Trials

Question 1

TST Trial (2021)

Answer 1

Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol.

Question 2

COMPASS Trial (2020)

Answer 2

Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease

Compared with ASA monotherapy, the combination of rivaroxaban 2.5 mg twice daily plus ASA resulted in fewer NCB events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, whereas severe bleedings were less frequent and with less clinical impact.

Question 3

EMBRACE Trial (2014)

Answer 3

Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal atrial fibrillation was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring.

Question 4

CRYSTAL AF Trial (2014)

Answer 4

ECG monitoring with an insertable cardiac monitor (ICM) was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke.

Question 5

NAVIGATE ESUS Trial (2018)

Answer 5

Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding.

Question 6

RESPECT ESUS Trial (2019)

Answer 6

In patients with a recent history of embolic stroke of undetermined source, dabigatran (Pradaxa) was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group.

Question 7

PROTECT Trial (2018)

Answer 7

Among patients with nonvalvular atrial fibrillation, the use of the WATCHMAN device for left atrial appendage ligation is feasible. This device demonstrated a noninferior rate of cardiovascular death, stroke, or systemic embolism, compared with warfarin alone, which was sustained to 5 years of follow-up. The rate of all strokes (ischemic or hemorrhagic) was noninferior between the groups, and there were significantly less hemorrhagic strokes in the device group.

Question 8

PREVAIL Trial (2014)

Answer 8

LAA (left atrial appendage) occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days’ post-procedure.

Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy.

Question 9

CAPRIE Trial (2016)

Answer 9

Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

Question 10

European Stroke Prevention Study 2 [ESPS-2] (1996)

Answer 10

Among patients with prior stroke or TIA, combination treatment with aspirin and dipyridamole was associated with greater reductions in the composite of death or stroke at 2 years compared with aspirin alone, dipyridamole alone, or placebo. Both aspirin alone and dipyridamole alone were associated with reductions in death or stroke compared with placebo. Despite the relatively low dose of aspirin used in the trial, bleeding rates were higher in both aspirin arms.

Question 11

Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS] (2008)

Answer 11

The results of this landmark clinical trial, which is the largest secondary prevention trial in patients with ischemic stroke, indicate that the combination of aspirin + dipyridamole is roughly similar to clopidogrel (although it did not meet strict criteria for noninferiority) in reducing the incidence of recurrent strokes, but is associated with an increased risk of intracranial bleeds.

Question 12

SOCRETES Trial [ticagrelor vs ASA] (2016)

Answer 12

In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor (Brillinta) was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days.

Question 13

THALES Trial [ticagrelor & ASA vs ASA alone] (2020)

Answer 13

In patients with TIA and minor ischemic stroke, ticagrelor (Brillinta) added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence.

Question 14

SPARCL Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial (2006)

Answer 14

In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.

Question 15

DEFUSE 1 & 2 (2006, 2012)

Answer 15

It is uncertain if endovascular stroke therapy leads to improved clinical outcomes due to a paucity of data from randomized placebo-controlled trials. The aim of this study was to determine if MRI can be used to identify patients who are most likely to benefit from endovascular reperfusion.

established “penumbral patterns” as predictors of good outcomes following revascularization procedures:
*Infarct size <70 mL (CBF)
*Ischemic tissue/infarct core ratio equal or greater than 1.8
*Absolute difference of of ischemic tissue-infarct core equal or greater than 15 mL

Target Mismatch patients who achieved early reperfusion following endovascular stroke therapy had more favorable clinical outcomes and less infarct growth. No association between reperfusion and favorable outcomes was present in patients without Target Mismatch. These data support a randomized controlled trial of endovascular treatment in patients with the Target Mismatch profile.

STEVEN WARACH

Question 16

DEFUSE 3 (2018)

Answer 16

Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted.

Hypoperfusion Index (HIR) greater or equal to 0.34 –AND– Cerebral Blood Volume (CBV) less or equal to 0.74 = ARE PREDICTED TO HAVE POOR COLLATERALS AND A LARGER THAN 25 mL STROKE CORE WITHIN 24 HRS. CAN HEMORRHAGE FOLLOWING EVT (REPERFUSION INJURY)

Question 17

DAWN Trial (2018)

Answer 17

Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.

Question 18

MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands (2014)

Answer 18

MR CLEAN was a well designed prospective, multicenter, clinical trial involving 500 patients presenting with acute ischemic stroke with a proximal intracranial arterial occlusion who were randomized to either receive usual care or intra-arterial treatment (delivery of a thrombolytic, mechanical thrombectomy, or both) plus usual care.

Intra-arterial therapy in conjunction with IV tPA is safe and effective in patients presenting with an acute ischemic stroke secondary to a large, proximal occlusion of the anterior circulation.

Question 19

INTERACT2 Trial (2013)

Answer 19

In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure.

Question 20

ATACH2 Trial (2016)

Answer 20

The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg.

Question 21

WARCEF Trial (2012)

Answer 21

Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

Question 22

CRASH Trial (2001)

Answer 22

CRASH is a randomised controlled trial (ISRCTN74459797) of the effect of corticosteroids on death and disability after head injury. There was no evidence that the effect of corticosteroids differed by injury severity or time since injury. These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury.

Question 23

POLAR-RCT Trial (2018)

Answer 23

Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

Question 24

FLAME Trial (2011)

Answer 24

In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit.

Question 25

EFFECTS Trial (2021)

Answer 25

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.

Question 26

WAKEUP Trial (2018)

Answer 26

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.

Question 27

MR WITNESS (2018)

Answer 27

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.

Question 28

TWIST Trial (2022)

Answer 28

In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT.

Question 29

CADISS (2019)

Answer 29

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

Question 30

STOP Trial (1998) Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results

Answer 30

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).

Recurrent transfusions are performed.
Stroke free survival appear to plateau after about 30 minutes.
TCDs then performed to monitor flow velocity.
Excessive cerebral flow velocities are related to severe anemia, vessel stenosis, and cerebral vasodilation caused by tissue hypoxia.

Question 31

MOST Trial (ends 02/28/2023)

Answer 31

The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with 0.9mg/kg IV rt-PA within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care.

Question 32

EXPRESS Trial (2007) Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke

Answer 32

Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.

Question 33

POINT Trial (2018)

Answer 33

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

Question 34

CHANCE Trial (2013)

Answer 34

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

Question 35

SAMMPRIS (2015)

Answer 35

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

Question 36

ATTEST (2015)

Answer 36

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)

Question 37

NOR-TEST (2017)

Answer 37

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)

Question 38

HERMES (2016)

Answer 38

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.

Question 39

ESCAPE (2015)

Answer 39

Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality.

Question 40

REVASCAT (2015)

Answer 40

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.

Question 41

SWIFT PRIME (2015)

Answer 41

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.

Question 42

EXTEND IA (2015)

Answer 42

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.

Question 43

ARCADIA (2024)

Answer 43

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.

Question 44

ACTION-CVT (Anticoagulation in the Treatment of Cerebral Venous Thrombosis)

Answer 44

Our findings provide real-world data supporting the use of DOACs as a reasonable alternative to warfarin treatment in patients with CVT.

Question 45

ECASS 3 (2008)

Answer 45

In this study, intravenous alteplase given 3 to 4.5 hours (median, 3 hours 59 minutes) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of symptomatic intracranial hemorrhage than that reported previously among patients treated within 3 hours.

Extended IV tPA window from 3 to 4.5 hours.

Question 46

IV thrombolysis INCLUSION criteria (3-4.5)

Answer 46

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

Question 47

INTERACT 3 (2023)

Answer 47

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.

Question 48

Thrombolytic Trials

Answer 48