [1,2,4]
.

Controversy 2: Not all patients in the bridging treatment group of the DIRECT-MT study received MT and some did not receive the standard dose of alteplase.
In the DIRECT-MT study, there were 31 cases (9.
4%) in the bridging group and 17 cases in the direct thrombectomy group (5.
2 %) No mechanical thrombectomy (MT) treatment was performed.
This 4.
2% difference may affect the reported results that facilitate direct thrombectomy, and more patients in the bridging group (17 vs 6) have distal thrombus migration Or thrombolysis
.

In addition, 30 patients (9.
1%) in the bridging group did not receive sufficient or any dose of alteplase, and 4 patients (1.
2%) who originally planned to directly remove the thrombus underwent IVT treatment, violating the research protocol [10 ]
.

Figure 4: Controversy about the proportion of patients who did not undergo MT in the DIRECT-MT study 3: DNT time delay in AIS patients The median (interquartile range) time to hospital to IVT (DNT) in the bridged group in the DIRECT-MT study was 59 (45– 78) min.
Compared with the 40 (29–55) min reported by the HERMES meta-analysis, there is a significant delay, which may lead to a 10% difference in the good prognosis rate of bridging patients in the two studies (90-day mRS 2 points: 36.
8% vs 46.
4%)
.

The adverse effect of this delay is huge.
The HERMES study showed that a 60-minute DNT delay is associated with a 53% reduction in the good functional prognosis of patients with IVT-only LVO [11]
.

In the DIRECT-MT study, the cost of alteplase was not reimbursed, and in most cases Chinese patients or their families must pay in advance to receive alteplase treatment [4], which may cause delays in patients’ informed consent and thus delays in DNT [9]
.

With a shorter DNT/onset to treatment time, IVT may still be more effective
.

Controversy 4: Limitations of the domestic referral model.
The DIRECT MT study explores that compared with many Western countries, China's prehospital triage system is more complicated: patients often go directly to the hospital by private transportation, and the stroke treatment team is usually when the patient is admitted to the hospital.
Treatment is initiated later, not before the patient arrives at the hospital [4]
.

The lack of pre-hospital forecasting mechanism may also be the reason that the time from onset of AIS to thrombolysis in Chinese patients is longer than that in Western countries
.

Controversy 5: The inclusion of different patients may lead to deviations in results.
The DEVT study excluded patients with M2 occlusion, which may affect the results of the study
.

In addition, the 90-day functional independence improvement rate of the bridging group in the study (46.
6%) was close to the HERMES study (46.
4%), but the 90-day overall functional independence improvement (50.
4%) was much higher than the DIRECT-MT study (36.
6%) ), may be due to the higher incidence of intracranial carotid artery occlusion in the DIRECT-MT study, and fewer patients in good collateral state [2]
.

What does the definitive guide say? Intravascular treatment should not skip intravenous thrombolysis! For the clinical decision-making of treatment options for AIS patients, major domestic and foreign guidelines have also given recommendations: ■ 2019 "Guidelines for the Early Management of Patients with Acute Ischemic Stroke in the United States" [12] recommends patients who are suitable for intravenous thrombolysis with alteplase Even if mechanical thrombosis is considered, intravenous thrombolytic therapy (IA) with alteplase should be given first
.

Because the efficacy of thrombolysis is time-dependent, patients who are eligible for thrombolysis should not delay thrombolytic therapy (IB-NR) due to additional imaging evaluations (such as CTP or MRP)
.

■ The 2019 “Chinese Guidelines for the Clinical Management of Cerebrovascular Diseases”[13] recommends that patients with indications for endovascular treatment should be treated as soon as possible
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When the standard for intravenous alteplase thrombolysis is met, intravenous thrombolysis should be performed first, and mechanical thrombectomy (IA) should be bridged at the same time
.

The academic community continues to explore endovascular treatment of acute ischemic stroke, but the latest research data released recently cannot break through the recommendations of rewriting authoritative guidelines.
Whether to skip intravenous thrombolysis and direct thrombosis still needs more solid evidence-based evidence to support it.
Application
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References: [1]Suzuki K, et al.
Effect of Mechanical ThrombectomyWithout vs With Intravenous Thrombolysis on Functional Outcome Among PatientsWith Acute Ischemic StrokeThe SKIP Randomized Clinical Trial.
JAMA.
2021;325(3):244-253.
[2]Zi W, et al.
Effect of Endovascular Treatment AlonevsIntravenous Alteplase Plus Endovascular Treatmenton Functional Independence in PatientsWith Acute IschemicStroke: The DEVTRandomizedClinical Trial.
JAMA.
2021 Jan 19;325(3):234-243.
[3]Katsanos AH et al.
Intravenous thrombolysis prior to mechanicalthrombectomy in large vessel occlusions.
Ann Neurol, 2019, 86(3): 395-406.
[4]Yang P, et al.
Endovascular Thrombectomy with orwithout Intravenous Alteplase in Acute Stroke.
N Engl J Med.
2020 May21;382( 21):1981-1993.
[5]2021 ISC Report.
Intravenous Thrombolysis Followed by Endovascular Thrombectomy versus Direct Endovascular Thrombectomy: A RandomizedControlled Trial.
[6]Goyal N, et al.
Comparative safety and efficacy of combined IVT and MT with direct MT in large vessel occlusion.
Neurology,2018:10.
1212/WNL.
0000000000005299[7 ]Behme D.
et al.
Intravenous Thrombolysis Facilitates SuccessfulRecanalization with Stent-Retriever Mechanical Thrombectomy in Middle CerebralArtery Occlusions.
J Stroke Cerebrovasc Dis.
2016 Apr;25(4):954-9.
[8]Ganesh A et al.
Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial(Endovascular Treatment for Small Core and Anterior Circulation ProximalOcclusion With Emphasis on Minimizing CT to Recanalization Times).
Stroke.
2016;47:2993-2998.
[9]LEKER RR, et al.
Is Bridging Necessary? A Pilot Study of Bridgingversus Primary Stentriever-Based Endovascular Reperfusion in Large AnteriorCirculation Strokes.
J Stroke Cerebrovasc Dis.
2015 Jun;24(6):1163-7.
[10]Berge E, et al.
European Stroke Organisation ( ESO)guidelines on intravenous thrombolysis for acute ischaemic stroke.
Eur StrokeJ.
2021 Mar;6(1):I-LXII.
[11]Nogueira RG, et al.
Large Vessel Occlusion Strokes After the DIRECT-MT and SKIP Trials: Is the Alteplase Syringe Half Empty orHalf Full? Stroke.
2020 Oct;51(10):3182-3186.
[12]Powers WJ, et al.
Guidelines for the Early Management ofPatients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
Stroke.
2019 Dec;50(12):e344-e418.
[13] Chinese cerebrovascular disease clinical management guidelines.
Chinese Journal of Stroke, 2019, v.
14(07):85-102.
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