Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest
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Design
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Double-blind, multicenter, randomized trial - Prematurely discontinued
N= 1,050
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Objective
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To determine whether thrombolysis with the use of tenecteplase during cardiopulmonary resuscitation can improve survival in adults with the witnessed out-of-hospital arrest of presumed cardiac origin |
Study Groups
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Tenecteplase (n= 525)
Placebo (n= 525)
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Inclusion Criteria
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Adults, out-of-hospital cardiac arrest initiating basic or advanced life support within 10 minutes after collapse |
Exclusion Criteria
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Non-cardiac cause of arrest, known internal bleeding, neurologic impairment, coagulation disorders, pregnancy, participation in any other clinical study, hypersensitivity to study medication, the institutionalization of the patient, any condition the investigator believed would place the patient at increased risk of being included into the trial |
Methods
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Mobile ICU personnel was charged with initiating advanced cardiac life-support if needed while assessing if the patient is eligible for the trial. If the selection was met, the patient was randomized immediately after intravenous (IV) cannulation to receive tenecteplase or placebo during ongoing cardiac resuscitation. Tenecteplase was dosed as such:
30 mg for patients weighing less than 60 kg
35 mg for patients weighing between 60 kg and 69 kg
40 mg for patients weighing between 70 kg and 79 kg
45 mg for patients weighing between 80 kg and 89 kg
50 mg for patients weighing 90 kg or more
Cardiopulmonary resuscitation may continue 30 minutes after treatment but heparin's use was discouraged until hospitalization.
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Duration
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30 days |
Outcome Measures
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Primary: 30-day survival
Secondary: hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, the neurologic outcome of surviving patients, safety outcomes including hemorrhage and stroke
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Baseline Characteristics
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Tenecteplase (n= 525)
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Placebo (n= 525)
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|
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Age, years
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64.9 ± 13.2 |
64.7 ± 13.7 |
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Female
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108/518 (20.8%) |
110/514 (21.4%) |
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White
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490/501 (97.8%) |
480/498 (96.4%) |
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Medical history
Current/former smoker
Hypertension
Acute coronary syndrome
Hyperlipidemia
Diabetes
Heart failure
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69.2%
51.7%
37.2%
27.8%
22.6%
18.8%
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67.6%
45.7%
35.0%
24.0%
20.1%
21.3%
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|
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Long-term medication
Angiotensin-converting-enzyme inhibitor
Aspirin
Beta-blocker
Statin
Calcium-channel blocker
Coumarin or warfarin
Antiarrhythmic drug
Clopidogrel or ticlopidine
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34.4%
29.7%
28.5%
23.8%
13.1%
10.2%
8.7%
6.0%
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31.4%
29.6%
27.5%
19.5%
14.2%
9.8%
8.6%
3.4%
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Presumed cause of cardiac arrest
Acute myocardial infarction
Primary arrhythmia
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74.8%
12.9%
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68.5%
16.4%
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Results
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Endpoint
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Tenecteplase (n= 525)
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Placebo (n= 525)
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Relative risk (95% confidence interval [CI])
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p-value
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Patients who were alive at 30 days
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77 (14.7%) |
89 (17.0%) |
0.87 (0.65 to 1.15) |
0.36 |
Hospital admission rates
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53.5% |
55.0% |
0.97 (0.87 to 1.09)
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0.67 |
Return of spontaneous circulation
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55.0% |
54.6% |
1.01 (0.90 to 1.13) |
0.96 |
24-hour survival
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30.6% |
33.3% |
0.92 (0.77 to 1.10) |
0.39 |
Survived to hospital discharge
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15.1% |
17.5% |
0.86 (0.65 to 1.14) |
0.33 |
Neurologic outcome
Good cerebral performance
Moderate cerebral disability
Severe cerebral disability
Coma
Brain death
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47.7%
15.1%
11.6%
16.3%
9.3%
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46.9%
9.4%
16.7%
18.8%
8.3%
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1.02 (0.75 to 1.38)
1.12 (0.88 to 1.42)
1.02 (0.86 to 1.21)
0.99 (0.90 to 1.08)
1.00
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0.69
--
--
--
--
--
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Safety endpoints
Symptomatic intracranial hemorrhage
Any intracranial hemorrhage
Major non-intracranial hemorrhage
Ischemic stroke
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0.8%
2.7%
7.7%
0.8%
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0
0.4%
6.4%
0.6%
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8.93 (0.48 to 165.45)
6.95 (1.59 to 30.41)
1.21 (0.77 to 1.88)
1.32 (0.30 to 5.88)
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0.13
0.006
0.48
1.00
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Adverse Events
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See above |
Study Author Conclusions
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When tenecteplase was used without adjunctive antithrombotic therapy during advanced life support for out-of-hospital cardiac arrest, we did not detect any improvement in outcome, in comparison with placebo.
The data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients.
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InpharmD Researcher Critique
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Notably, prehospital emergency care is difficult to perform in a randomized controlled study. The randomization began on the field and many unpredictable factors exist during first response care. Determining the underlying cause of death and whether tenecteplase had possibly improved one factor of care was left unexplored. |