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Late thrombolysis benefits selected stroke patients

In imaging-selected acute ischemic stroke, intravenous clot-busting therapy after 4.5 hours improved 90-day function but increased symptomatic brain bleeding.
*Systematic review and meta-analysis of randomized trials; Level 1a.

Citation

Patel S, Nischal SA, Kale KM, Gooch MR, Tjoumakaris SI, Jabbour PM. Intravenous Thrombolysis Beyond the Conventional Time Window for Acute Ischemic Stroke. JAMA Network Open. 2026;9(8):e2626990. doi:10.1001/jamanetworkopen.2026.26990

Background

Clot-busting treatment is proven within 4.5 hours of ischemic stroke, but many patients arrive later or wake with symptoms. Imaging can identify patients who may still have brain tissue that can be saved.

Patients

Adults with acute ischemic stroke treated at least 4.5 hours after last known well. Trials generally excluded large completed strokes or very severe deficits.

Intervention

Intravenous alteplase or tenecteplase, often guided by advanced brain imaging.

Control

Placebo or standard medical care.

Outcome

Excellent function, good function, death, and symptomatic brain bleeding. Function used the modified Rankin scale (0=no symptoms, 6=death).

Follow-up Period

90 days.

Results

Outcome Relative effect Absolute impact
Excellent function at 90 days (primary) Risk ratio 1.22 (95% CI 1.14 to 1.31) 1 extra excellent outcome per 12 treated
Good function at 90 days (primary) Risk ratio 1.12 (95% CI 1.06 to 1.18) 1 extra good outcome per 16 treated
Symptomatic brain bleeding (primary safety) Risk ratio 2.44 (95% CI 1.45 to 4.09) 1 extra harm per 62 treated
Death by 90 days (primary) NS —

The review included 14 randomized trials and 4174 patients. Evidence certainty was rated high for primary outcomes.

Limitations

Patients were highly selected, usually by imaging, so results should not be applied to all late-presenting strokes. Study-level data limited patient-specific analysis. Imaging methods, treatment windows, and use of clot removal procedures varied across trials.

Funding

No funding reported; consultant conflicts outside study.

Clinical Application

Consider late intravenous thrombolysis only when imaging shows salvageable brain tissue; possible indication creep beyond selected patients.

Top Journal Rankings - September 2026

1577 abstracts scored across 7 criteria. Click any article to expand criterion scores.
1. 8.3
Intravenous Thrombolysis Beyond the Conventional Time Window for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.
Overall: A strong meta-analysis of randomized trials demonstrates meaningful functional improvement from imaging-selected extended-window thrombolysis, although increased symptomatic hemorrhage and the need for advanced stroke workflows temper the net benefit.
View 7 Criterion Scores
Validity, Bias Control & Precision 9.0
Systematic review of 14 randomized trials involving 4174 patients, with duplicate extraction, formal risk-of-bias assessment, random-effects pooling, and reasonably precise functional-outcome estimates; heterogeneity and publication-bias findings were not reported.
Patient-Oriented Outcomes 9.5
The principal outcomes—90-day functional status, mortality, and symptomatic intracerebral hemorrhage—are clearly defined and directly important to patients.
Magnitude of Net Benefit 8.0
Functional benefit was clinically meaningful, with a number needed to treat of 12 to 16, while symptomatic intracerebral hemorrhage increased with a number needed to harm of 62; mortality was unchanged.
Implementability & Practicality 6.5
Thrombolysis is established in US stroke care, but extended-window treatment requires rapid advanced imaging, careful selection, and coordinated stroke expertise that may not be universally available.
Practice-Changing Potential 8.5
The pooled randomized evidence supports expanding treatment eligibility beyond 4.5 hours for appropriately imaging-selected patients and could materially influence acute stroke protocols.
Emergency Medicine Relevance & Applicability 9.0
Emergency clinicians routinely evaluate acute or unknown-onset stroke and initiate time-sensitive imaging, thrombolysis decisions, and stroke-team activation.
Neurology Relevance & Applicability 9.5
Extended-window thrombolysis selection is a central acute stroke neurology decision, and the intervention and outcomes are directly applicable to US stroke pathways.
2. 8.2
Personalized Blood Pressure Targeting After Endovascular Therapy for Acute Ischemic Stroke: A Randomized Clinical Trial.
Overall: A well-conducted randomized trial found a large improvement in 90-day functional independence using a feasible, reperfusion-guided blood pressure strategy, with no evident increase in major safety outcomes.
View 6 Criterion Scores
Validity, Bias Control & Precision 8.2
This multicenter randomized trial used blinded endpoint assessment, intention-to-treat analysis, 90-day follow-up, and confidence intervals, although treatment was open-label and the sample was moderately sized.
Patient-Oriented Outcomes 9.0
The primary outcome was functional independence at 90 days, with mortality, symptomatic intracranial hemorrhage, and serious adverse events also reported.
Magnitude of Net Benefit 8.5
The strategy increased favorable functional outcomes by 13.3 percentage points and reduced hemorrhagic transformation, without differences in mortality or symptomatic intracranial hemorrhage, though serious adverse events were numerically higher.
Implementability & Practicality 7.5
Blood pressure monitoring and intravenous vasoactive treatment are routinely available after thrombectomy at comprehensive US stroke centers, but individualized targets over 72 hours require close monitoring and protocol adherence.
Practice-Changing Potential 8.0
The substantial functional benefit provides a clear alternative to a uniform post-thrombectomy target, although confirmation and incorporation into guidelines may be needed before broad adoption.
Neurology Relevance & Applicability 9.0
Post-thrombectomy blood pressure management is a direct and common decision for vascular neurologists and neurocritical care teams, and the intervention is transferable to US comprehensive stroke centers.
3. 8.2
Atorvastatin, Cardiovascular Events, and Disability-free Survival in Older Adults.
Overall: This rigorous, large trial shows that atorvastatin moderately reduces major cardiovascular events in healthy older adults without extending disability-free survival, offering directly actionable evidence for US preventive care.
View 8 Criterion Scores
Validity, Bias Control & Precision 9.2
This large double-blind, randomized, placebo-controlled trial used identical placebo, prespecified hierarchical testing, nearly six years of follow-up, and precise estimates for its primary outcomes.
Patient-Oriented Outcomes 9.5
Both primary composites comprised important clinical outcomes, including cardiovascular death, myocardial infarction, stroke, revascularization, all-cause death, dementia, and persistent physical disability.
Magnitude of Net Benefit 5.2
Atorvastatin produced a clinically meaningful but moderate reduction in major cardiovascular events, with an absolute reduction of approximately 2.3 percentage points, but did not improve disability-free survival and increased several adverse-event categories.
Implementability & Practicality 8.5
Once-daily atorvastatin is widely available and familiar in US practice, although long-term treatment and monitoring for musculoskeletal, hepatobiliary, and diabetes-related effects add some burden.
Practice-Changing Potential 8.5
The trial directly addresses longstanding uncertainty about statins for primary prevention after age 70 and provides strong evidence for cardiovascular benefit while clarifying the absence of improved disability-free survival.
Cardiology Relevance & Applicability 8.8
Primary cardiovascular prevention in adults aged 70 years or older is a common cardiology decision, and the intervention and population are readily transferable to US cardiovascular care.
Primary-Care Relevance & Applicability 9.0
The study was conducted in general practices and evaluates a common medication decision routinely made by US primary care physicians for community-dwelling older adults.
Geriatrics Relevance & Applicability 9.5
The exclusively older population and explicit assessment of dementia, persistent disability, mortality, cardiovascular events, and treatment harms make the findings highly pertinent to geriatric practice.
4. 8.1
Low-Voltage Ablation in Persistent Atrial Fibrillation: The IDEAL-AF Randomized Clinical Trial.
Overall: This randomized multicenter trial found a large improvement in arrhythmia-free survival and quality of life without greater serious harm, supporting a potentially practice-changing but specialized ablation strategy.
View 6 Criterion Scores
Validity, Bias Control & Precision 8.2
This multicenter randomized trial used an appropriate active comparator and reported a large effect with reasonably tight confidence intervals, although blinding, attrition, monitoring intensity, and analysis population were not described.
Patient-Oriented Outcomes 7.5
The study assessed arrhythmia recurrence without antiarrhythmic drugs and health-related quality of life, but did not report effects on hospitalization, stroke, mortality, or other major clinical events.
Magnitude of Net Benefit 8.8
Adjunctive ablation increased arrhythmia-free survival by 30.3 percentage points, improved quality of life, and did not increase serious adverse events, though the added procedural burden and detailed safety rates were not reported.
Implementability & Practicality 7.5
The strategy is feasible in US electrophysiology centers already performing electroanatomical mapping and AF ablation, but requires specialized expertise, equipment, patient selection, and additional ablation.
Practice-Changing Potential 8.5
The large benefit from a randomized trial could materially alter ablation strategy for selected patients with persistent AF and substantial low-voltage zones, although confirmation beyond five Swedish centers would strengthen adoption.
Cardiology Relevance & Applicability 8.5
The findings directly inform electrophysiologists and cardiologists referring patients for persistent AF ablation and are compatible with established US ablation workflows, though they apply only to the subgroup with significant low-voltage zones.
5. 8.1
Sirolimus-Coated Balloon Angioplasty for Infrainguinal Artery Disease.
Overall: This well-conducted randomized trial found a clinically meaningful reduction in repeat limb procedures or major amputation without an evident one-year safety penalty, supporting potential adoption during infrainguinal angioplasty.
View 7 Criterion Scores
Validity, Bias Control & Precision 8.5
This large randomized trial used an appropriate comparator, prespecified sequential testing, blinded outcome adjudication, and reported confidence intervals; open-label treatment, unreported attrition, and industry funding modestly limit certainty.
Patient-Oriented Outcomes 8.5
The outcomes included major amputation, repeat revascularization, and mortality, all clinically important, although the composite results do not show the separate contribution of each component.
Magnitude of Net Benefit 8.0
Sirolimus-coated balloons reduced major adverse limb events from 15.0% to 8.8% and broader limb events from 30.8% to 23.0%, with similar mortality and overall adverse events; device cost and burden were not reported.
Implementability & Practicality 7.0
The intervention can be incorporated into an existing endovascular angioplasty procedure, but it requires a specific coated device and the abstract provides no information on US availability, cost, coverage, or added workflow.
Practice-Changing Potential 8.5
A sizable reduction in clinically important limb events from a direct randomized comparison could influence balloon selection during infrainguinal interventions, though longer-term outcomes and external applicability are not described.
Cardiology Relevance & Applicability 5.0
The decision is directly relevant to interventional and vascular cardiologists but narrower for general cardiology, and the abstract does not identify the study setting or establish transferability to routine US practice.
Surgery (Other) Relevance & Applicability 5.0
The findings are relevant to vascular surgeons performing endovascular limb procedures but less applicable to surgeons outside that subspecialty, with the geographic and health-system setting unspecified.
6. 8.1
PERC-Peds rule for bedside exclusion of pulmonary embolism without radiation in children in the USA (BEEPER): a multicentre, prospective, observational, diagnostic accuracy study.
Overall: This large, precise, multicenter US study strongly supports PERC-Peds as a practical rule-out tool, but implementation benefits such as fewer imaging studies and better patient outcomes were not directly tested.
View 7 Criterion Scores
Validity, Bias Control & Precision 8.8
This large prospective study enrolled a consecutive series across 21 US pediatric emergency departments, used standardized data collection, independent adjudication, 45-day follow-up, and reported precise confidence intervals; clinician-directed testing remains a limitation.
Patient-Oriented Outcomes 7.0
Missed pulmonary embolism or proximal DVT is clinically important, but the study primarily measured diagnostic accuracy rather than directly demonstrating reduced radiation exposure, complications, or improved patient outcomes.
Magnitude of Net Benefit 7.0
PERC-Peds had 99.6% sensitivity and a 0.1% false-negative rate, while sequential use with D-dimer ruled out disease in 54.3% with a 0.9% false-negative rate; actual reductions in testing and associated harms were not measured.
Implementability & Practicality 9.0
The bedside rule uses readily collected clinical information, and D-dimer testing is routinely available in US emergency departments, allowing adoption with little equipment, training, or workflow burden.
Practice-Changing Potential 8.5
The multicenter US evidence addresses a major pediatric evidence gap and could reduce low-value testing, although an observational accuracy study does not establish the effects of implementing the rule on imaging use or clinical outcomes.
Pediatric Emergency Medicine Relevance & Applicability 10.0
The study directly evaluates a bedside decision made by pediatric emergency clinicians across 21 US pediatric emergency departments using a realistic point-of-care workflow.
Pediatrics (General) Relevance & Applicability 4.0
Pulmonary embolism can arise in general pediatric patients, but diagnostic rule-out and imaging decisions for suspected cases are generally handled in emergency or specialty settings.
7. 8.0
Sustained benefit of compression therapy for preventing recurrent leg cellulitis: extended follow-up of a randomised controlled trial.
Overall: This small but well-conducted randomized trial found a large, durable reduction in recurrent cellulitis and hospitalization with a practical intervention, though its open-label single-center design and unreported harms limit certainty.
View 8 Criterion Scores
Validity, Bias Control & Precision 7.0
Randomization, prespecified interim analysis, stratification, registry documentation, and intention-to-treat analysis strengthen validity, but the open-label, single-center design, small sample, early cessation, and subsequent control-group access to compression limit certainty.
Patient-Oriented Outcomes 9.0
Cellulitis recurrence and cellulitis-related hospitalization are clearly defined, clinically important outcomes.
Magnitude of Net Benefit 8.5
Compression reduced recurrence from 47% to 20% and hospitalization from 18% to 9%, with sustained adherence; however, adverse effects and the practical burden of garment use were not reported.
Implementability & Practicality 8.0
Compression garments are a nonpharmacologic intervention that can be incorporated into outpatient care, although fitting, availability, cost, and sustained daily use may create some friction.
Practice-Changing Potential 7.5
The large reduction in recurrence supports earlier use of compression for chronic leg edema, but a small, single-center Australian trial is less definitive than multicenter evidence for changing US practice on its own.
Dermatology Relevance & Applicability 8.0
Prevention of recurrent leg cellulitis in patients with chronic edema is directly relevant to dermatologists involved in managing these conditions, and compression is transferable to US outpatient care.
Primary-Care Relevance & Applicability 8.0
US primary care physicians commonly encounter chronic leg edema and recurrent cellulitis and can initiate education, prescribe compression, or coordinate fitting.
Infectious Disease Relevance & Applicability 7.5
Recurrent cellulitis prevention and reduced antibiotic exposure are relevant to infectious disease practice, although compression management may often be shared with primary care, dermatology, or edema services.
8. 7.9
Stereotactic Body Radiotherapy vs Moderately Hypofractionated IMRT for Localized Intermediate-Risk Prostate Cancer: A Randomized Clinical Trial.
Overall: A strong multicenter randomized trial supports five-fraction SBRT as a convenient option with meaningful quality-of-life advantages, but it does not establish superior disease control.
View 7 Criterion Scores
Validity, Bias Control & Precision 8.3
This adequately powered phase 3 randomized trial enrolled 698 patients across 136 international centers and reported prespecified outcomes, although its open-label design and incompletely reported attrition limit certainty for patient-reported outcomes.
Patient-Oriented Outcomes 9.0
The primary outcomes included urinary and bowel quality of life and disease-free survival, supplemented by urinary incontinence, sexual function, and serious genitourinary adverse events.
Magnitude of Net Benefit 7.0
SBRT reduced clinically important bowel deterioration by 8.9 percentage points, improved several other quality-of-life measures, lowered serious genitourinary toxicity, and required far fewer treatments, but did not improve urinary irritation or disease-free survival.
Implementability & Practicality 8.0
Five-fraction SBRT substantially reduces treatment visits compared with 20 or 28 fractions and is feasible in US radiation oncology practice, though it requires appropriate stereotactic equipment and expertise.
Practice-Changing Potential 7.3
The results could support greater use of a shorter SBRT regimen for eligible patients, but the absence of superior disease-free survival and lack of demonstrated equivalence temper a definitive change.
Oncology Relevance & Applicability 9.0
This directly informs radiation treatment selection for a common localized prostate cancer population and included numerous centers in the United States and comparable health systems.
Urology Relevance & Applicability 8.5
Urologists routinely counsel and refer patients with localized intermediate-risk prostate cancer, making the comparative cancer-control, quality-of-life, toxicity, and treatment-burden findings highly applicable.
9. 7.9
Natural Compared With Artificial Cycle Endometrial Preparation for Frozen Embryo Transfer: A Systematic Review and Meta-analysis.
Overall: Natural-cycle preparation, particularly a modified natural cycle, produced modest improvements in live birth and miscarriage outcomes across randomized trials, with good feasibility but some uncertainty limiting immediate universal adoption.
View 7 Criterion Scores
Validity, Bias Control & Precision 8.5
This registered systematic review included 11 randomized trials and 9,955 women, used a comprehensive search, independent extraction, and Cochrane risk-of-bias assessment; estimates were reasonably precise, although the evidence was rated moderate quality.
Patient-Oriented Outcomes 9.5
Live birth and miscarriage are clearly defined, highly patient-important reproductive outcomes.
Magnitude of Net Benefit 6.5
Natural-cycle preparation modestly increased live births and reduced miscarriages, with an estimated live-birth NNT of 23; treatment burdens and other harms were not reported.
Implementability & Practicality 7.5
Natural and artificial preparation are established fertility-care strategies, although modified natural cycles require ovulation monitoring and an hCG trigger.
Practice-Changing Potential 7.5
The findings could favor modified natural-cycle preparation in frozen embryo transfer, but the modest benefit, moderate-quality evidence, and lack of benefit for true natural cycles temper immediate broad change.
Gynecology Relevance & Applicability 5.5
The question is relevant to reproductive gynecology, but frozen embryo transfer protocols are primarily managed by fertility subspecialists rather than general gynecologists.
Obstetrics Relevance & Applicability 1.5
Endometrial preparation before embryo transfer occurs in fertility care and is not ordinarily a clinical decision made in routine obstetric practice.
10. 7.9
Complete Revascularization Guided by Functional Coronary Angiography in STEMI.
Overall: A large randomized trial found that physiology-guided complete revascularization produced a meaningful reduction in clinical events and fewer major safety events than conventional angiographic guidance.
View 6 Criterion Scores
Validity, Bias Control & Precision 8.5
This international randomized trial enrolled 1823 patients, used an active comparator and time-to-event analysis, and reported statistically precise efficacy and safety estimates, although attrition and analysis-population details are not provided.
Patient-Oriented Outcomes 7.5
The primary composite included death, myocardial infarction, cerebrovascular events, and repeat revascularization, but results for the individual components are not reported.
Magnitude of Net Benefit 8.0
Physiology guidance reduced primary events from 13.7% to 8.9%, an absolute reduction of 4.8%, while also reducing major bleeding or contrast-associated kidney injury from 7.1% to 4.6%.
Implementability & Practicality 7.0
The strategy can be incorporated into invasive STEMI care but requires functional coronary assessment during complete revascularization, adding procedural capability and workflow demands.
Practice-Changing Potential 8.5
The trial directly addresses an unresolved choice between two revascularization-guidance strategies and demonstrates clinically meaningful efficacy and safety advantages.
Cardiology Relevance & Applicability 9.5
Selecting nonculprit lesions for treatment after STEMI is a direct and common interventional cardiology decision, and the international randomized design is readily applicable to US catheterization practice.
Score Guide: 9-10 Exceptional 7-8 Strong 5-6 Moderate 3-4 Weak 1-2 Poor
Showing top 10 of 1577

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