Stroke Thrombectomy Extended to 24 Hours: How the DAWN and DEFUSE 3 Trials Changed Treatment

What Is Mechanical Thrombectomy for Stroke?

Ischemic stroke, which accounts for approximately 87% of all strokes, occurs when a blood clot (thrombus) blocks a cerebral artery, depriving brain tissue of oxygen and glucose. When the blockage involves a large intracranial artery (the internal carotid artery, middle cerebral artery M1 or M2 segment, basilar artery, or anterior cerebral artery), it is termed a large vessel occlusion (LVO), which accounts for approximately 30–40% of ischemic strokes and produces the most devastating outcomes. Without intervention, LVO strokes have mortality rates of 30–40% and leave most survivors severely disabled.

Mechanical thrombectomy is performed by neurointerventionalists who navigate a catheter from the femoral artery (in the groin) or radial artery through the vascular system to the site of the clot in the brain. Modern devices primarily use stent retrievers (such as Solitaire and Trevo), which are deployed through the clot, capturing it in a mesh cage that is then withdrawn, or aspiration catheters (such as Penumbra) that use suction to extract the clot. The procedure achieves successful recanalization (restoration of blood flow, defined as TICI grade 2b/3) in approximately 80–90% of cases.

The concept that "time is brain" is quantified by the estimate that approximately 1.9 million neurons, 14 billion synapses, and 12 km of myelinated nerve fibers are destroyed per minute during an untreated stroke (Saver, 2006, Stroke). This translates to the brain aging approximately 3.6 years for each hour without treatment. The urgency of stroke treatment led to the development of stroke systems of care, including primary stroke centers (capable of IV tPA administration) and comprehensive stroke centers (capable of thrombectomy and neurosurgical intervention), connected by transfer protocols to ensure patients reach the right level of care as quickly as possible.

How Did DAWN and DEFUSE 3 Extend the Treatment Window?

Prior to 2018, the thrombectomy time window was limited to approximately 6 hours after symptom onset, based on the landmark MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, and REVASCAT trials (collectively published in 2015). However, clinicians recognized that some patients presenting beyond 6 hours still had salvageable brain tissue visible on advanced imaging, and the rigid time cutoff was leaving many patients undertreated.

The DAWN trial (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention), published in the New England Journal of Medicine in January 2018, enrolled 206 patients with LVO stroke presenting 6–24 hours after last known well. Eligibility required a mismatch between clinical deficit severity (measured by NIHSS score) and infarct volume (measured by diffusion-weighted MRI or CT perfusion). Results were striking: 49% of thrombectomy patients achieved functional independence (modified Rankin Scale 0–2) at 90 days compared to 13% of controls (adjusted difference 33%, p<0.001). The trial was stopped early due to overwhelming efficacy.

The DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3), also published in the NEJM in 2018, enrolled 182 patients 6–16 hours after stroke onset with LVO and a perfusion imaging mismatch between ischemic core and penumbra (the surrounding at-risk tissue). Thrombectomy plus medical therapy achieved functional independence in 45% of patients vs. 17% in the medical therapy alone group (risk ratio 2.67, p<0.001). Like DAWN, DEFUSE 3 was stopped early for efficacy. Together, these trials established that the biological state of the brain—not simply the clock time—should determine treatment eligibility, fundamentally shifting the paradigm of acute stroke care.

What Is the Role of IV tPA in Acute Stroke Treatment?

Intravenous alteplase (tissue plasminogen activator, tPA) was the first FDA-approved treatment for acute ischemic stroke, with the NINDS trial (1995) establishing a 3-hour treatment window and the ECASS III trial (2008) extending it to 4.5 hours with slightly more restrictive criteria. Alteplase works by activating plasminogen to plasmin, which breaks down fibrin clots. It is administered as a 0.9 mg/kg IV dose (maximum 90 mg), with 10% given as a bolus and the remainder infused over 60 minutes. Tenecteplase, a modified form of tPA with a longer half-life allowing single-bolus dosing, is increasingly used in practice based on non-inferiority data from multiple trials.

For large vessel occlusion strokes, IV tPA alone achieves recanalization in only approximately 10–30% of cases because LVO clots are typically too large for pharmacological dissolution alone. The current standard of care is a "drip and ship" or "drip and drive" model: IV tPA is initiated at the nearest stroke-capable hospital while simultaneously arranging transfer to a comprehensive stroke center for thrombectomy. The AHA/ASA guidelines recommend that IV tPA should not delay thrombectomy, and the two treatments are complementary rather than competing.​

The DIRECT-MT trial (2020, published in The Lancet) and the MR CLEAN-NO IV trial (2021) explored whether thrombectomy alone (without preceding IV tPA) might be sufficient for LVO strokes. Results were mixed: thrombectomy alone was non-inferior in some analyses but showed trends toward slightly worse outcomes. Current AHA/ASA guidelines continue to recommend IV tPA before thrombectomy when eligible, unless there are specific contraindications to thrombolytics (recent surgery, active bleeding, coagulopathy). The door-to-needle time target for IV tPA is 60 minutes or less, and the door-to-groin puncture time target for thrombectomy is 90 minutes or less at comprehensive stroke centers.

How Is Stroke Care Organized to Ensure Fast Treatment?

The American Heart Association and The Joint Commission certify stroke centers at four levels: acute stroke-ready hospitals (basic protocols and transfer agreements), primary stroke centers (IV tPA capability, 24/7 CT imaging, stroke teams), thrombectomy-capable stroke centers (endovascular-capable without full neurosurgical backup), and comprehensive stroke centers (full neurointerventional, neurosurgical, and neurointensive care capabilities). This tiered system ensures that patients are directed to the appropriate level of care while minimizing delays. In the US, approximately 1,700 hospitals are certified as primary or comprehensive stroke centers.

Mobile stroke units (MSUs) are specially equipped ambulances carrying CT scanners, point-of-care laboratory testing, and telemedicine capability, allowing diagnosis and IV tPA administration in the field. The BEST-MSU trial (Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit, 2021, published in The Lancet) demonstrated that MSU treatment significantly improved functional outcomes and reduced disability-adjusted life years compared to standard ambulance transport. MSU patients received IV tPA a median of 72 minutes from symptom onset compared to 108 minutes with standard care.

Telemedicine has been transformative for stroke care access, particularly in rural areas far from comprehensive stroke centers. Tele-stroke networks connect emergency physicians at community hospitals with vascular neurologists via real-time video and imaging review, enabling remote assessment and treatment decisions including IV tPA administration. The AHA endorses tele-stroke as equivalent to in-person neurological consultation for acute stroke evaluation. Public education about stroke recognition using the BEFAST mnemonic (Balance problems, Eyes/vision changes, Face drooping, Arm weakness, Speech difficulty, Time to call 911) complements the medical infrastructure by encouraging rapid activation of emergency medical services.