Introduction
There are a limited number of medications which can be used to treat an acute thrombus. Tissue Plasminogen Activators (tPA), such as alteplase and tenecteplase, are the mainstay of thrombolytic therapy.
Since the mid-1990s, numerous case reports and clinical trials have been published regarding the use of thrombolytic therapy in cardiac arrest, however there is conflicting evidence regarding results about benefit and outcomes. The 2015 AHA guidelines recommend considering thrombolytic therapy for cardiac arrest due to PE. A more recent review article recommended a standard dose for this indication but this is anecdotal based on a combination of studies. The clinical controversy includes route of administration, dose, and patient selection.
Key Points
- tPA agents such as alteplase and tenecteplase are the mainstay of thrombolytic therapy for acute thrombus.
- Thrombolysis in cardiac arrest has been studied since the mid-1990s, but evidence on benefit and outcomes is conflicting.
- The 2015 AHA guidelines suggest thrombolysis may be considered when cardiac arrest is suspected to be due to PE, but give no guidance on inclusion criteria, timing, drug, or dose.
- The clinical controversy centers on route of administration, dose, and patient selection.
Clinical Detail
| Attribute | Alteplase |
|---|---|
| Dose | Various dosing strategies utilized in cardiac arrest – up to 100 mg max • 50 mg or 100 mg bolus over 1-15 min x 1 dose • 50 mg bolus followed by second 50 mg bolus 10-20 minutes later |
| Administration | IV as bolus dose or infusion |
| Mechanism of Action | Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin |
| PK/PD | Duration: 80% cleared within 10 min; some fibrinolytic activity persists for 1 hr t½ = 5 min |
| Adverse Effects | Hemorrhage (intracranial, GI, GU) Ecchymosis |
| Drug Interactions and Warnings | Contraindications • Active bleeding • h/o recent stroke, spinal surgery, head trauma • Uncontrolled HTN Interactions • Antiplatelets (↑ bleeding) • Anticoagulants (↑ bleeding) • Nitroglycerin (↓ concentration of alteplase) |
| Compatibility | NOT compatible with • Dobutamine • Dopamine • Heparin • Nitroglycerin |
Evidence
| Author, Year | Design / Sample Size | Population | Intervention & Comparison* | Outcome | Comments |
|---|---|---|---|---|---|
| Bottiger, 2001 | Prospective, observational n = 40 | • Out of hospital arrest • Any rhythm • No ROSC after 15 min | 50 mg alteplase + 5000 units heparin • Repeat dose after 30 min of CPR | Bleeding: 5% (not associated with tPA) ROSC: 68% tPA vs 44% no-tPA Discharge: 15% tPA vs 8% no-tPA | tPA is safe & effective for treatment of CA due to PE |
| Abu-Laban, 2002 | Randomized, double blind, placebo controlled n = 117 | • Out of hospital arrest • PEA rhythm • No ROSC after 3 min | 100 mg alteplase infused over 15 min | ROSC: 21.4% tPA vs 23.3% no-tPA Discharge: 0.9% tPA vs 0% no-tPA | No difference in rate of ROSC or hospital discharge; possibly due to prolonged time to tPA infusion (35 min) |
| Janata, 2003 | Retrospective n = 36 | • Out of hospital arrest | 0.6-1 mg/kg, max 100 mg | Bleeding: 25% tPA vs 10% no-tPA ROSC: 67% tPA vs 43% no-tPA Discharge: 19% tPA vs 7% no-tPA | No association with prolonged CPR and bleeding complications |
| Fatovich, 2004 | Randomized, double blind, placebo controlled n = 19 | • Out of hospital arrest • Any rhythm | 50 mg tenecteplase | ROSC: 42% TNKase vs 6% no-TNKase Survival to hospital admission: 10% TNKase vs 6% no-TNKase Discharge: 5% TNKase vs 6% no-TNKase Bleeding Events: 0 | TNKase increased ROSC in CA due to any cause, however did not increase hospital discharge |
| Bottiger, 2008 | Randomized, double blind, placebo controlled n = 525 | • Out of hospital arrest • Initial rhythm PEA/asystole OR VF/VT after ≤ 3 defibrillation attempts | Weight-based tenecteplase | 30-day survival: 14.7% TNKase vs 17% no-TNKase ROSC: 55% TNKase vs 54.66% no-TNKase ICH: 2.6% TNKase vs 0.4% no-TNKase | No difference in 30-day survival with use of thrombolytics in CA and increased risk of ICH; median time to thrombolytic therapy 18 minutes |
| Er, 2009 | Retrospective n = 104 | • In-hospital arrest • Any rhythm • Suspicion for PE | 80.5 ± 2.4 mg alteplase (determined by rescue team) | Bleeding: 23% ROSC: 38.5% Time to tPA: 13.6 min ROSC vs 34.7 min no-ROSC Discharge: 47.5% Time to tPA: 11 min d/c vs 23 min no-d/c | Early tPA is associated with better outcomes |
| Sharifi, 2016 | Retrospective identification, prospectively followed n = 23 | • In-hospital arrest • PEA rhythm + Confirmed PE | 50 mg alteplase over 1 min + 2000-5000 units heparin (no comparator group) | Bleeding Events: 0 ROSC: 96% Discharge: 91% | • 50 mg/1 min is safe and effective in PEA & PE • Quicker admin of tPA may be beneficial (6.5 min) |
| Peppard, 2018 | Retrospective n = 35 | • CA due to confirmed or suspected PE | Various alteplase dosing strategies – bolus, infusion or bolus + infusion (no comparator group) | Bleeding Events: 5 Higher cumulative doses associated with higher bleeding risk ROSC: 49% Median time to ROSC: 25 min Discharge: 14% | Shorter time to ROSC (15.1 min) with bolus dose of alteplase compared with infusion (46.4 min) or bolus + infusion (48 min); most common bolus dose 50 mg |
*Compared with no thrombolytics unless specified. CA = cardiac arrest.
Conclusions
- tPA for PE-induced cardiac arrest has been studied for over 20 years but there is still no clear answer on how to dose tPA.
- AHA Guidelines state that thrombolysis may be considered when cardiac arrest is suspected to be caused by a PE, but provides no recommendation on inclusion criteria, thrombolytic timing, drug or dose.
- Studies support rapid utilization of a thrombolytic in patients with confirmed or highly suspicious for a PE is beneficial.
References
- Peppard SR. Am J Health-Syst Pharm. 2018; 75:870-875.
- Logan JK. Amer J Emerg Med 2014; 32:789-796.
- Out of hospital
- Any rhythm
- No ROSC after
- Repeat dose after
Alteplase. [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 6, 2018, from
http://www.micromedexsolutions.com/
Link MS. Circulation. 2015; 132[suppl 2]:S444-S464.
Bottiger BW. Lancet. 2001; 357:1583-5.
Abu-Laban RB. N Engl J Med. 2002; 346:1522-1528.
Janata K. Resuscitation. 2003; 57:49-55.
Fatovich DM. Resuscitation. 2004; 61:309-313.
Bottiger BW. N Engl J Med. 2008; 359:2651-2662.
Er, PLoS One. 2009; 4:e8323-8.
Sharifi M. Amer J Emerg Med. 2016; 34:1963-1967.
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Overview of Evidence
Author,
year
Design/
sample size
Population
Intervention &
Comparison*
Outcome
Comments
Bottiger,
2001
Prospective,
observational
n = 40
arrest
15min
50mg alteplase +
5000units heparin
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