Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. There were no declared conflicts of interest, intellectual or otherwise, by task force members or authors.
CoSTR Citation
Djarv T, Chang WT, Zideman D, Singletary EM, Swain J, Cimpoesu D
Collaborators:
Bendall J, Berry D, Borra V, Carlson JN, Cassan P, Charlton NP, Douma M, Epstein J, Hood NA, Meyran D, Orkin A, Woodin JA, Sakamoto T.
First Aid Use of Aspirin for Non-traumatic Chest Pain: Earlier Compared with Late Administration Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force, 2019 December 16. Available from http://ilcor.org
Methodological Preamble and Link to Published Systematic Review
The continuous evidence evaluation process for the production of the Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of early compared with late administration of aspirin in non-traumatic chest pain in the first aid settings (Djarv T 2019 – PROSPERO 2019 CRD153316). The search was conducted by an ILCOR First Aid Task Force systematic review team. Evidence was sought and considered by the First Aid Task Force.
The 2015 CoSTR on this topic assessed early compared with late administration of aspirin for chest pain due to suspected MI. This current review differs in that the population of interest in the first aid setting includes adults with symptoms of non-traumatic chest pain, rather than adults with chest pain from suspected MI. This change reflects the possible inability of first aid providers to diagnose myocardial infarction, and therefore the need to provide first aid treatment based on signs and symptoms alone. Studies were included where the times to administration in relation to outcomes were presented. All settings for the administration of aspirin were included. All doses of aspirin were included. ‘Early administration’ was defined as administration of aspirin in the prehospital phase or within two hours from onset of pain. ‘Late administration’ was defined as administration of aspirin after 2 hours from the onset of chest pain or in-hospital.
The included studies assessed time to aspirin administration in relation to outcome, however, since it was expected that studies including first aid providers would be lacking, the administration of aspirin was not restricted to first aid providers.
Systematic Review
Djarv T, Swain J M, Chang W, et al. (February 03, 2020) Early or First Aid Administration Versus Late or In-hospital Administration of Aspirin for Non-traumatic Adult Chest Pain: A Systematic Review. Cureus 12(2): e6862. doi:10.7759/cureus.6862
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe):
Population: Adults who experience non-traumatic chest pain
Intervention: early or first aid administration of aspirin
Comparators: late or in-hospital administration of aspirin
Outcomes: Survival, complications and incidence of cardiac arrest were ranked as critical outcomes. Cardiac functional outcome, infarct size and chest pain resolution were ranked as important outcomes.
Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies), case series of 5 or more subjects were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded.
Timeframe: All years and all languages were included; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to October 22, 2019.
PROSPERO: CRD42020153316
NOTE FOR RISK OF BIAS:
In most cases bias was assessed per comparison rather than per outcome, since there were no meaningful differences in bias across outcomes. It was noted where there were differences in risk of bias existed between outcomes.
Consensus on Science
For the critical outcome of survival (at 7 days), we identified very low certainty evidence (down- graded for risk of bias and indirectness) from 2 observational studies (Freimark 2002 381 Barbash 2002 141) with a total of 2122 patients with acute myocardial infarction (MI) showing benefit from the early administration of aspirin (median 1.6 hours from pain onset to 160 mg aspirin administration and >200 mg aspirin administered prehospitally, respectively) compared with late administration of aspirin (median 3.5 hours from pain onset to 160 mg aspirin administration and >200mg aspirin administered at hospital admission) (97,5% versus 93,5%; p<0.001,RR, 1.04; 95% CI, 1.02–1.06; 37 more patients per 1000 treated survived to 7 days with early administration of aspirin, 95% CI, from 18 more to 56 more).
For the critical outcome of survival (at 30 days), we identified very low certainty evidence (down- downgraded for risk of bias and indirectness) from 2 observational studies (Freimark 2002 381, Barbash 2002 141) with a total of 2122 patients with acute MI showing benefit from the early administration of aspirin (median 1.6 hours from pain onset to 160 mg aspirin administration and >200 mg aspirin administered prehospitally, respectively) compared with late administration of aspirin (median 3.5 hours from pain onset to 160 mg aspirin administration and >200mg aspirin administered at hospital admission) (95,2% versus 91,2%) (RR, 1.05; 95% CI, 1.01–1.09); 46 more patients per 1000 treated survived to 30 days with early administration of aspirin, 95% CI from 9 more to 82 more ).
For the critical outcome of survival (at 35 days), we identified low certainty evidence (downgraded for indirectness) from sub-group analysis from 1 RCT (ISIS2 1988 3491) enrolling 8587 patients with acute MI showing no benefit from aspirin administration (162.5 mg, enteric-coated) within 2 hours of the onset of symptoms compared with aspirin administration (162,5mg, enteric coated) between 3-24 hours (91,2% versus 90,5%) (RR, 1.01;95% CI, 0.99–1.03); 9 more patients per 1000 treated survived to 30 days with early administration of aspirin, 95% CI from 9 fewer to 27 more).
For the critical outcome of survival (at 1 year), we identified very low certainty evidence (downgraded for indirectness) from 1 observational study (Freimark 2002 381) with 1200 patients with acute MI showing benefit from early aspirin administration (median 1.6 hours from pain onset to 160 mg aspirin administration) compared with late aspirin administration (median 3.5 hours from pain onset to 160 mg aspirin administration) (95,0% versus 89,4%) (RR, 1.06; 95% CI, 1.03–1.10); 54 more patients per 1000 treated survived to 30 days with early administration of aspirin, 95% CI from 26 more to 89 more).
For the critical outcome of complications, we identified very low certainty evidence (downgraded for indirectness) from 2 observational study (Barbash 2002 141, Freimark 2002 381) with a total of 2122 patients with acute MI showing no significant difference in the risk of developing complications with early administration of aspirin (median 1.6 hours from pain onset to 160 mg aspirin administration and >200mg aspirin administered prehospitally, respectively) when compared with late administration of aspirin (median 3.5 hours from pain onset to 160 mg aspirin and >200 mg aspirin administered in hospital) (RR, 0.83; 95% CI, 0.37-1.84).
For the critical outcome of incidence of cardiac arrest, we identified 2 observational studies (Barbash 2002 141, Freimark 2002 381) with conflicting results.
We identified very low certainty evidence (downgraded for indirectness) from 1 observational study (Barbash 2002 141) with a total of 922 patients with acute MI showing no difference in the incidence of dysrhythmias associated with a cardiac arrests (asystole, sustained VT, primary VF) among those with early administration of aspirin (>200 mg aspirin administered prehospitally) compared with late administration of aspirin (>200 mg aspirin administrated at hospital arrival) (RR 0.82, 95% CI 0.56-1.20). The same study additionally showed a reduced risk of need for resuscitation among early compared with late administration of aspirin (RR 0.38, 95%CI 0.20-0.69).
We identified very low certainty evidence (downgraded for risk of bias and indirectness) from a second observational study (Freimark 2002 381) with a total of 1200 patients with acute MI showing a higher incidence of dysrhythmias associated with cardiac arrest (VF/VT) in the group that received early aspirin administration (median 1.6 hours from pain onset to 160 mg aspirin administration) compared with late aspirin administration (median 3.5 hours from pain onset to 160 mg aspirin administration) (RR 1.53; 95% CI, 1.12–2.08).
For the important outcomes of cardiac functional outcome and infarct size as well as the important outcome of chest pain resolution, there were no comparator studies evaluating the time of aspirin administration.
Treatment Recommendations
For adults with non-traumatic chest pain, we suggest the early administration of aspirin by first aid providers as compared with the late, in-hospital, administration of aspirin (weak recommendation, very low certainty evidence).
Justification and Evidence to Decision Framework Highlights
This PICO was prioritized for review by the First Aid Task Force based on: a) the likelihood of encountering a person with non-traumatic chest pain in a first aid setting; b) the administration of oral aspirin as being a simple, safe and readily available intervention for first aid use; c) the potential for increased survival from early administration of aspirin in the event of a myocardial infarction.
The treatment recommendation remains unchanged from the 2015 Early Compared with Late Administration of Aspirin CoSTR.
In making these recommendations, the First Aid Task Force considered:
- We recognize that although we identified the population of interest to be adults with symptoms of non-traumatic chest pain in the first aid setting, the included evidence is considered indirect as it was limited to adults with suspected MI and not all causes of nontraumatic chest pain.
- We place a higher value on the benefits of aspirin, such as survival from a MI, which outweigh the possible risks identified in one study, i.e. an increased risk of ventricular tachycardia or ventricular fibrillation in-hospital not influencing survival, and the adverse effect of minor bleeding identified in ISIS 2 and described in a 2015 CoSTR (Singletary 2015 S269)
- We did not perform a meta-analysis of all three included studies even though they report survival outcomes at relatively similar times (30 days and 35 days). The FATF discussed the possibility that these studies may have included different populations (suspected MI versus ST-segment elevation AMI), different doses of administered aspirin, have different study designs (cohort versus RCT) and also that the studies were performed at different chronological times (1988 versus 2002) where clinical practice, for example reperfusion therapy, has changed both the management and outcomes of the illness.
- We recognize that all included studies were performed about two to three decades ago and that even if the population and exposure might be comparable the care offered today, the outcome of MI has improved.
- The Task Force felt that it was unlikely that any major new studies will be performed on this topic considering the cost effectiveness of the simple administration of aspirin.
- First Aid guideline groups will need to consider that prescribing practices in Europe and Asia might require self-administration for first aid, rather than direct administration of aspirin by a first aid provider due to national, regional, state or provincial regulations.
- The Task Force discussed concerns about first aid providers being able to differentiate chest pain of cardiac origin from other causes of chest discomfort. The term non-traumatic was added to the descriptor to enhance and simplify the clinical signs and the differential diagnosis of chest pain possibly related to the onset of a myocardial infarction. However, with any treatment recommendation using a symptoms-based approach such as chest pain, the task force expressed a consensus opinion that it is very important that first aid educational materials clearly indicate what signs and symptoms the first aid provider should look for. Furthermore, that the absolute contraindications for the administration of aspirin (i.e, allergy or active bleeding) be emphasized. Guideline organizations may also want to consider including additional first aid behaviors appropriate for their geographic locations, such as activating emergency medical services.
Knowledge Gaps
Current knowledge gaps include but are not limited to:
- Is aspirin safe if given to patients with non-traumatic chest pain of all etiologies (i.e. not only suspected MI)?
- What is the time critical window for the effective administration of aspirin in adult patients with acute myocardial infarction?
- What is the minimal effective dose for the oral administration of aspirin for non-traumatic chest pain in adults?
- What formulations of aspirin should be used in the first aid setting (i.e. enteric coated tablets, uncoated tablets)?
Attachments
Acknowledgements
We acknowledge the assistance of Michelle Welsford, MD and Peter Morley, MBBS in the task force discussions for this CoSTR and the Evidence to Decision table.
References
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Freimark D, Matetzky S, Leor J, Boyko V, Barbash I, Behar S, Hod H. Timing of aspirin administration as a determinant of survival of patients with acute myocardial infarction treated with thrombolysis. Am J Cardiol 2002;89(4):381-5.
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Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2(8607):349-60.
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