PACUPod is your trusted source for AI-infused evidence-based insights tailored to advanced clinical pharmacists and physicians. Each episode dives into the latest primary literature, covering medication-focused studies across emergency medicine and critical care. We break down study designs, highlight key findings, and objectively discuss clinical implications—without the hype—so you stay informed and ready to apply new evidence in practice. Whether you’re preparing for board certification or striving for excellence in patient care, PACUPod helps you make sense of the data, one study at a time.
Britany: Welcome back to PACULit, your go-to podcast for clinical literature updates. Today, we’re discussing a study on alteplase use for posterior circulation ischemic stroke (PCIS) administered between 4.5 and 24 hours after symptom onset. Seth, PCIS often flies under the radar, right?
Seth: Absolutely, Britany. Posterior circulation strokes make up about 20% of ischemic strokes but are tricky to diagnose early due to variable symptoms. Brainstem and cerebellar involvement can cause disabling deficits, so timely reperfusion is critical. Yet, the standard intravenous alteplase window is limited to 4.5 hours, leaving many PCIS patients untreated, especially those presenting late or with unclear onset.
Britany: That’s where this study by Yan et al., published in the New England Journal of Medicine this year, fills a gap. Prior trials like WAKE-UP and EXTEND focused mainly on anterior circulation strokes or used advanced imaging. Evidence for PCIS beyond 4.5 hours was sparse.
Seth: Exactly. Posterior circulation strokes might have slower infarct progression due to better collateral circulation, potentially extending the thrombolysis window. The study evaluated whether intravenous alteplase between 4.5 and 24 hours improves functional outcomes safely in PCIS patients not planned for thrombectomy.
Britany: Important point—patients not eligible for thrombectomy. The study was a prospective, multicenter, randomized, open-label trial with blinded endpoint assessment (PROBE design). They enrolled 234 adults with confirmed PCIS, symptom onset 4.5 to 24 hours prior, and NIH Stroke Scale (NIHSS) scores ≤10, indicating mostly mild strokes.
Seth: They excluded patients with large established infarcts on CT, hemorrhage, thrombolysis contraindications, severe strokes, or planned endovascular therapy. Alteplase was dosed at 0.9 mg/kg (max 90 mg), given as a 10% bolus then 90% infusion over one hour. The comparator was standard medical therapy without thrombolysis.
Britany: The primary outcome was functional independence at 90 days, defined as modified Rankin Scale (mRS) 0–2. Secondary outcomes included symptomatic intracranial hemorrhage, 90-day mortality, ordinal mRS shift, and neurological improvement by NIHSS. They used intention-to-treat analysis with adjusted risk ratios and p<0.05 for significance.
Seth: Subgroup analyses included age, baseline NIHSS, and time from symptom onset. The 90-day follow-up allowed comprehensive assessment of efficacy and safety. This design balances rigor and real-world applicability.
Britany: The mean age was about 65, with balanced sex distribution. The cohort was predominantly Chinese, recruited from multiple centers across China. Median NIHSS was 6, reflecting mild stroke severity. Mild strokes often get overlooked but can cause significant disability, especially in posterior circulation.
Seth: Focusing on mild strokes is both a strength and limitation. It provides evidence for a group often excluded from thrombectomy but leaves questions about applicability to more severe PCIS. The single-country setting may limit generalizability, though the multicenter approach helps.
Britany: Key findings: functional independence at 90 days was 89.6% in the alteplase group versus 72.6% in standard therapy. The adjusted risk ratio was 1.16 (95% CI 1.03–1.30), p=0.01, showing statistical significance.
Seth: Impressive. Symptomatic intracranial hemorrhage was low—1.7% with alteplase versus 0.9% controls. Mortality was reduced: 5.2% versus 8.5%. These safety outcomes are reassuring given the extended window.
Britany: This suggests alteplase can be safely given up to 24 hours after symptom onset in selected PCIS patients without significantly increasing hemorrhagic complications, challenging the traditional 4.5-hour cutoff for this stroke subtype.
Seth: Prior studies like Ma et al. (2019) showed alteplase up to 9 hours improved outcomes in imaging-selected patients but with increased hemorrhage risk. Campbell’s meta-analysis confirmed benefits beyond 4.5 hours but noted hemorrhagic concerns. This trial extends the window further with favorable safety.
Britany: Current guidelines, such as Powers et al., recommend imaging-based selection beyond 4.5 hours, balancing benefits and risks. Yan et al.’s study adds by focusing specifically on PCIS and excluding thrombectomy candidates—a unique contribution.
Seth: Clinically, we should consider alteplase up to 24 hours post-onset in mild PCIS patients without extensive CT hypodensity. CT or advanced imaging to guide selection remains essential. Close monitoring for symptomatic intracranial hemorrhage is still warranted despite low incidence.
Britany: A key clinical pearl. The study excluded patients with large infarcts or severe strokes, so caution is needed when extrapolating to those groups. Safety and efficacy in moderate to severe PCIS or thrombectomy candidates remain unknown.
Seth: Also, drug interactions matter. Alteplase’s fibrinolytic activity can be potentiated by anticoagulants or antiplatelets, increasing bleeding risk. Careful medication reconciliation is critical, especially in extended windows where patients may have started other therapies.
Britany: In special populations like the elderly or those with renal impairment, subgroup analyses showed consistent benefits, but real-world vigilance is necessary. The mean age was 65, so data on very elderly patients remain limited.
Seth: Strengths include randomized design, extended window, and comprehensive outcomes. Limitations are predominance of mild strokes, single-country setting, and exclusion of thrombectomy candidates, which may affect generalizability.
Britany: Future research should evaluate alteplase in moderate to severe PCIS, include thrombectomy candidates, and refine imaging selection. Validation in diverse populations is needed to confirm findings globally.
Seth: Integrating predictive models like Li et al.’s 2024 tool could help identify patients most likely to benefit, optimizing individualized care.
Britany: To sum up, intravenous alteplase between 4.5 and 24 hours after symptom onset significantly improves functional independence at 90 days with low symptomatic intracranial hemorrhage risk in predominantly mild PCIS patients not scheduled for thrombectomy.
Seth: This study challenges existing paradigms and opens the door for extending thrombolysis windows in carefully selected PCIS patients, potentially improving outcomes for a historically underserved group.
Britany: Thanks for the discussion, Seth. Listeners, review the full article by Yan et al. in NEJM, 2025; volume 392, issue 13, pages 1288–1296. DOI: 10.1056/NEJMoa2413344.
Seth: Remember to consider patient-specific factors and institutional protocols when applying these findings. Stroke care is evolving rapidly; staying current is key.
Britany: That wraps up today’s PACULit update. Thanks for tuning in. Stay curious and keep optimizing patient care!
Seth: Take care, everyone!