Safety and Efficacy of Bridging Intravenous Thrombolysis Versus Direct Endovascular Therapy in Acute Ischemic Stroke Treated in the 6- to 24-Hour Time Window: A Propensity Score-Matched Analysis

In a propensity score-matched analysis of patients with acute ischemic stroke treated within the 6- to 24-hour window, bridging intravenous thrombolysis prior to endovascular thrombectomy demonstrated no significant difference in functional outcomes, recanalization rates, or safety risks compared to direct endovascular therapy alone.

The Gist

Imagine your brain is a bustling city, and a major highway (a large blood vessel) has been suddenly blocked by a giant traffic jam (a blood clot). This is an acute ischemic stroke. The longer the traffic stays blocked, the more the city's neighborhoods (brain tissue) suffer and die.

Doctors have two main ways to clear this jam:

1. The "Air Drop" (IVT): They send a chemical "clean-up crew" (intravenous thrombolysis) through the bloodstream to try to dissolve the clot from the top down.
2. The "Special Ops" (EVT): They send a tiny mechanical team (endovascular therapy) up the artery to physically grab and pull the clot out.

For a long time, the standard rule was: "Send the Air Drop first, then send the Special Ops." This is called Bridging Therapy.

The Big Question

This study asks a very specific question: What if the traffic jam has been there for a long time (between 6 and 24 hours)?

In the early hours (0–4.5 hours), the Air Drop works great. But after 6 hours, the "clean-up crew" might be too late to save the city, or they might cause accidental damage (bleeding) while trying to clear a stubborn, old clot.

The researchers wanted to know: In this "late window" (6–24 hours), is it better to do both (Air Drop + Special Ops), or just skip the Air Drop and go straight to the Special Ops?

The Study: A Massive Detective Work

The researchers looked at data from 772 patients across 10 hospitals in China and Singapore.

• Group A (The Bridging Group): 110 patients got the Air Drop before the Special Ops.
• Group B (The Direct Group): 662 patients went straight to the Special Ops.

Because the two groups started out slightly different (the Bridging group happened to have slightly better brain scans and arrived a bit faster), the researchers used a statistical tool called Propensity Score Matching.

Think of this like a high-stakes matchmaking service: They took every patient who got the Air Drop and found two "twins" from the Direct group who were almost identical in age, health, and stroke severity. This ensured they were comparing apples to apples, not apples to oranges.

The Results: The "Air Drop" Didn't Help (or Hurt)

After matching the patients, the results were surprisingly clear:

1. Did the Air Drop save more lives? No. The number of people who recovered well after 3 months was almost exactly the same in both groups.
2. Did the Air Drop clear the jam better? No. The mechanical team (Special Ops) cleared the blockage successfully in about 90% of cases, regardless of whether the Air Drop was used first.
3. Did the Air Drop cause more bleeding? No. Surprisingly, the group that got the Air Drop actually had fewer bleeding complications, though the difference wasn't statistically significant enough to be a rule.

The "Why" Behind the Results

The authors suggest a few reasons why the Air Drop didn't help in the late window:

• The "Old Clot" Problem: By 6–24 hours, the clot is often old, hard, and stuck tight. A chemical dissolver just can't penetrate it effectively anymore.
• The "Mechanical" Advantage: Modern mechanical tools are so good at grabbing clots that the chemical help is redundant. It's like trying to use a feather duster to clean a heavy mud stain when you already have a high-pressure hose.
• Time is Tissue: The patients who got the Air Drop actually arrived at the hospital faster (on average 425 minutes vs. 655 minutes). Even with this advantage, they didn't do better than the group that went straight to the mechanical removal.

The Takeaway for Patients and Families

If you or a loved one has a major stroke and arrives at the hospital 6 to 24 hours after it started:

• Don't panic about skipping the "Air Drop." This study suggests that rushing straight to the mechanical clot removal is just as effective as waiting for the chemical treatment first.
• It's safe. Adding the chemical treatment didn't increase the risk of dangerous bleeding in this specific late window.
• The decision is flexible. In hospitals that have the mechanical team ready, doctors might choose to skip the chemical step to save precious time. In hospitals where the mechanical team is far away, the chemical treatment might still be a good "bridge" to keep the patient stable while waiting for transfer.

In short: In the late hours of a major stroke, the "Special Ops" mechanical team is the star player. The "Air Drop" chemical team doesn't seem to add any extra power, but it also doesn't seem to cause trouble. The best move is to get the mechanical team to the scene as fast as possible.

Technical Summary

1. Problem Statement

While Endovascular Thrombectomy (EVT) is the standard of care for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) up to 24 hours, the role of bridging intravenous thrombolysis (IVT) prior to EVT in this extended time window (6–24 hours) remains controversial.

• Context: Bridging IVT is standard in the 0–4.5 hour window. However, in the late window, the ischemic core is often larger, and the potential for IVT to salvage tissue is reduced.
• Uncertainty: It is unclear whether the potential benefits of bridging IVT (early reperfusion, distal clot dissolution) outweigh the risks (hemorrhagic transformation, delayed EVT initiation) specifically for patients presenting between 6 and 24 hours.
• Gap: There is a paucity of randomized data specifically addressing this late-window population, necessitating robust observational analysis.

2. Methodology

Study Design:

• Retrospective analysis of prospective data from an international multicenter registry (10 comprehensive stroke centers in China and Singapore).
• Timeframe: 2019–2024.

Population & Inclusion Criteria:

• Patients: Adults (≥18 years) with anterior circulation LVO (ICA, M1/M2, or A1).
• Treatment Window: Underwent EVT between 6 and 24 hours of symptom onset.
• Imaging/Clinical Criteria: ASPECTS ≥6, pre-EVT NIHSS ≥6, pre-stroke mRS ≤2.
• Exclusions: Posterior circulation stroke, missing 3-month mRS or sICH data.

Study Groups:

• Bridging IVT Group: Patients receiving IVT followed by EVT.
• Direct EVT Group: Patients receiving EVT alone (non-IVT).

Statistical Analysis:

• Propensity Score Matching (PSM): Performed at a 1:2 ratio (IVT : Non-IVT) using nearest-neighbor matching without replacement.
• Covariates: Sex, age, hypertension, coronary heart disease, atrial fibrillation, diabetes, dyslipidemia, smoking, onset-to-puncture time (OPT), ASPECTS, and NIHSS.
• Balance Check: Absolute Standardized Mean Difference (SMD) <0.10 considered acceptable.
• Primary Outcome: 3-month favorable functional outcome (modified Rankin Scale [mRS] 0–2).
• Secondary Outcomes: Successful recanalization (mTICI 2b–3), symptomatic intracranial hemorrhage (sICH), any hemorrhagic transformation (HT), and 3-month mortality.
• Tests: Cochran–Mantel–Haenszel test for matched binary outcomes; Multivariable logistic regression for adjusted analyses.

3. Key Contributions

• Large Multicenter Dataset: One of the largest observational studies specifically focusing on the 6–24 hour window, a population often excluded from standard IVT guidelines.
• Rigorous Matching: Utilized propensity score matching to minimize selection bias, a common limitation in retrospective stroke studies where IVT patients are often selected based on better imaging profiles.
• Comprehensive Outcomes: Evaluated both efficacy (functional outcome, recanalization) and safety (sICH, HT, mortality) simultaneously.
• Real-World Evidence: Provided data from diverse centers (China and Singapore), reflecting real-world clinical practices rather than strict trial protocols.

4. Results

Cohort Characteristics:

• Total Included: 772 patients (110 bridging IVT, 662 direct EVT).
• Pre-Matching Imbalance: The IVT group had significantly higher ASPECTS (median 9 vs. 8), shorter onset-to-puncture times (425 vs. 655 min), and lower coronary heart disease prevalence.
• Post-Matching: 101 IVT patients were matched to 202 non-IVT patients. All covariates were well-balanced (SMD <0.10).

Primary Outcome (3-month mRS 0–2):

• IVT Group: 44.55%
• Direct EVT Group: 47.03%
• Statistical Significance: No significant difference (Common OR 0.91; 95% CI 0.56–1.46; p = 0.675).

Secondary Outcomes:

• Successful Recanalization (mTICI 2b–3): 91.09% (IVT) vs. 90.10% (Direct EVT); OR 1.11 (p = 0.789).
• Symptomatic Intracranial Hemorrhage (sICH): 5.94% (IVT) vs. 9.41% (Direct EVT); OR 0.61 (p = 0.302). Note: Numerically lower in IVT group but not statistically significant.
• Hemorrhagic Transformation (HT): 23.76% (IVT) vs. 23.27% (Direct EVT); OR 1.03 (p = 0.923).
• 3-Month Mortality: 15.84% (IVT) vs. 13.37% (Direct EVT); OR 1.22 (p = 0.561).

Multivariable Analysis:

• Adjusted logistic regression confirmed that bridging IVT was not independently associated with improved efficacy or increased safety risks compared to direct EVT alone.

5. Significance and Implications

• Clinical Guidance: The study suggests that in the 6–24 hour window, bridging IVT does not provide a significant efficacy advantage over direct EVT, nor does it increase the risk of hemorrhagic complications.
• Treatment Strategy: Direct EVT appears to be a reasonable and potentially preferred alternative in late-window patients, particularly in centers where EVT is readily available, to avoid potential delays in mechanical reperfusion.
• Contextual Nuance: The authors note that in centers without EVT capabilities, bridging IVT remains a practical strategy to initiate treatment while transferring patients. However, in comprehensive stroke centers, routine bridging may not be necessary.
• Alignment with Recent Trials: These findings align with recent data (e.g., TIMELESS trial, TNK-PLUS, ATTENTION LATE) suggesting that the benefit of IVT diminishes in the extended time window, especially when high recanalization rates (>90%) are achievable with modern EVT techniques.
• Future Directions: Highlights the need for individualized decision-making and shared decision-making with patients/families, rather than a blanket protocol for bridging therapy in the late window.

Limitations Noted:

• Retrospective design (potential for unmeasured confounding).
• Small sample size of the IVT group (n=110), limiting power for subgroup analyses.
• Lack of central imaging adjudication.
• No data on specific thrombolytic agents or dosages.