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.

Clinical Detail

Pharmacology - Alteplase
DoseVarious dosing strategies utilized in cardiac arrest- up to 100 mg max
o 50 mg or 100 mg bolus over 1-15 min x 1 dose
o 50 mg bolus followed by second 50 mg bolus 10-20 minutes later
AdministrationIV as bolus dose or infusion
Mechanism of ActionInitiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin
PK/PDDuration: 80% cleared within 10min; some fibrinolytic activity persists for 1 hr
t1/2 = 5 min
Adverse EffectsHemorrhage (Intracranial, GI, GU)
Ecchymosis
Drug Interactions and warningsContraindications
o Active bleeding
o h/o recent stroke, spinal surgery, head trauma
o Uncontrolled HTN
Interactions
o Antiplatelets (↑ bleeding)
o Anticoagulants (↑ bleeding)
o Nitroglycerin (↓ concentration of alteplase)
CompatibilityNOT compatible with
o Dobutamine
o Dopamine
o Heparin
o Nitroglycerin

Evidence

Author, YearDesign / Sample SizePopulationIntervention & Comparison*OutcomeComments
Bottiger, 2001Prospective, observational
n = 40		o Out of hospital arrest
o Any rhythm
o No ROSC after 15min		50mg alteplase + 5000units heparin
o Repeat dose after 30min 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, 2002Randomized, double blind, placebo controlled
n = 117		o Out of hospital arrest
o PEA rhythm
o No ROSC after 3min		100mg alteplase infused over 15minROSC: 21.4% tPA vs 23.3% no-tPA
Discharge: 0.9% tPA vs 0% no-tPA		No different in rate of ROSC or hospital discharge; possibly due to prolonged time to tPA infusion (35min)
Janata, 2003Retrospective
n = 36		o Out of hospital arrest0.6-1 mg/kg, max 100mgBleeding: 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, 2004Randomized, double blind, placebo controlled
n = 19		o Out of hospital arrest
o Any rhythm		50 mg tenecteplaseROSC: 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, 2008Randomized, double blind, placebo controlled
n = 525		o Out of hospital arrest
o Initial rhythm PEA/asystole OR VF/VT after ≤ 3 defibrillation attempts		Weight-based tenecteplase30-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, 2009Retrospective
n = 104		o In-hospital arrest
o Any rhythm
o Suspicion for PE		80.5 ±2.4mg alteplase (determined by rescue team)Bleeding: 23%
ROSC: 38.5%
Time to tPA: 13.6 min ROSC vs 34.7min no-ROSC
Discharge: 47.5%
Time to tPA: 11min d/c vs 23min no-d/c		Early tPA is associated with better outcomes
Sharifi, 2016Retrospective identification, prospectively followed
n = 23		o In-hospital arrest
o PEA rhythm + Confirmed PE		50mg alteplase over 1 min + 2000-5000 units heparin
(no comparator group)		Bleeding Events: 0
ROSC: 96%
Discharge: 91%		o 50mg/1min is safe and effective in PEA & PE
o Quicker admin of tPA may be beneficial (6.5min)
Peppard, 2018Retrospective
n = 35		o CA due to confirmed or suspected PEVarious 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%		o Shorter time to ROSC (15.1 min) with bolus dose of alteplase compared with infusion (46.4) 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

  • 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.
  • Peppard SR. Am J Health-Syst Pharm. 2018; 75:870-875.
  • Logan JK. Amer J Emerg Med 2014; 32:789-796.
Tags:tPA cardiac arrest thrombosis alteplase