ALS 3203 The Effect of Thrombolysis for Cardiac Arrest: TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: BB was the lead author of the TROICA trial. No other authors have any conflict of interest to declare.

CoSTR Citation

Grunau B, Dehghani S, Ohshimo S, Giustini D, Couper K, Böttiger BW, Scquizzato T, Nikolaou N, on behalf of the International Liaison Committee on Resuscitation Advanced Life Support Task Force. The Effect of Thrombolysis for Cardiac Arrest: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2025. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review (Dehghani, 2025; PROSPERO citation https://www.crd.york.ac.uk/PROSPERO/view/CRD420251121194). All available evidence was considered by the ALS Task Force, and treatment recommendations were drafted.

Systematic Review: Pre-Submission.

PICOST

The PICOST

Population: Adults and children in any setting (in-hospital or out-of-hospital) with cardiac arrest

Intervention: Administration of thrombolytic medication during cardiopulmonary resuscitation (CPR)

Comparators: No administration of thrombolytic medication during cardiopulmonary resuscitation

Outcomes: Survival at hospital discharge or 30 days, survival with favourable neurological outcomes at hospital discharge or 30-days were ranked as critical outcomes. Return of spontaneous circulation (ROSC) and post-discharge outcomes including survival or favourable neurological outcomes or quality-of-life metrics (at any time juncture) were ranked as an important outcome. We also evaluated important safety outcomes pertaining to bleeding complications.

Study Designs: Randomized controlled trials (RCTs) were eligible for inclusion. Non-randomized studies (non-randomized controlled trials, cohort studies, and case-control studies), animal studies, reviews, abstracts only, conference proceedings, letters, editorials, commentaries, unpublished trials, case reports, and case series were not included. All relevant publications in any language were included as long as there was an English abstract or full text available.

Timeframe: There were no limits on the timeframe. The search was run on Aug. 7, 2025.

Prospero Registration CRD420251121194

Risk of bias in randomized controlled trials was assessed using version 2 of the Cochrane Risk-of-Bias tool for individually randomized parallel-group trials. Risk of bias was assessed for each outcome within a study but is reported at the study level as the highest risk of bias score across all outcomes. In most studies, the risk of bias was the same across all outcomes. If the bias was different depending on the outcome, this was noted.

Consensus on Science

Search Results

The systematic review identified 565 unique titles of which 20 full manuscripts were assessed for eligibility. We identified three randomized controlled trials (RCT) examining intra-arrest thrombolytics that met our pre-defined inclusion criteria. Abu-Laban and colleagues (2002), in British Columbia, Canada, enrolled 233 adult patients with cardiac arrest in the out-of-hospital (OHCA) or ED settings who had over one minute of pulseless electrical activity (PEA).¹ They were randomized to tissue plasminogen activator (t-PA) or placebo. Resuscitation was to continue for a minimum of 15 min post-drug administration. Fatovich and colleagues (2004), in Perth, Australia, included 35 OHCAs of presumed cardiac origin who were enrolled upon ED arrival and randomized to Tenecteplase or placebo.² Böttiger and colleagues (2008), performed the TROICA study in 66 European emergency medical systems (EMS), including adult patients with witnessed OHCA of presumed cardiac origin and initiation of resuscitation within 10 minutes after collapse.³ Exclusion from the study was “permitted for cases in which pulmonary embolism was suspected to be the cause of the cardiac arrest.”³ Participants were randomized to Tenecteplase or placebo, and resuscitation was to continue for a minimum of 30 min post-drug administration. The study enrolled 1050 patients, at which time it was terminated early due to assessment of futility. It originally included all rhythms, but approximately halfway through the study patients with an initial rhythm of asystole were excluded due to low survival.

Outcome of Survival to Hospital Discharge

For the critical outcome of survival at hospital discharge, we identified moderate-certainty evidence (downgraded for imprecision) from three RCTs, including 1299 enrolled patients. No increase in survival was detected with the use of intra-arrest thrombolytics when compared with no thrombolytic use (thrombolytics 79/653 [12%] vs. no thrombolytics 91/646 [14%]; RR 0.86 (95% CI 0.65, 1.1); Absolute Difference -2.0% [95% CI, -5.7% to 1.7%]; 20 fewer patients/1000 survived with the intervention [95% CI 49 fewer to 20 more patients/1000 survived with the intervention]).

Outcome of Survival with Favourable Neurological Outcome at Hospital Discharge

For the critical outcome of survival with favourable neurological outcome at hospital discharge, we identified moderate-certainty evidence (downgraded for imprecision) from three RCTs, including 1299 enrolled patients. No benefit was detected from the use of intra-arrest thrombolytics when compared with no thrombolytic use (thrombolytics 55/646 [8.5%] vs. no thrombolytics 55/653 [8.4%]; RR, 1.0 [95% CI, 0.70 to 1.4]; Absolute Difference 0.091% [95% CI -2.9% to 3.1%]; 0 more patients/1000 survived with the intervention [95% CI 25 fewer to 35 more patients/1000 survived with the intervention]).

Post-Discharge Outcomes

For the important post-discharge outcomes of survival, neurological outcomes, and quality-of-life metrics, we identified no studies.

Outcome of ROSC

For the important outcome of ROSC (at any time), we identified moderate-certainty evidence (downgraded for imprecision) from three RCTs, including 1294 enrolled patients. No benefit was detected from the use of intra-arrest thrombolytics when compared with no thrombolytic use (thrombolytics 316/651 [49%] vs. no thrombolytics 307/643 [48%]; RR, 1.0 [95% CI, 0.72 to 1.5]; Absolute Difference 0.80% [95% CI -4.6% to 6.2%]; 19 more patients/1000 obtained ROSC with the intervention [95% CI 134 fewer to 243 more patients/1000 survived with the intervention]).

Safety Outcomes

For the important safety outcome of bleeding complications, we identified low-certainty evidence (downgraded for risk of bias and imprecision) from 3 RCTs including 1318 enrolled patients.^1–3 Definitions of bleeding outcomes were inconsistent across between studies, but results consistently demonstrated that thrombolysis appeared to increase the incidence of bleeding complications. A single safety outcome from one RCT, examining “any intracranial hemorrhage” was statistically significant (thrombolytics 14/518 [2.7%] vs. no thrombolytics 2/514 [0.39%]; RR, 6.95 [95% CI, 1.6 to 30.4]; Absolute Difference 2.3% [95% CI 0.82% to 3.8%]; 22 more patients/1000 obtained ROSC with the intervention [95% CI 2 more to 111 more patients/1000 survived with the intervention]).

Treatment Recommendations

We recommend against the routine administration of thrombolytics during cardiopulmonary resuscitation for the treatment of cardiac arrest (strong recommendation, moderate certainty of evidence).

Justification and Evidence to Decision Framework Highlights

• This PICOS is for undifferentiated cardiac arrest. Cardiac arrest suspected to be due to pulmonary embolism (PLS 4160.10, ALS 3400) has been addressed elsewhere.^4,5
• The population of interest for this CoSTR was not dependent on the suspected or confirmed etiology of the cardiac arrest, but pertains to the routine/standard treatment of cardiac arrest. Although each study had a specific inclusion criterion (“presumed cardiac origin^2,3 [i.e. no obvious non-cardiac cause], witnessed arrest,³ or PEA¹, and acknowledging also that one study “permitted [exclusion] for cases in which pulmonary embolism was suspected to be the cause of the cardiac arrest”³) these categories were still broad, certainly including a wide range of arrest etiologies^6,7. For cardiac arrest cases known (or “suspected”) to be due to PE, please consult the CoSTR on this topic for adult⁵ and pediatric⁴ populations.
• Three RCTs which examined the benefit of thrombolytics (vs. no thrombolytics) during cardiac arrest. Overall, available data did not demonstrate a benefit of thrombolytics for any clinical outcome, but indicated a risk of harm due to an increased risk of intracranial bleeding.
• Risk of bias was judged to be low for two large RCT’s^1,3, and high for a small pilot study². However, we elected not to downgrade the certainty of evidence based on the high risk of bias for the single study, given that: (1) in the meta-analysis the small study had minimal impact on the overall results; (2) results were consistent after removal of the small study; and (3) the results of the small study were consistent with the two larger studies.
• All safety outcomes examining bleeding were suggestive of an increased risk of bleeding from thrombolytic therapy. A single outcome of “any intracranial hemorrhage” showed a statistically significant risk of harm.³ We classified safety outcomes at a high risk of bias (specifically verification bias), given that all cases were not evaluated for the outcome of interest. For example, those that died early in the course of treatment did not survive long enough to be evaluated. Even those who survived initial treatment were not all evaluated for bleeding complications. It is likely that bleeding (even life-threatening bleeding) was missed given that all patients were critically ill and did not all undergo evaluation for bleeding. However, the direction of bias would likely be in underestimating the harms of thrombolytics, and thus a comprehensive evaluation of bleeding would likely only increase the current findings, which already suggest a risk of increased bleeding.
• We downgraded the certainty of evidence due to imprecision, given that confidence intervals were broad and contained clinically important benefit and harm.
• We considered the resource implications of administering this therapy, which were not negligible. The therapy often costs over $1000 USD, requires refrigerated storage, and needs to be reconstituted prior to administration.
• Although analyses examining subgroups should be considered exploratory and at risk of type I error given multiple comparisons, it is notable that among cases with bystander CPR thrombolytic therapy, in comparison with no thrombolytic therapy, resulted in an increased proportion of non-survivors. The subgroup of cases with initial shockable rhythms was also suggestive of harm, but not statistically significant.
• We did not limit our search to any subgroups, but searched for all studies examining intra-arrest thrombolytics. Only one study included cases with in-hospital cardiac arrest¹ and only one study included cases of all ages² (two studies limited inclusion to adult patients^1,3). Within these studies there are likely other phenotypes that were also under-represented.
• The Task Force acknowledged that, among out-of-hospital and in-hospital cardiac arrests, pulmonary embolism and acute coronary occlusions are potential etiologies;^6,7 accepted treatment options for these conditions among non-cardiac arrest patients include thrombolytics.

EtD: ALS 3203 Table Et D

Knowledge Gaps

• There were no studies which specifically evaluated this clinical question in a pediatric population, and there were no pediatric patients specifically reported in any studies
• There were no studies which specifically enrolled cases of STEMI or PE; however this was not the aim of this CoSTR. Further, correctly identifying these cases would be difficult for the majority of cardiac arrest cases and difficult to practically implement in cardiac arrest studies.
• There were few study subjects (n=9) with in-hospital cardiac arrest identified in this review
• No studies reported patient outcomes beyond hospital discharge/30-days.

References

1. Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue Plasminogen Activator in Cardiac Arrest with Pulseless Electrical Activity. New England Journal of Medicine. 2002;346(20):1522-1528. doi:10.1056/NEJMoa012885

2. Fatovich DM, Dobb GJ, Clugston RA. A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation. 2004;61(3):309-313. doi:10.1016/j.resuscitation.2004.01.016

3. Böttiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest. New England Journal of Medicine. 2008;359(25):2651-2662. doi:10.1056/NEJMoa070570

4. Tiwari L, Scholefield B, Kleinman M, et al. Reversible Causes of Pediatric Cardiac Arrest - Pulmonary Embolism - Paediatric Consensus on Science with Treatment Recommendations.; 2024. Accessed November 24, 2025. https://costr.ilcor.org/docume...

5. Wetsch W, Böttiger B, Andersen L, Berg K, Callaway C, Deakin C. Cardiac Arrest Associated with Pulmonary Embolism Consensus on Science with Treatment Recommendations.; 2020. Accessed November 24, 2025. https://costr.ilcor.org/docume...

6. Lind PC, Risager BH, Gammelager H, et al. Why do patients develop in-hospital cardiac arrest? A prospective clinical observational study (WHY-IHCA). Resuscitation. Published online August 2025:110782. doi:10.1016/j.resuscitation.2025.110782

7. Tseng ZH, Olgin JE, Vittinghoff E, et al. Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death. Circulation. 2018;137(25):2689-2700. doi:10.1161/CIRCULATIONAHA.117.033427