Trials Flashcards

Question

EFFECTS Trial (2021)

Answer 1

Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance.

Answer 2

In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. Can give thrombolytic to FLAIR neg stroke.

Answer 3

Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Perfusion imaging (CT/MRI) can show potential viable brain tissue beyond 4.5 hours of stroke onset. Endovascular therapy has been demonstrated to improve outcomes in patients with salvageable brain tissue up to 24 hours after stroke onset DAWN, DEFUSE 3. There is therefore the potential for thrombolysis to have a benefit for some patients who have a longer duration post stroke onset. Aleplase therapy in patients that had a favourable perfusion-imaging profile between 4.5 – 9 hours after stroke onset or on awakening with stroke symptoms resulted in no or minor neurologic deficits more often than the use of placebo.

Answer 4

The TWIST stroke trial refers to the Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) — a major randomized clinical study designed to evaluate whether the clot-busting drug tenecteplase improves outcomes in people who wake up with symptoms of an acute ischaemic stroke when selected using a simple non-contrast CT scan. ⸻ 🧠 What Was the Question TWIST Tried to Answer? People who wake up with stroke symptoms often don’t know when the stroke began, so they traditionally aren’t offered intravenous thrombolysis (clot-busting therapy) because the benefit vs bleeding risk depends on symptom onset timing. Advanced imaging (like MRI or CT perfusion) can help select patients likely to benefit, but such imaging isn’t always available. TWIST tested whether plain non-contrast CT — which is widely available in most hospitals — could be used to safely select wake-up stroke patients to receive tenecteplase within 4.5 hours of waking. ⸻ 📊 Study Design • Type: International, multicentre, randomized, open-label, blinded endpoint trial. • Intervention: Tenecteplase IV thrombolysis (0.25 mg/kg, up to 25 mg) vs standard care without thrombolysis. • Participants: Adults with acute ischaemic stroke upon awakening, NIHSS ≥3 or aphasia, and eligibility for treatment within 4.5 h of waking. • Imaging selection: Non-contrast CT (simple CT scan only; no advanced perfusion/MRI criteria). • Primary outcome: Functional status at 90 days measured by the modified Rankin Scale (mRS). • Sites: 77 hospitals in 10 countries. • Enrollment: 578 participants (slightly under planned target due to COVID and other barriers). ⸻ 📌 Key Results • Functional outcomes: There was no statistically significant improvement in overall functional outcomes at 90 days in the tenecteplase group vs control. • mRS outcomes: Numerically more patients treated with tenecteplase achieved excellent outcomes in some analyses, but differences were not statistically significant. • Safety: Rates of symptomatic intracranial hemorrhage and overall mortality were similar between groups. • Because the trial was slightly underpowered, it could not definitively rule out a modest benefit. ⸻ 🔍 Interpretation & Clinical Importance TWIST’s findings suggest that: • Using plain CT alone to select wake-up stroke patients for tenecteplase thrombolysis did not clearly improve outcomes in this trial. • Advanced imaging (MRI/CT perfusion) remains the more validated way to identify patients with wake-up stroke who might still be in the thrombolysis time window and benefit from treatment.

Answer 5

What is the recurrent stroke risk after carotid and vertebral artery dissection, and are antiplatelets or anticoagulants more effective at reducing this risk? The risk of recurrent stroke after carotid and vertebral dissection is low; there was no evidence that antiplatelets or anticoagulants were more effective at reducing this risk. Rachel prefers DAPT x 3 months, then repeat vessel imaging, if stable ASA 325mg qD What CADISS Taught Us • Anticoagulation is NOT superior to antiplatelet therapy • Recurrent stroke risk after cervical artery dissection is low • Antiplatelet therapy is sufficient for most patients

Answer 6

Randomized trial to evaluate whether chronic transfusion could prevent initial stroke in children with sickle-cell anemia at high risk as determined by transcranial Doppler (TCD). The STOP trial changed standard of care: • ✅ Routine TCD screening is now recommended for children with sickle cell anemia (starting around age 2). • ✅ Chronic transfusion therapy is standard for children with abnormal TCDs. • ❗ Risks of transfusion (iron overload, alloimmunization) are weighed against the very high stroke risk.

Answer 7

The MOST–Argatroban Stroke Trial refers to the Multi-arm Optimization of Stroke Thrombolysis (MOST) trial evaluating adjunctive antithrombotic therapy added to IV alteplase (tPA) in acute ischemic stroke—with argatroban being one of the key investigational agents. This is a modern thrombolysis-optimization trial, distinct from classic secondary-prevention studies (CAPRIE, PRoFESS, ESUS). ⸻ 🧠 Purpose of the MOST Trial To determine whether adding adjunctive antithrombotic agents to standard IV alteplase can: • Improve early reperfusion • Reduce re-occlusion • Improve functional outcomes • Without increasing symptomatic intracranial hemorrhage (sICH) ⸻ 📋 Study Design • Type: Phase II, multicenter, randomized, adaptive trial • Population: Acute ischemic stroke patients eligible for IV alteplase • Time window: Standard tPA window • Design: Multi-arm platform trial Treatment Arms (Key Ones) • Alteplase alone (control) • Alteplase + Argatroban (direct thrombin inhibitor) • (Other arms studied at different phases, e.g., eptifibatide) ⸻ 💊 Why Argatroban? • Direct thrombin inhibitor • Short half-life • Rapid onset/offset • Theoretical benefits: • Prevents fibrin-mediated re-thrombosis • May improve clot lysis durability • Avoids platelet activation cascade seen with some agents ⸻ 🎯 Primary Outcomes • Safety: Symptomatic intracranial hemorrhage (sICH) • Efficacy: Functional outcome (mRS 0–1 or 0–2 at 90 days), early recanalization (exploratory) ⸻ 📊 Key Findings (Argatroban Arm) 🩸 Safety • No significant increase in sICH compared with alteplase alone • Overall bleeding rates were acceptable and comparable 🧠 Efficacy • Signals of: • Improved early neurological improvement • Potential improvement in functional outcomes • Not powered to definitively prove efficacy ➡️ Conclusion: Alteplase + argatroban appeared feasible and safe, justifying further study, but not practice-changing. ⸻ 🧩 Clinical Interpretation What MOST–Argatroban Taught Us • Adjunctive anticoagulation can be safely combined with IV tPA under controlled protocols • Re-occlusion after thrombolysis is a real problem • However: • No clear, definitive outcome benefit yet • Not recommended outside clinical trials

Answer 8

🧠 Why EXPRESS Changed Practice Before EXPRESS: • TIAs were often managed as low-urgency outpatient problems After EXPRESS: • TIA recognized as a medical emergency • Led to: • Rapid-access TIA clinics • Immediate antiplatelet/statin initiation • Use of ABCD² score to triage risk ⸻ 📌 Key Teaching Points (Boards / Clinical) • TIA = high early stroke risk • Delays kill neurons • Secondary prevention should begin immediately, not days later • Benefit comes from system-level speed, not a single drug ⸻ 🧠 One-Line Summary The EXPRESS trial showed that urgent, same-day initiation of secondary stroke prevention after TIA or minor stroke reduces early recurrent stroke risk by about 80%, transforming TIA into a true medical emergency.

Answer 9

POINT demonstrates that 90 days of DAPT reduces the rate of recurrent stroke and increases rates of major bleeding among patients with minor ischemic stroke and high-risk TIA. Further analysis suggests that 90 days of DAPT is unnecessarily long. The majority of efficacy events occurred during the first 7 days, and 80-90% occurred within the first 30 days, while the bleeding rate was roughly stable during the 90-day follow-up. Until further guidelines are available it seems reasonable to limit DAPT to the 30 days following minor ischemic stroke or high-risk TIA. Clopidogrel (600 mg loadthen 75 mg/day) plus aspirin 50-325 mg/day vs aspirin 50-325 mg/day for 90 days

Answer 10

The 2013 Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial randomized 5,170 Chinese patients with high-risk TIA or minor ischemic stroke within 24 hours of symptom onset to either combination aspirin/clopidogrel or aspirin alone. In the combination group, aspirin was continued for 21 days; all other therapy was continued for 90 days. At 90 days, combination aspirin/clopidogrel was associated with a 3.5% absolute and a 30% relative reduction in subsequent strokes compared to aspirin monotherapy (8.2% vs. 11.7%; NNT=29) driven predominantly by a reduction in ischemic stroke. There was no between-group difference in bleeding rates, which was the trial's primary safety outcome. Clopidogrel (300 mg load, 75 mg/day), aspirin 75 mg/ day ×21 days then aspirin only vs aspirin 75 mg/day

Answer 11

In patients with recent TIA/CVA due to 70-99% intra-cranial arterial stenosis, angioplasty and stenting was associated with an increased risk of recurrent stroke compared to medical therapy alone. ASA 325mg qD for entire follow-up Clopidogrel 75mg qD x 90 days

Answer 12

Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study Neurological and radiological outcomes did not differ between the tenecteplase and alteplase groups. (EQUIVOCAL)

Answer 13

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial Tenecteplase was not superior to alteplase and showed a similar safety profile. (EQUIVOCAL)

Answer 14

Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location.

Answer 15

Does rapid endovascular thrombectomy, in addition to best medical therapy, improve outcomes in patients with acute ischemic stroke from proximal large-vessel occlusion, compared with medical therapy alone? ESCAPE used fast, practical imaging: • Non-contrast CT → exclude large established infarct • CT angiography (CTA) → confirm LVO • Good collateral circulation required This helped avoid futile reperfusion and focused treatment on patients most likely to benefit. ⸻ 🎯 Primary Outcome • Functional independence at 90 days • Modified Rankin Scale (mRS 0–2) 🧠 Why ESCAPE Matters ESCAPE, along with MR CLEAN, EXTEND-IA, SWIFT PRIME, and REVASCAT, formed the 2015 thrombectomy revolution, showing that: • Mechanical thrombectomy: • Dramatically improves outcomes • Reduces mortality • Is safe when patients are properly selected • Speed matters (“time is brain”) • Imaging-based selection is critical The ESCAPE trial showed that rapid endovascular thrombectomy significantly improves functional outcomes and reduces mortality in patients with acute ischemic stroke from proximal large-vessel occlusion, establishing thrombectomy as standard care.

Answer 16

Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence.

Answer 17

In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days.

Answer 18

In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy WITH the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome.

Answer 19

To test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy. The ARCADIA trial did not demonstrate that apixaban is superior to aspirin for preventing recurrent stroke in cryptogenic stroke patients with atrial cardiopathy but without atrial fibrillation. • This suggests that empiric anticoagulation based on atrial cardiopathy alone may not reduce recurrent stroke risk and should not be routinely used outside research settings. • The findings highlight the complexity of stroke mechanisms in ESUS (embolic stroke of undetermined source) and suggest that AF still remains the main proven indication for anticoagulation.

Answer 20

Our findings provide real-world data supporting the use of DOACs as a reasonable alternative to warfarin treatment in patients with CVT. 💊 Anticoagulation Strategies DOACs Used • Apixaban (most common) • Rivaroxaban • Dabigatran Traditional Therapy • Initial heparin (UFH or LMWH) • Transition to warfarin (INR 2–3) 🧠 Efficacy • Recurrent thrombosis: ➖ No significant difference between DOACs and warfarin • Functional outcomes (mRS 0–2): ➖ Similar between groups • Mortality: ➖ No significant difference ⸻ 🩸 Safety (Major Takeaway) • Major bleeding: ✅ Significantly lower with DOACs • Intracranial hemorrhage: ➖ Lower rates in the DOAC group ➡️ This was the most practice-influencing finding of ACTION-CVT.

Answer 21

The ECASS trials were a landmark series of European studies that helped define who benefits from IV thrombolysis (alteplase, tPA) after acute ischemic stroke and when it is safe to give it. ⸻ Why ECASS Was Important Before ECASS, thrombolysis was controversial due to bleeding risk. ECASS clarified: • Time windows for tPA use • Imaging criteria to exclude patients at high risk for hemorrhage • The balance between functional recovery vs. intracranial bleeding ⸻ ECASS I (1995) • Time window: ≤ 6 hours • Dose: Alteplase 1.1 mg/kg (higher than current standard) • Key issue: Inclusion of patients with large early infarcts • Results: • ↑ Symptomatic intracranial hemorrhage • No clear functional benefit • Impact: Demonstrated the danger of late treatment and large infarct cores ⸻ ECASS II (1998) • Time window: ≤ 6 hours • Dose: Alteplase 0.9 mg/kg (current standard) • Results: • Trend toward better functional outcomes • Bleeding risk still present • Impact: Showed benefit was possible but time and patient selection mattered ⸻ ECASS III (2008) — Most Influential • Time window: 3–4.5 hours • Key Exclusions: • Age >80 • Severe stroke (NIHSS >25) • History of both stroke and diabetes • Oral anticoagulant use • Key Result: • Significantly improved functional outcomes (mRS 0–1 at 90 days) • Slight ↑ in symptomatic ICH, but no increase in mortality • Practice-Changing Outcome: • Expanded IV tPA window from 3 hours to 4.5 hours

Answer 22

NO history of BOTH diabetes and prior stroke NIHSS of 25 of less NO DOAC use except warfarin as long as INR < 1.7 Imaging evidence of no more than 1/3 MCA territory ischemia

Answer 23

CARE BUNDLE of active management: 1) Intensive BP lowering to systolic target of <140mmHg 2) Glucose control target 6.1-7.8 mmol/l for non-diabetic; 7.8-10.0 mmol/l for diabetic patients; 3) Treatment of pyrexia to a target body temperature ≤37.5 ℃; 4) Reversal of anticoagulation to target INR <1.5 involving use of vitamin K and prothrombin complex concentrate (PCC) or alternatively, fresh frozen plasma (FFP). The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial is the only randomised controlled trial involving a care bundle that included intensive blood pressure lowering treatment in acute intracerebral haemorrhage. The primary result was that the implementation of the care bundle across participating hospitals resulted in patients having a better functional outcome (measured on the modified Rankin Scale) at 6 months post-treatment compared with usual care.

Trials Flashcards

(48 cards)