Should Alteplase Be Used Before Endovascular Thrombectomy in Patients With Acute Stroke?
Stroke remains a leading global cause of death, disability, and socioeconomic burden, with ischemic stroke accounting for a significant proportion of cases. The standard treatment for acute ischemic stroke within 4.5 hours of onset includes intravenous thrombolysis (IVT) with alteplase, a recombinant tissue plasminogen activator, followed by endovascular thrombectomy (EVT) in eligible patients with large-vessel occlusion (LVO). However, the clinical utility of bridging therapy—combining IVT with EVT—compared to direct EVT (dEVT) without prior thrombolysis has sparked considerable debate, with conflicting evidence driving uncertainty in clinical practice.
The Controversy Over Bridging Therapy vs. Direct EVT
Current guidelines endorse IVT as the first-line therapy for eligible patients, yet a significant subset of individuals fails to achieve functional independence due to incomplete recanalization or complications such as symptomatic intracranial hemorrhage (sICH). The advent of EVT revolutionized stroke care by enabling mechanical removal of thrombi in LVO cases. However, whether administering alteplase prior to EVT improves outcomes remains contentious.
A meta-analysis pooling data from multiple studies demonstrated a potential advantage of bridging therapy. Patients treated with IVT followed by EVT exhibited better functional outcomes (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.22–1.69, P < 0.001) and lower 90-day mortality (OR 1.38, 95% CI 1.09–1.75) compared to those receiving dEVT alone. Notably, this analysis found no significant difference in sICH rates between the two approaches. These findings suggested that IVT might enhance clot dissolution or improve microcirculatory perfusion, thereby complementing EVT.
Contrasting this, a landmark multicenter randomized controlled trial (RCT) conducted across 41 tertiary centers in China challenged these conclusions. The study enrolled patients with anterior circulation LVO eligible for both IVT and EVT, randomizing them to either bridging therapy or dEVT. Results demonstrated that dEVT was non-inferior to bridging therapy in achieving functional independence at 90 days, with comparable safety profiles. This trial highlighted the potential redundancy of IVT in certain settings, particularly when rapid EVT access is available.
Clinical Observations From a High-Volume Stroke Center
The authors of this correspondence report insights from their experience at a senior stroke center adhering to guideline-recommended protocols. Patients arriving within 4.5 hours of symptom onset receive IVT with alteplase, followed by emergent CT or MR angiography to assess EVT eligibility. Despite strict protocol adherence, the authors observed a concerning trend: a subset of bridging therapy patients developed hyperperfusion syndrome, intracerebral hemorrhage (ICH), or even cerebral herniation post-thrombolysis. These complications, though not universally observed, underscore the heterogeneous response to IVT and the potential risks of combining therapies.
For instance, hyperperfusion syndrome—characterized by cerebral edema and hemorrhagic transformation—was noted in patients with compromised cerebrovascular autoregulation, particularly those with pre-existing hypertension or poor collateral circulation. Similarly, ICH occurred more frequently in patients with extensive infarct cores or delayed recanalization times. These observations align with prior studies identifying variables such as thrombus length, occlusion type (in situ thrombosis vs. embolism), and collateral quality as critical determinants of EVT success and complication risks.
Implications for Future Research and Clinical Practice
The conflicting evidence necessitates a nuanced approach to refining stroke protocols. The authors propose three key considerations for future research:
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Multicenter RCTs Across Diverse Populations
Replicating the Chinese trial in other global cohorts is imperative to validate the generalizability of dEVT non-inferiority. Variations in healthcare infrastructure, time-to-puncture intervals, and patient demographics (e.g., prevalence of atherosclerosis vs. cardioembolic stroke) may influence outcomes. Trials should stratify randomization based on baseline stroke severity (NIHSS score), infarct core size (via diffusion-weighted imaging), and perfusion mismatch to identify subgroups most likely to benefit from bridging therapy. -
Methodological Rigor in Observational Studies
Non-randomized studies must account for confounding variables through propensity score matching. Variables such as antithrombotic use (e.g., tirofiban, vitamin K antagonists), contrast agent volume, glycemic control, and procedural factors (e.g., number of thrombectomy attempts, onset-to-recanalization time) significantly impact outcomes. For example, prolonged time from onset to recanalization (>6 hours) and multiple thrombectomy attempts (>3 passes) correlate with increased hemorrhagic transformation and mortality. -
Subgroup-Specific Analyses
Future trials should prioritize subgroup analyses to disentangle the heterogeneous treatment effects observed in prior studies. Key subgroups include:- Functional Disability: Differentiating patients with motor deficits (e.g., limb paralysis) from those without may clarify the impact of EVT on functional recovery.
- Thrombus Characteristics: Stratifying by thrombus length, location, and composition (e.g., fibrin-rich vs. red blood cell-dominant clots) could predict responsiveness to IVT or EVT.
- Collateral Circulation: Robust collaterals may mitigate infarct growth, allowing safer IVT administration, while poor collaterals may favor expedited EVT.
- Etiology: Cardioembolic strokes, often associated with larger, softer thrombi, may respond better to IVT than atherosclerotic occlusions.
Conclusion
The debate over bridging therapy versus dEVT reflects the complexity of acute stroke management. While existing data support both approaches, the absence of definitive superiority underscores the need for personalized treatment algorithms. Clinicians must weigh factors such as time-to-treatment, thrombus characteristics, and patient comorbidities when selecting therapies. Until further evidence emerges, adherence to institutional protocols and guideline recommendations remains prudent. However, the growing body of observational and RCT data—coupled with advances in neuroimaging and endovascular techniques—herald a future where tailored therapeutic strategies optimize outcomes for this heterogenous patient population.
doi.org/10.1097/CM9.0000000000001178
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