Highlights
In this multinational Registry of Stroke Care Quality (RES-Q) cohort, the association between intravenous thrombolysis before endovascular thrombectomy and better discharge outcomes was strongly time-dependent.
The most consistent benefit of IVT+EVT versus EVT alone was observed in the earliest treatment windows, especially within 100 minutes and, to a lesser extent, between 100 and 150 minutes.
Beyond 150 minutes, the favorable associations weakened, supporting the concept that any incremental value of bridging thrombolysis may be highly sensitive to treatment speed.
As an observational analysis, the study informs routine practice but does not settle causality; patient selection, workflow, and residual confounding remain important considerations.
Background
For patients with acute ischemic stroke caused by anterior-circulation large-vessel occlusion, endovascular thrombectomy has become a cornerstone of care. In eligible patients presenting within the thrombolysis window, clinicians often face a practical question: should intravenous thrombolysis be administered before thrombectomy, or can thrombectomy alone suffice?
This question has remained controversial despite multiple randomized trials. Some trials suggested noninferiority of direct EVT compared with bridging therapy, whereas others supported maintaining IV thrombolysis before thrombectomy in eligible patients. One reason for the ongoing debate is that the effect of IVT may not be constant across all patients and treatment settings. A biologically plausible hypothesis is that IVT offers the greatest added value when delivered very early, before the clot becomes more resistant and before irreversible ischemic injury progresses. Early thrombolysis might promote partial recanalization, distal clot softening, improved microvascular reperfusion, or earlier restoration of flow while the EVT team is mobilized.
The RES-Q analysis by Mikulik and colleagues addresses this issue directly by examining whether treatment timing modifies the association between IVT+EVT and short-term in-hospital outcomes in routine clinical practice across 38 countries. The clinical relevance is substantial: if the benefit of bridging therapy is concentrated in the earliest minutes, then debates framed as a simple “bridging versus direct EVT” comparison may miss the more important determinant, namely time.
Study Design and Methods
Design and data source
This was a multinational observational registry cohort study using data from the Registry of Stroke Care Quality (RES-Q) collected between 2022 and 2024. RES-Q is a quality-improvement registry that captures stroke care processes and outcomes across multiple healthcare systems. The current analysis focused on patients with anterior-circulation large-vessel occlusion treated with EVT.
Population
Among 3,132 eligible patients, 3,009 formed the analytic cohort after restricting to those treated with either IVT+EVT or EVT alone. The mean age was 69.2 years (SD 13.2), and 45.6% were female. The abstract does not provide the exact distribution of treatment groups, but all included patients underwent thrombectomy for anterior-circulation occlusion.
Exposure and comparator
The main comparison was bridging therapy with intravenous thrombolysis followed by endovascular thrombectomy versus endovascular thrombectomy alone. Because this was not a randomized study, treatment assignment reflected local practice, eligibility, and workflow realities.
Outcomes
The primary outcome was ordinal modified Rankin Scale (mRS) at discharge. This shift analysis evaluates whether the overall disability distribution is more favorable across the full mRS range rather than only at a single cutoff. Secondary outcomes were discharge mRS 0-2, representing functional independence, and in-hospital survival.
Time stratification
The investigators explicitly evaluated effect modification by treatment timing. Time strata were defined as 100 minutes or less, more than 100 to 150 minutes, more than 150 to 255 minutes, and more than 255 minutes. For EVT-only patients, onset-to-needle time was predicted solely to assign them to comparable time strata, an approach intended to facilitate time-based comparisons but one that also introduces modeling assumptions.
Confounding control
To reduce measured confounding, the investigators used stabilized inverse probability of treatment weighting based on a propensity score. Weights were truncated at 10 to limit the influence of extreme observations. The propensity score included arrival mode, admission location or department, vascular risk factors including hypertension, diabetes, hyperlipidemia, atrial fibrillation, prior stroke, and smoking, imaging type, and baseline National Institutes of Health Stroke Scale score.
This is a thoughtful analytic approach for registry data, particularly in a multinational cohort with expected variation in workflow and patient selection. Even so, weighting can only address measured confounders. Important factors such as occlusion site specifics, collateral status, infarct core size, thrombolysis contraindications, prestroke disability, anticoagulant use, door-in-door-out transfer delays, anesthesia strategy, and successful reperfusion grade are not mentioned in the abstract and may have influenced both treatment choice and outcomes.
Key Results
Evidence of time-dependent association
The central finding was a significant treatment-by-time interaction for both the primary outcome and one of the major secondary outcomes. For ordinal discharge mRS, the interaction p value was 0.002. For discharge mRS 0-2, the interaction p value was 0.02. These results indicate that the association between treatment strategy and outcome varied meaningfully across treatment windows rather than remaining uniform over time.
Clinically, that is the headline message of the study: the earlier the patient was treated, the more strongly IVT+EVT was associated with better discharge outcomes relative to EVT alone.
Earliest window: 100 minutes or less
In the earliest treatment window, bridging therapy showed the strongest and most consistent associations with benefit. For ordinal discharge mRS, the odds ratio was 1.99 (95% CI, 1.49-2.63), suggesting substantially better overall disability outcomes at discharge with IVT+EVT than with EVT alone. For in-hospital survival, the odds ratio was 1.81 (95% CI, 1.13-2.92). For functional independence at discharge, defined as mRS 0-2, the odds ratio was 1.76 (95% CI, 1.24-2.51).
These are clinically meaningful effect sizes. Although discharge mRS is not equivalent to the customary 90-day endpoint used in stroke trials, a near-doubling of the odds of a favorable mRS shift at discharge is difficult to dismiss, especially when accompanied by a survival signal in the same early time window.
Early window: more than 100 to 150 minutes
In the next time stratum, the favorable association persisted but was attenuated relative to the earliest period. For ordinal mRS, the odds ratio was 1.58 (95% CI, 1.21-2.06), and for mRS 0-2, the odds ratio was 1.64 (95% CI, 1.16-2.31). The abstract does not report a statistically significant survival advantage in this interval.
This pattern is important. It suggests that the benefit curve may begin to flatten even within what many clinicians still consider an early treatment period. The implication is not simply that “sooner is better,” which is already axiomatic in stroke care, but that the incremental value of adding IVT may be especially front-loaded in time.
Beyond 150 minutes
Associations were attenuated beyond 150 minutes. The abstract does not provide exact odds ratios for the later strata, but the authors’ summary indicates that the advantage of IVT+EVT was no longer consistently demonstrable. This attenuation is compatible with several biological and practical explanations. The ischemic penumbra shrinks over time, clot composition may become less thrombolysis-responsive, and patients selected for later treatment windows may differ systematically in ways that reduce the incremental contribution of IVT.
Interpreting the magnitude of benefit
Because the primary analysis used ordinal mRS, the reported odds ratios are shift odds ratios rather than direct measures of absolute risk difference. That matters for bedside interpretation. Odds ratios near 2.0 sound dramatic, but the absolute gains depend on baseline prognosis, case mix, and how many patients in each time stratum were eligible for and actually received thrombolysis. Still, the consistency of the earliest-window findings across disability, functional independence, and survival supports the conclusion that the association was not limited to a single outcome metric.
Clinical Interpretation
What this study adds to the bridging-versus-direct EVT debate
The study reframes an often binary controversy. Randomized trials comparing direct EVT and bridging therapy have generated divergent conclusions, in part because treatment times, transfer pathways, thrombolytic agents, and regional workflows vary substantially across studies. RES-Q suggests that timing itself may explain some of this heterogeneity. If IVT adds value predominantly in the earliest minutes after onset, then trials or practice environments with longer treatment delays may naturally show less benefit from bridging therapy.
This interpretation aligns with stroke pathobiology. Intravenous alteplase or tenecteplase may facilitate early partial reperfusion before groin puncture, soften thrombus, reduce distal embolic burden, and improve microcirculatory flow. These potential advantages are more likely to matter when viable tissue remains abundant and before extensive infarction is established. Conversely, when treatment is delayed, successful macrovascular reperfusion by EVT may dominate outcomes, leaving less room for IVT to improve prognosis.
Implications for workflow
The findings support aggressive efforts to avoid false tradeoffs between speed and treatment completeness. In eligible early presenters at thrombectomy-capable centers, clinicians should not allow concerns about bridging therapy to create avoidable delays. The operative principle remains that the entire workflow must be optimized so that IVT, when indicated, is delivered rapidly and without slowing transfer to the angiography suite.
For systems of care, the study underscores the importance of onset-based triage, prenotification, parallel imaging and laboratory workflows, and early decision-making. It also speaks to transfer networks. If the incremental benefit of IVT is most pronounced very early, then drip-and-ship systems may derive the greatest advantage when thrombolysis can be initiated quickly at the first hospital while EVT arrangements are underway.
Relevance to current evidence and guidelines
Current major stroke guidelines generally recommend intravenous thrombolysis for eligible patients with large-vessel occlusion who are also candidates for thrombectomy, while acknowledging the evolving evidence base around direct EVT in selected settings. The RES-Q study does not overturn that position; rather, it strengthens a nuanced version of it. The benefit of bridging therapy may be conditional on rapid administration, and therefore the quality of the system may be as important as the nominal choice of strategy.
Strengths and Limitations
Strengths
This study has several notable strengths. First, it is large and multinational, drawing from 38 countries and therefore reflecting real-world stroke care beyond a single trial network or national system. Second, it addresses a clinically important modifier, time, rather than treating all treatment windows as equivalent. Third, the use of inverse probability weighting with prespecified covariates is an appropriate and transparent attempt to reduce bias in observational data.
Limitations
The main limitation is confounding by indication. Patients who did not receive IVT may have had contraindications such as recent anticoagulant exposure, bleeding risk, uncertain onset, large core infarction, or severe premorbid disability, all of which could also worsen outcomes independently of treatment strategy. Even robust propensity weighting cannot fully resolve this if such variables were unmeasured or incompletely recorded.
Second, the primary and secondary efficacy outcomes were assessed at discharge rather than at 90 days. Discharge mRS is useful for registry-based evaluation and correlates with longer-term function, but it is not the standard endpoint used in pivotal stroke trials. Length of stay, rehabilitation access, and country-level discharge practices may influence discharge status.
Third, the method used to assign EVT-only patients to time strata relied on predicted onset-to-needle time. While understandable analytically, this introduces model dependency. Misclassification of timing strata could dilute or distort the observed interaction.
Fourth, safety outcomes are not reported in the abstract. Symptomatic intracranial hemorrhage is a critical counterweight when assessing thrombolysis. A complete clinical interpretation requires balancing any efficacy advantage against bleeding risk, especially in very early presenters who may proceed rapidly to thrombectomy regardless.
Finally, the abstract does not specify the thrombolytic agent, recanalization quality, center volume, occlusion anatomy, or transfer versus mothership patterns. Each of these factors could modify both treatment selection and benefit.
Expert Commentary
From a translational standpoint, RES-Q offers a persuasive signal that “bridging benefit” is not a static property of a treatment regimen but a dynamic function of time. This has practical consequences for how clinicians interpret prior randomized data. Trials conducted in settings with ultra-fast EVT, different thrombolytic agents, or longer prehospital delays may not be directly comparable. A null average treatment effect across a heterogeneous cohort can conceal meaningful benefit concentrated in a narrow early-treatment subgroup.
At the same time, caution is essential. Observational registry analyses can generate hypotheses that are clinically compelling but still vulnerable to bias. The strongest way to confirm this time-dependent effect would be an individual-patient meta-analysis or a prospective trial explicitly powered to test treatment-by-time interaction. Future work should also examine whether the pattern holds at 90 days, whether it differs by thrombolytic agent such as alteplase versus tenecteplase, and whether it varies by transfer model, clot location, or collateral profile.
For now, the message for clinicians is pragmatic rather than dogmatic: in an IVT-eligible patient with anterior-circulation large-vessel occlusion presenting very early, current evidence continues to support prompt thrombolysis without delaying thrombectomy. The quality of execution may matter more than ideological commitment to one strategy over the other.
Conclusion
In the RES-Q registry, intravenous thrombolysis before endovascular thrombectomy was most consistently associated with better in-hospital outcomes when treatment began early, particularly within 100 minutes from onset and still within 150 minutes to a lesser degree. Beyond 150 minutes, the apparent benefit attenuated. These findings strengthen the case for rapid bridging therapy in eligible early presenters while reinforcing the broader principle that time remains the dominant modifiable factor in acute ischemic stroke care. Because the study is observational and uses discharge outcomes, it should inform but not replace randomized evidence. Even so, it provides an important clinical insight: when bridging therapy helps, it likely helps most in the earliest minutes.
Funding and Trial Registration
The abstract does not report a specific funding source. No ClinicalTrials.gov registration number is listed in the provided citation details. As this was a registry-based observational study, formal trial registration may not have been applicable.
References
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