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RE-SPECT ESUS Trial: Dabigatran for Prevention of Recurrent Stroke after Cryptogenic Stroke

2019, RE-SPECT ESUS Trial Summary: Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source | Source: NEJM

LEAP trial (2019): Early vs Delayed Levodopa in Parkinson’s Disease

Leap trial visual abstract parkinson's disease

LEAP Trial Summary: The LEAP trial was a Multicenter, randomized, double-blind, placebo-controlled, delayed-start trial that randomized 445 patients with Parkinson’s disease (mean age 65) and similar baseline clinical characteristics to early-start group (levodopa + cardbidopa
for 80 weeks) (n=222) or delayed-start group (Placebo for 40 wks then
levodopa + cardbidopa for 40 weeks) (n=223). The primary objective of the study was to evaluate whether levodopa has a disease-modifying effect on patients with early Parkinson’s disease who had insufficient disability to warrant treatment with antiparkinson medication. No difference was found in the primary outcome of change in UPDRS score from baseline to week 80 among both groups (p=0.44). The authors of LEAP trial concluded that Treatment with levodopa in combination with carbidopa had no disease- modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks.

Summarized by Ricardo Vivanco

Source: NEJM

CHANCE Trial (2013): Clopidogrel with aspirin in acute minor stroke or transient ischemic attack

CHANCE Trial Visual Summary

CHANCE Trial Summary: Wang et al. randomized 5,170 patients (≥40 years) with either minor ischemic stroke (NIHSS score ≤3) or high-risk TIA (ABCD2 score ≥4) to either aspirin/clopidogrel combination or aspirin alone. The primary objective was to assess if early administration of aspirin/clopidogrel reduces rates of subsequent strokes when compared to aspirin monotherapy in patients with acute TIA or minor ischemic stroke.

The results showed a significant decrease in recurrence of stroke (P<0.001; NNT=29). Bleeding risk did not show a significant difference between both groups (P=0.09). The results were based on Chinese population. In 2018, the POINT trial studied similar outcomes and showed an increased risk of bleeding with dual antiplatelet therapy.

The authors of the CHANCE trial concluded that in patients with minor ischemic stroke or high-risk TIA, starting aspirin/clopidogrel within 24h of symptom onset reduces the 90-day stroke incidence without increasing bleeding rates, when compared to aspirin monotherapy.

Source: NEJM

BRIDGE Trial (2015): Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

BRIDGE Trial visual abstract

BRIDGE Trial Summary: Douketis JD et al. randomized 1,884 patients on warfarin (INR 2-3 for ≥3m) with AF or A-flutter and CHADS2 Score ≥1 to LMWH: dalteparin (100 IU/kg BID) or placebo. The objective was to assess if bridging anticoagulation reduce rates of arterial thromboembolism compared to no bridging in patients with atrial fibrillation undergoing an invasive procedure. The results showed noninferiority (P=0.01) of the primary outcome (TIA or stroke or arterial embolism) in patients with no bridging as compared with bridging. The authors of the BRIDGE trial concluded that among patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing an invasive procedure, periprocedural bridging anticoagulation with LMWH did not reduce the incidence of arterial thromboembolism when compared to no bridging, but did increase the risk of major bleeding.

Source: NEJM

POINT Trial (2018): Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

POINT Trial Summary: Johnston et al. randomized 4,881 patients who presented with low risk stroke or high risk TIA to either a combination of aspirin and clopidogrel or aspirin alone. Their objective was to assess the efficacy of dual antiplatelet therapy on recurrence of stroke, MI or mortality associated with ischemia. The results of POINT trial were significantly in favor of dual antiplatelet therapy when it comes to primary end point (P=0.02). However, the effect was masked by the increase in major hemorrhage risk that these patients were exposed to (P=0.01)

Full POINT trial results available at NEJM

RESPECT Trial (2013): Closure of PFO versus Medical Therapy after Cryptogenic Stroke

2013, Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke, NEJM

RESPECT Trial Key Points:

  1. Patients with cryptogenic stroke have higher incidence of PFO compared to general population. This led to the concept that closing PFO might be beneficial in terms of preventing recurrence of stroke in this population.
  2. The initial CLOSURE I trial showed no benefits of closing PFO percutaneously. In contrast, RESPECT trail showed benefits of PFO closure with the Amplatzer device.
  3. Patients deriving the maximum benefit from PFO closure were those with high grade shunt with presence of left atrial aneurysm.
  4. CLOSE and REDUCE are two more recent trials that show similar benefits of PFO closure over medical management.

Guideline changes based on the RESPECT Trial:

The last AHA/ASA guidelines were from 2014 which were published based on results of CLOSURE I and RESPECT trial. They recommended:

For patients with an ischemic stroke or TIA and a PFO who are not on anticoagulation therapy, antiplatelet therapy is recommended. (Class I, LOE B)

For patients with an ischemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is indicated, depending on stroke characteristics. (Class I, LOE A). When anticoagulation is contraindicated, an inferior vena cava filter is reasonable. (Class IIa, LOE C).

For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, available data does not support a benefit for PFO closure. (Class III, LOE A)

In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT. (Class IIb, LOE C)


DEFUSE-3 Trial (2018): Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

defuse 3 trial visual abstract about the use of thrombectomy in patients with stroke

DEFUSE-3 Trial Summary: Gregory W et al. randomized 182 patients with proximal middle-cerebral-artery or internal carotid artery occlusion, an initial infarct size of <70 ml, and a ratio of the volume of ischemic tissue to infarct volume ≥ 1.8 to either thrombectomy endovascular therapy group (n=92) or medical therapy group (n=90). The primary objective was to assess the utility of thrombectomy in patients 6 to 16 hours after they were last known to be well and who were likely to have salvageable ischemic brain tissue. The primary outcome of the modified Rankin scale score at 90 days was 3 in the thrombectomy group compared to 4 in medicine group (OR 2.77, 95% CI 1.63 – 4.70; P<0.001). The authors of the DEFUSE-3 trial concluded that 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.

Source: 2018, Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging, NEJM

WAKE-UP: MRI guided thrombolysis with alteplase in stroke

2018, MRI guided thrombolysis with alteplase in stroke with unknown time of onset, NEJM

EXTEND-IA TNK: Tenecteplase vs Alteplase in Ischemic Stroke

2018, Tenecteplase vs Alteplase in Ischemic Stroke, NEJM

SOCRATES: Ticagrelor versus aspirin in acute stroke or TIA

2016, Ticagrelor versus aspirin in acute stroke or TIA, NEJM

SPARCL: High-dose atorvastatin after stroke or TIA

2006, High-dose atorvastatin after stroke or transient ischemic attack (TIA), NEJM

CRYSTAL-AF: Cryptogenic Stroke and Underlying Atrial Fibrillation

2014, 30 Days AF monitoring in patients with Cryptogenic Stroke, NEJM

CRYSTAL AF Trial Summary

The Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) trial randomized 441 patients ,who were 40 years or older and with a diagnosis of cryptogenic stroke or transient ischemic attack within 90 days, in a 1:1 ratio to Insertable Cardiac Monitor (ICM) implantation or routine monitoring at the investigator’s discretion. Prior to randomization, all patients underwent at least 24 hours of ECG monitoring and had no evidence of atrial fibrillation at baseline. Patients were enrolled in 55 centers in Canada, Europe, and the United States. The primary endpoint was the time to first detection of atrial fibrillation, lasting >30 seconds, within 6 months. Approximately, 8.9% of patients in the ICM group were diagnosed with AF, compared with 1.4% in the control group (HR: 6.4; 95%CI: 1.9 to 21.7; p<0.001). Results were consistent through 12 months and 36 months.  Atrial fibrillation diagnosed in the ICM group was more frequently asymptomatic than in the control group. Prescription of oral anticoagulants was more than doubled in the ICM group, as compared with the control group, at both 6 and 12 months.

HACA: Hypothermia in Cardiac Arrest

2002, Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest, NEJM

DAWN Trial: Mechanical Thrombectomy 6 to 24 Hours after Stroke

The DAWN trial was a major success when it comes to mechanical thromebectomy eligibility time.Both the DAWN and DEFUSE 3 trial led to modification of AHA/ACC 2018 guidelines for stroke which recommended that in selected acute stroke patients within 6-24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy with a stent retriever is reasonable.


STRIVE Trial: Erenumab for Episodic Migraine

The STRIVE trial introduced Erenumab, a once monthly self injectable drug for prevention of episodic migraine. It’s calcitonin-gene-related peptide (CGRP) antagonist. It is recently approved by FDA for its use in migraine. Check out the STRIVE trial visual summary and visual abstract to understand how effective was Erenumab for episodic migraine.

Source: NEJM

Tenecteplase versus Alteplase for Ischemic Stroke

Source: NEJM

Association Between Cirrhosis and Stroke in a Nationally Representative Cohort

Contribution by
Leon Averbukh,
Internal Medicine
UConn Health

Source: JAMA Neurology

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