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Direct Mechanical Thrombectomy Versus Combined Intravenous and Mechanical Thrombectomy in Large-Artery Anterior Circulation Stroke

A Topical Review
Originally publishedhttps://doi.org/10.1161/STROKEAHA.117.017208Stroke. 2017;48:2912–2918

Intravenous thrombolysis (IVT) with recombinant intravenous (IV) tPA (tissue-type plasminogen activator) significantly improves the odds of good outcome after ischemic stroke when delivered within 4.5 hours of stroke onset, irrespective of age and over a broad range of stroke severity, and despite an increased risk of intracranial hemorrhage (ICH).1 Therefore, in the absence of contraindications, IVT is the standard therapy for all patients presenting with an acute ischemic stroke (AIS) within 4.5 hours after symptom onset.2 However, IVT has some important limitations, such as a narrow time window with a rapidly decreasing efficacy and a rapidly increasing number needed to treat,1 the overall increase of fatal ICH compared with placebo,1 a poor recanalization rate in patients with large thrombus burden,3 and various contraindications, such as pretreatment with oral anticoagulants and unclear time of symptom onset.

Endovascular stroke treatment (EVT) in combination with IVT (ie, bridging thrombolysis) has the potential to overcome some limitations of IVT, especially the poor recanalization rate of patients with large vessel occlusions (LVOs). Three randomized controlled trials (RCTs) published in 2013 failed to demonstrate superior clinical outcomes of EVT.46 However, since December 2014, 8 RCTs testing newer devices have consistently shown that mechanical thrombectomy (MT) in addition to best medical treatment (with and without IV tPA) improves outcome in anterior circulation (AC) ischemic stroke patients with LVO compared with best medical treatment alone.714 These later trials used second-generation devices, required imaging confirmation of LVO, emphasized rapid time to reperfusion, and excluded patients with a priori high chance of futile recanalization (ie, patients with large areas of brain tissue who had already undergone infraction or patients with poor collaterals). MT with stent retriever in addition to IVT is now the recommended treatment for AIS patients with LVO based on class I level A evidence.15,16 Because all IVT-eligible patients with LVO in the pivotal trials received IVT before undergoing randomized MT or control treatment, current American and European recommendations advocate that IVT should be offered to all eligible patients with LVO before MT.15,16

The positive trials also demonstrated that MT alone is an effective therapy for acute ischemic stroke, improving outcomes among patients ineligible for IV tPA.17 Whether MT alone is as good, worse, or better than pretreatment with IV tPA before MT among IVT-eligible AIS patients with LVO in the AC has now become a matter of debate. This topical review addresses this question, summarizing evidence in favor and against treatment with IV tPA before MT in patients with LVO in the AC.

Arguments in Favor of Bridging Thrombolysis

Early Reperfusion

IVT can be started earlier than MT, and in some patients, IV tPA might completely lyse proximal occlusions before MT starts. A recent meta-analysis found a complete recanalization within 3 hours after application of IV tPA in 21% of M1 occlusions, in 38% of M2 occlusions, and in 4% of internal carotid artery (ICA) occlusions.18 However, in clinical practice, recanalization may not occur early enough to obviate the need for subsequent MT. A recent study analyzed early recanalization rates after IVT and before EVT in bridging patients.19 Relevant recanalization rates before EVT in bridging patients were dependent on the occlusion site: 19 patients with ICA occlusions or 12 patients with M1 occlusions had to be treated with IVT before EVT to achieve one relevant recanalization before EVT, whereas in M2 occlusions, the number needed to treat was 6.19 Furthermore, recanalization rates were lower in mothership than in drip-and-ship patients: only 3.8% versus 7.3% of ICA occlusions, 5.9% versus 12.8% of M1 occlusions, and 9.5% versus 30.8% of M2 occlusions had a relevant early recanalization.19 The higher recanalization rates in drip-and-ship patients compared with mothership patients are most likely because of a longer exposure time to tPA. This has major implications on outcome because early recanalization is clearly related with a favorable outcome.1 Therefore, according to current evidence, all patients in the drip-and-ship model should be pretreated with IVT.

Early recanalization was also observed in the pivotal trials of EVT. In REVASCAT (The Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset), patients were randomized only if an arterial occlusion persisted 30 minutes after administration of IV tPA infusion, but in the other initial 4 trials (MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], SWIFT PRIME [Solitaire™ With the Intention for Thrombectomy as Primary Endovascular Treatment Trial], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial Trial], and ESCAPE [Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times Trial]), MT was started as soon as possible after randomization.711 Even though recanalization rates before MT reported in the REVASCAT trial (7.1%) may be biased because only IV tPA nonresponders were included, rates were also low in the MR CLEAN (7.9%), SWIFT PRIME (7.1%), EXTEND-IA (14.3%), and ESCAPE (6.7%) trials.711 Of note, some of the aforementioned numbers (for REVASCAT, MR CLEAN, and ESCAPE) are calculated assuming that all recanalizations revealed on first angiography runs and all clinical improvements obviating the need for MT (despite allocated to the intervention arm) occurred in patients receiving IVT.7,9,11 It is also important to consider that recanalization rates before MT were low, despite the fact that the majority of patients had middle cerebral artery occlusions and many patients were treated in a drip-and-ship fashion. In addition, a small study by Rai et al20 described similar rates of preinterventional recanalization rates in patients with and without preceding administration of IV tPA, 5.8% (3/52) versus 5.3% (2/38) for spontaneous versus IV tPA associated, respectively.

In summary, preinterventional recanalization rates are relatively low (7.7% for pooled recanalization rates of the RCTs), are dependent on the occlusion site with low rates in ICA and M1 occlusions, and seem to be dependent on the exposure time to tPA. Further studies are required to compare rates of preinterventional lysis in patients receiving IV tPA to those ineligible for IV tPA.

Thrombus Softening and Facilitation of Successful Reperfusion

It has been hypothesized that IVT before MT may increase recanalization rates and facilitate the endovascular procedure by softening the thrombus and, thus, reduce the duration of the procedure with fewer passes of stent retrievers. However, there is a considerable between-study variance whether IV tPA facilitates successful and faster reperfusion in subsequent EVT.2025 Observations suggesting a positive effect are mainly derived from small single-center retrospective cohort studies and are not supported by post hoc analyses of recent RCTs.26,27 Better recanalization rates were not observed in patients pretreated with IV tPA in a pooled post hoc analysis of SWIFT PRIME and STAR (Solitaire Flow Restoration Thrombectomy for Acute Revascularization), nor a post hoc analysis of MR CLEAN.26,27 It is also important to keep 2 further considerations in mind: first, softening of thrombi may induce increased clot fragility, which can encourage fragmentation and distal embolization at MT, lowering the rate of Thrombolysis In Cerebral Infarction (TICI) 3 reperfusions, thus, diminishing the clinical benefit.28 Second, lower recanalization rates in patients ineligible for IV tPA may be an epiphenomenon of different clot histology and clot characteristics. Patients ineligible for medical treatment are more likely to have thrombi of cardiogenic origin.25,29 These cardiogenic thrombi were found to have a higher fibrin content, which is associated with lower rates of successful reperfusion.3033 Considering the neutral results of post hoc RCTs, the potential difference in clot characteristics and the likelihood of publication bias, the evidence that IV tPA actually promotes good angiographic reperfusion results is rather low. However, further prospective studies should compare recanalization rates in patients with and without IVT before EVT.

Recanalization Rates in Patients With MT Failure

In a small cohort of patients, MT may be delayed or simply not feasible because of the impossibility to achieve arterial access or to reach the target occlusion. In SWIFT PRIME, arterial access was not possible in 2% of patients; in EXTEND-IA in 2.9%; in ESCAPE in 3.6%; in MR CLEAN in 5%; and in REVASCAT, information was not provided.711 IVT offers a chance of reperfusion if thrombectomy is aborted. However, whether IVT significantly increases the odds of favorable outcome in this particular subset of patients has not yet been assessed. Furthermore, it is increasingly feasible to use transbrachial or direct carotid alternative arterial access routes, if femoral access is not possible.

Reperfusion of Remaining Distal Occlusions After MT

IV tPA may help to recanalize thrombi in small arteries and in the microvasculature, which are inaccessible for thrombectomy devices, increasing achievement of complete reperfusion.34 This may have relevant clinical implications because TICI 3 reperfusions are associated with less neurological deficits and better functional outcome.35,36 It has been shown that most distal branch occlusions leading to incomplete reperfusions are not present before MT but commonly occur during endovascular treatment.37 However, this potential benefit is constrained by the low proportion of patients who still have a running IV tPA infusion at the time of TICI 2b reperfusion, allowing IV tPA to access distal emboli. Considering the median IV tPA administration to first reperfusion intervals reported in the RCTs, IV tPA infusions have usually already ended when substantial reperfusion is achieved. Therefore, concentrations of circulating tPA may already be relatively low because tPA has a comparatively short half-life of 5 to 10 minutes in the human blood. Withholding IV r-tPA before thrombectomy may open the door for tailored medical reperfusion strategies: IV r-tPA could then be selectively administered during or after EVT in patients with incomplete reperfusion (<TICI 3), ensuring that therapeutic concentrations are reached when needed.

Arguments Against Bridging Thrombolysis

Recanalization Rates

IVT is not effective in the vast majority of patients with LVO with a large thrombus burden. Patients with LVO in the ICA and M1 segment of the middle cerebral artery treated with IVT have low recanalization rates.3,38,39 If IV tPA will provide little benefit in these patients, the risks it confers become more unacceptable.

Safety

From a safety perspective, IV tPA increases the risk of symptomatic and asymptomatic ICH, as well as systemic and arterial access bleeding complications compared with placebo.1,40 In the pivotal MT RCTs, hemorrhage rates were not higher in the endovascular than nonendovascular group, suggesting that the great preponderance of the bleeding complications in patients with MT plus IVT were related to IV tPA rather than to MT.17 Intravenous tPA is much more strongly associated with vessel injury and blood-barrier disruption than MT alone.41,42 Especially in patients with a high risk of ICH after IVT, such as patients with early infarct signs, microbleeds, extensive leukoaraiosis, high baseline National Institutes of Health stroke scale scores, high baseline glucose values, and older age, the bleeding risk of IV tPA may exceed the potential benefit.43,44

Peri-Interventional Techniques

IVT limits additional procedures during EVT: administration of antiplatelet agents is contraindicated after IV tPA but potentially beneficial after endovascular intervention and clearly indicated when stenting has to be performed during the endovascular procedure. Furthermore, in rare situations, heparin or glycoprotein IIb/IIIa receptor antagonists may be necessary to treat ongoing thrombus formation. Besides, future development of MT may include treatment in more distal vessels, where the risk of ICH may be increased by the smaller diameter of the arteries. In these patients, IVT may potentiate the risks.

Thrombus Fragility and Thrombus Migration

Periprocedural thrombus fragmentation is a relevant risk in EVT. In a small retrospective analysis, bridging thrombolysis was associated with an increased risk of distal emboli.45 IV tPA may induce migration of thrombi from proximal into distal vessels, where MT is no longer possible, converting a treatable LVO into an untreatable medium vessel occlusion. How much IV tPA facilitates the risk of thrombus migration over the spontaneous rate is currently a matter of debate.46 Similarly, IV tPA may also lyse thrombi in the left atrial appendage or in other proximal sources, precipitating new thromboemboli. However, prospective studies comparing thrombus migration after IVT with patients receiving no treatment are lacking.

Other Considerations

In the United States, IV tPA has also a considerable impact on costs: according to Rai et al,20 100 mg vial of alteplase (Activase; Genentech, San Francisco, CA) used in the preparation of an IV dose for stroke thrombolysis costs $7800. In their analysis, costs of combined MT and IVT were considerably higher than MT alone.20

Administration of IV tPA before endovascular clot retrieval is an important argument to support the drip-and-ship model; however, MT in drip-and-ship patients is delayed compared with mothership patients. And even in centers where patients can be quickly moved to the endovascular suite administration of IV tPA may delay MT. Finally, IV tPA causes some rare side effects, such as life-threatening orolingual angioedema.

Table summarizes the potential harms and benefits with IV tPA administration before MT.

Table. Pros and Cons of Bridging Therapy

Potential benefitEffect
 Early reperfusion at first angiography run (5%–10%), especially if short thrombi or residual flow High rates of excellent clinical outcome for this subpopulation
 Thrombus softening and facilitation of successful reperfusion Fewer passes of stent devices/less cost, shorter procedure time, and better outcomes
 Chance of reperfusion when no EVT access to thrombus possible Higher proportion with early reperfusion translating to better outcomes
 Reperfusion of remaining distal occlusions after mechanical thrombectomy Potential better outcomes since more complete reperfusion (TICI 3) and less severe capillary microthrombosis
Potential harmEffect
 IV tPA-related local and systemic bleeding complications Puncture-site hematoma (1%–2%) and major systemic bleeding (1%)
 IV tPA-related coagulopathy and small vessel fragility More large symptomatic extraischemic parenchymal hemorrhage (1%–2%)
 IV tPA-related coagulopathy and sICH in patients at risk Higher rates of sICH and aICH with poor functional outcome
 IV tPA-related blood–brain barrier breakdown, coagulopathy, and potentiated large vessel damage because of stent retrievers Increased symptomatic parenchymal hemorrhage when infarct. Poorer functional outcome and increased infarct volume
 Tandem extracranial and intracranial occlusions may require additional procedures during EVT and potentially immediate antiplatelet therapy Increased symptomatic intracranial hemorrhage (10%)
 Distal thrombus migration Inability to retrieve thrombus with MT. Neurological deterioration and more severe/extensive ischemia
 Increase thrombus fragility by softening the thrombus Higher rates of peri-interventional thrombus fragmentation leading to lower rates of complete (TICI 3) reperfusions
 IV tPA lysis of left atrial appendage or other proximal thrombus Early stroke recurrence or multiple systemic emboli
 Delay to MT initiation Later median onset to reperfusion resulting in worse outcomes
 IV tPA-associated allergic reactions (1%) During IV tPA infusion/EVT procedure, which may worsen ischemia or require intubation/prolonged ICU stay
 IV tPA-related neurotoxicity in animal models More neuronal loss
 IV tPA cost Adds to procedural cost

Reprinted from Chandra et al47 with permission of the publisher. Copyright ©. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. aICH indicates asymptomatic intracerebral hemorrhage; EVT, endovascular stroke treatment; ICU, intensive care unit; MT, mechanical thrombectomy; sICH, symptomatic intracerebral hemorrhage; and tPA, tissue-type plasminogen activator.

Current Clinical Evidence

Comparison of Direct MT and Bridging Therapy in IVT-Ineligible Patients

A pooled analysis of 5 RCTs (MR CLEAN, SWIFT PRIME, EXTEND-IA, ESCAPE, and REVASCAT) suggested that the treatment effect size of MT does not differ between patients receiving IVT and those treated with MT alone (P interaction, 0.43; Goyal et al).17

Besides post hoc RCT analyses, there are a myriad of observational studies reporting on rates of successful reperfusion and functional outcome stratified according to IV tPA pretreatment status. These results have not been systematically collated.

Comparison of Direct MT and Bridging Therapy in IVT-Eligible Patients

Only 2 studies compared the outcome of IVT-eligible patients treated with direct MT and treated with bridging thrombolysis. Broeg-Morvay et al48 compared clinical and radiological outcomes in 156 patients treated with bridging thrombolysis and 40 IVT-eligible patients treated with direct MT. Baseline characteristics in both groups were similar. Clinical outcome at 3 months did not differ between groups (Table I in the online-only Data Supplement). There was a trend toward a better improvement on the National Institutes of Health stroke scale score from baseline to 3 months follow-up in the direct MT group (P=0.049). Recanalization and reperfusion rates did not differ, but patients in the MT group had higher recanalization rates 24 hours after intervention (P=0.043).

In the same study, 40 IVT-eligible patients treated with direct MT were matched with 40 patients from the bridging cohort by multivariate matched pairs analysis. Recanalization and reperfusion rates, as well as symptomatic intracerebral hemorrhage and systemic bleeding complications did not differ between groups in multivariate matching analyses, but rates of asymptomatic intracerebral hemorrhage were significantly higher in the bridging cohort than in patients after MT (P=0.023). Functional outcome, as measured with the mRS, did not differ substantially between both groups, neither for favorable nor excellent outcome.

In another study, Weber et al compared the safety and effectiveness of patients treated with direct MT with patients receiving bridging thrombolysis.49 A total of 250 patients were included in the analysis, of which 105 received bridging thrombolysis and 145 direct MT. Among the patients with direct MT, 48% (70/145) were tPA-eligible but were treated with MT alone per the discretion of the attending physician. Overall, baseline characteristics did not differ between the 2 treatment groups. Patients receiving IVT were more often referred from another hospital for MT with IVT starting in the referring hospital (98.1% versus 69.0%; P<0.001), had significantly less frequent atrial fibrillation (25.5% versus 38.9%; P=0.028), and history of previous cerebrovascular events (12.9% versus 23.8%; P=0.033) when compared with patients treated with direct MT. There were no differences in successful recanalization rates (TICI 2b-3; 73.8% versus 73.1%; P=0.95), complication rates, and long-term favorable outcome (mRS, 0–2; 35.2% versus 40%; P=0.44) between patients receiving bridging thrombolysis and those receiving direct MT. Preceding use of IVT was not an independent predictor of favorable outcome in patients treated with MT.

Considering IVT-eligible patients only, direct MT compared with bridging MT was associated with shorter times from symptom onset to groin puncture, first imaging to groin puncture, and symptom onset to end of thrombectomy. Successful recanalization (IVT+MT, 73.8%; MT alone, 74.3%), symptomatic intracerebral hemorrhage (IVT+MT, 5.9%; MT alone, 2.9%), and mortality rates (IVT+MT, 26.7%; MT alone, 25.7%) were similar in both groups. Favorable outcome rates were nominally higher in the direct MT group (bridging, 35.2%; MT alone, 48.6%); however, a statistical analysis comparing the 2 groups was not performed.

Summary of Current Evidence

Available clinical evidence from several single-center studies and limited multicenter studies demonstrates that immediate and direct MT is equally effective and not inferior to bridging thrombolysis if patients are immediately treated in a stroke center with rapid access to endovascular procedures. Two clinical series addressing the efficacy of direct MT in patients eligible for IV tPA have suggested that direct MT may be at least as effective as bridging thrombolysis.

Future RCTs

Whether treatment with IV tPA before MT in patients with LVO AC stroke is of any benefit is currently an important unanswered question in acute stroke management. Multicenter RCTs comparing these 2 treatment approaches will provide definitive information on the efficacy and safety of direct MT compared with the combined approach of IV tPA followed by MT. Ideal candidates for such a comparison are patients with one single target LVO in the AC, with a large thrombus burden in the ICA and M1, with a high risk of symptomatic intracerebral hemorrhage, and with immediate access to MT. Several trials (SWIFT DIRECT [Solitaire™ With the Intention for Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke], and MR CLEAN-NO IV) are in preparation or under way to address this urgent clinical question. SWIFT DIRECT will assess whether tPA-eligible subjects with AIS because of LVO in the AC presenting to a stroke center with endovascular facilities will have noninferior functional outcome at 90 days when directly treated with MT alone compared with IV tPA plus MT. A total of 404 subjects will be included in the trial. The sample size calculation is based on a noninferiority margin of 12%. However, SWIFT DIRECT will not provide the answer whether IVT should be skipped in the prehospital phase. The RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion; NCT02795962) addresses the question whether patients with suspicion of LVO in the prehospital setting should directly be referred to the next stroke center for endovascular treatment, bypassing the next IVT capable stroke unit.

Conclusions

Until definitive randomized trial evidence becomes available, conventional care will remain that IV tPA-eligible patients with LVOs are pretreated with IVT before endovascular therapy. However, current evidence suggests that direct MT may be equally, and possibly more, effective compared with bridging thrombolysis in patients with large AC stroke. There is clinical equipoise that calls for randomized trials comparing direct MT with bridging therapy in patients with a large thrombus burden who have immediate access to endovascular therapy.

Footnotes

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.117.017208/-/DC1.

Correspondence to Urs Fischer, MD, MSc, Department of Neurology, Inselspital, University of Bern, Freiburgstrasse 10, 3010 Bern, Switzerland. E-mail

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