|Year : 2023 | Volume
| Issue : 2 | Page : 133-137
Role of intravenous aspirin versus oral aspirin in the treatment of acute coronary syndrome: Answering a clinical query by systematic review and meta-analysis of randomized controlled trials
Hardeep Kaur1, Phulen Sarma2, Anusuya Bhattacharyya3, Manojkumar Rohit4, Manisha Prajapat1, Subodh Kumar1, Ajay Prakash1, Bikash Medhi1
1 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pharmacology, AIIMS, Guwahati, India
3 Department of Ophthalmology, Government Medical College and Hospital, Chandigarh, India
4 Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||02-Dec-2020|
|Date of Decision||08-May-2023|
|Date of Acceptance||12-May-2023|
|Date of Web Publication||03-Jun-2023|
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
BACKGROUND: Aspirin is indicated in the emergency management of acute coronary syndrome. However, oral aspirin has erratic bioavailability compared to i.v. formulation.
OBJECTIVE: The objective of this study was to evaluate the comparative efficacy and safety of intravenous (IV) and oral aspirin in acute coronary syndrome.
STUDY DESIGN: This was a systematic review and meta-analysis.
RESULTS: Two randomized controlled trials were included. Compared to oral aspirin, lower platelet aggregability was seen with IV aspirin at 5 min and 20 min. Lower thromboxane B2 and lower platelet CD-62p levels were noted in the IV group; however, no significant difference was observed in terms of “composite cardiovascular death, stroke, and myocardial infarction (MI) at 4–6 weeks,” “any cause mortality,” “cardiovascular mortality,” “occurrence of stroke,” and “occurrence of MI/reinfarction.” However, no difference was noted in terms of the occurrence of serious adverse events.
CONCLUSION: IV aspirin showed some advantages in terms of platelet aggregability biomarkers at 20 min and 1 week with comparable safety to oral aspirin. No difference was seen in terms of clinical outcomes (at 24 h, 7, and 30 days) and the occurrence of serious adverse events.
Keywords: Acute coronary syndrome, intravenous aspirin, oral aspirin
|How to cite this article:|
Kaur H, Sarma P, Bhattacharyya A, Rohit M, Prajapat M, Kumar S, Prakash A, Medhi B. Role of intravenous aspirin versus oral aspirin in the treatment of acute coronary syndrome: Answering a clinical query by systematic review and meta-analysis of randomized controlled trials. Indian J Pharmacol 2023;55:133-7
|How to cite this URL:|
Kaur H, Sarma P, Bhattacharyya A, Rohit M, Prajapat M, Kumar S, Prakash A, Medhi B. Role of intravenous aspirin versus oral aspirin in the treatment of acute coronary syndrome: Answering a clinical query by systematic review and meta-analysis of randomized controlled trials. Indian J Pharmacol [serial online] 2023 [cited 2023 Oct 4];55:133-7. Available from: https://www.ijp-online.com/text.asp?2023/55/2/133/378025
| » Introduction|| |
Aspirin is the most commonly used anti-platelet agent (predominantly COX-1 inhibitor), and its efficacy is well established in the management of acute coronary syndrome (ACS). Responsiveness of oral aspirin is highly variable, and possible sources of variability are due to the alteration of kinetic/dynamic properties (e.g. alteration in formulation, drug–drug interaction, drug-target turnover rate, and aging). As platelet activation and its subsequent aggregation play a major role in the pathophysiology of ACS, early inhibition of the same is desirable. However, variability in the kinetics of oral aspirin may act as a hindering factor. In healthy volunteers, intravenous (IV) administration of aspirin showed better and consistent inhibition of platelet function compared to oral formulation. In diabetics, reduced bioavailability and underexposure are important causes of “aspirin resistance.” IV formulation of aspirin cuts down the bioavailability issues with oral aspirin (100% bioavailability). A complete inhibition of platelet aggregation within 5 min by IV aspirin reflects its rapid onset of action compared to oral aspirin (due to incomplete inhibition of platelet aggregation at the same time point) with no additional serious adverse event has been reported. In Europe, the use of IV aspirin was discussed as early as 2008. The 2017-ESC guideline on acute myocardial infarction presenting with ST-segment elevation, the role of IV aspirin as antiplatelet, is well defined as antiplatelet co-therapy with fibrinolysis (Class I, Level B evidence). In patients who were already on oral aspirin (100 mg) therapy and presented with ACS, IV aspirin further reduced thromboxane B2 (TXB2) level and also prolonged the collagen epinephrine closure time further; chronic intake of 100 mg aspirin is not maximally effective in patients with ACS, and only 37% show response to oral aspirin. However, IV aspirin was successful in the same scenario. Hence, here comes the need for a comparison between IV versus oral aspirin in the management of ACS.
The treatment of ACS is time dependent. As early and predictable platelet inhibition is required in the management of ACS, theoretically, IV aspirin seems to be beneficial. However, till now, no systematic review or meta-analysis has addressed this issue. Therefore, we have conducted this systematic review and meta-analysis to evaluate the comparative efficacy and safety of oral versus IV aspirin in the settings of ACS. The findings of this study may help in the choice of antiplatelet drugs (IV vs. oral aspirin) during the initial hours of ACS.
| » Methods|| |
A systematic review and meta-analysis was conducted. The protocol is registered in PROSPERO (CRD42019122699). The null hypothesis of our study is that there is no difference in safety and efficacy between IV aspirin and oral aspirin in patients with ACS.
Inclusion and exclusion criteria
The inclusion criteria were: (1) randomized controlled trials (RCTs), (2) patients suffering from “ACS,” (3) a trial comparing “IV aspirin” versus “oral aspirin,” and (4) age >16 years. The exclusion criteria were study design other than randomized trials.
The primary outcome was the efficacy of IV and oral aspirin on platelet activation and aggregability biomarkers.
The secondary outcomes were the cause of mortality (within 24 h, 7 days), stroke and myocardial infarction (MI) (up to 30 days), cardiovascular mortality (within 24 h, 7 days), occurrence of stroke (within 24 h, 7 days), occurrence of MI/reinfarction (within 24 h, 7 days), and any adverse event.
Literature search and extraction
We searched eight literature databases (PubMed, Cochrane Central Library, Embase, Scopus, CINAHL, Web of Science, OVID, and Google Scholar) using appropriate keywords: “ACS,” “unstable angina,” “ST-elevated MI,” “non-ST-elevated MI,” “oral aspirin,” and “IV aspirin” without language restrictions. Two authors (PS and HK) independently screened the titles/abstracts using the inclusion/exclusion criteria. For relevant articles, full text was obtained and evaluated as per the inclusion/exclusion criteria. In case of any discrepancy, BM was consulted, and data extraction was done independently by two authors (HK and PS) using a pretested data extraction form following the template provided by the Cochrane data extraction form. After independent verification by AB and BM, the data were then entered into RevMan Software by PS.
Risk of bias assessment
The methodological quality of the included trials was assessed using the Cochrane Handbook for Systematic Reviews of Interventions criteria. Quality of evidence was reported according to the GRADE principles as described by Higgins 2011 and Atkins 2004. GRADEpro software was used to assist in the preparation of the “summary of findings” table.
The RevMan 5.3 software (The Cochrane Collaboration, England and Wales). Both fixed-effects and random-effects models were used, as per the I2 value and variability in the studies (For I2<50%, fixed-effects model and for I2 >50%, random-effects model were used). Risk ratios (RRs) were calculated for dichotomous data, and mean difference (MD)/standardized MD was calculated for continuous data.
| » Results|| |
After screening eight literature databases, a total of 648 articles were retrieved, and 264 articles were further assessed after removing duplicates for eligibility by screening the titles and abstracts. The full-text screening was done for 21 articles, and out of these, two articles were included meeting the inclusion/exclusion criteria in the final meta-analysis., The PRISMA flowchart is shown in [Supplementary Figure 1]. The details of included studies are shown in [Supplementary Table 1].
Effect of intravenous aspirin on platelet aggregability/activation biomarkers
With respect to platelet aggregability biomarkers at different time points [Figure 1]a, lower platelet aggregability was seen in IV aspirin at 5 min (MD −53.78 [−61.80–45.76]) and 20 min (MD − 20.59 [−27.64 to −13.53]) compared to oral aspirin; however, no difference was seen with any of the methods applied like either arachidonic acid (AA)-induced (MD 0.44 [−4.00–4.87]) or Adenosine diphosphate (ADP)-induced platelet aggregation (MD −1.28 [−7.06–4.51]) at 1 week. With respect to the effect of IV aspirin on other platelet activation-associated biomarkers, a significantly lower level of TXB2 was noted at 20 min in the IV arm (single study). However, a low level of platelet-derived biomarker was seen even at 1 week (CD-62p level was lower in the IV aspirin arm compared to oral aspirin at 1 week). [Supplementary Table 2].
|Figure 1: Safety and efficacy analysis of intravenous versus oral aspirin. (a) Platelet aggregability/activation biomarkers. (b) Composite of cardiovascular death, stroke, and myocardial infarction up to 30 days. (c) Serious adverse effect. (d) Bleeding as per thrombolysis in myocardial infarction classification. SD = Standard deviation, IV = Intravenous. SD = Standard deviation, RR = Risk ratio, MD = Mean difference|
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Composite of cardiovascular death, stroke, and myocardial infarction up to 30 days
No difference was found between the two arms at 30 days in terms of cardiovascular death, stroke, and MI (two studies, n = 213 in IV aspirin, n = 182 in oral aspirin, RR: 0.37, 95% confidence interval [CI] 0.06–2.2) [Figure 1]b.
Any cause mortality
Regarding any cause mortality, no significant difference was observed among the two groups at 24 h (two studies, n = 213 in IV aspirin, n = 182 in oral aspirin, RR: 1.69, 0.07–41.08) and 7 days (RR: 0.56, 0.04–8.86) [Table 1].
|Table 1: Various parameters comparing intravenous aspirin with oral aspirin in acute coronary syndrome patients|
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Regarding cardiovascular mortality, no significant difference was observed among the two groups at 24 h (two studies, n = 213 participants in the IV aspirin arm, n = 182 in the oral aspirin arm RR: 1.69, 0.07–41.08) and 7 days (RR: 0.56, 0.04–8.86) [Table 1].
Occurrence of stroke
Regarding the occurrence of a stroke at 24 h, (two studies, n = 213 in IV aspirin and n = 182 in oral aspirin), no significant difference was seen among the two groups in terms of ischemic stroke (RR: 0.19, 0.01–4.56) and hemorrhagic stroke (no case of hemorrhagic stroke) [Table 1], and also at 7 days, no significant difference was seen among two groups (two studies, n = 213 in IV aspirin, n = 182 in oral aspirin) in terms of ischemic stroke (RR: 0.56, 0.04–8.86) and hemorrhagic stroke (no case of hemorrhagic stroke occurred) [Table 1].
Occurrence of myocardial infarction/reinfection
No significant difference was seen (two studies, n = 213 in IV aspirin, n = 182 in oral aspirin) regarding the occurrence of MI/reinfarction at 24 h (RR: 1.69, 95% CI 0.07–41.08) and 7 days (RR: 0.56, 95% CI 0.04–8.86) [Table 1].
Serious adverse event
Two studies reported serious adverse events (n = 213 in the IV aspirin, n = 182 in oral aspirin, RR of 1.01 [0.49–2.08], I2 = 0%, fixed-effects model) [Figure 1]c. No significant difference was observed regarding thrombolysis in the myocardial infarction (TIMI) major category of bleeding (RR: 0.94 [0.14–6.27], I2 = 0%). Regarding TIMI minor bleeding, two events were recorded in the IV aspirin group and no event in the oral aspirin group (RR: 2.82 [0.14–58.07]). Regarding bleeding events in the category “required medical attention,” 18 events were recorded in the IV aspirin group (n = 213) and 12 events were recorded in the oral aspirin group (n = 182). The risks in the two groups were not significantly different (RR: 0.94 [0.46–1.92], I2 = 0%, fixed-effects model) [Figure 1]d.
Risk of bias across studies
The overall quality of included studies is good. Details of the data are represented in [Supplementary Figure 2]. Certainty of evidence was graded as per the GRADE methodology. In our study, most of the evidence was of moderate-to-low certainty [Supplementary Table 3].
| » Discussion|| |
Our meta-analysis is the first one to compare the safety and efficacy of IV versus oral aspirin in the treatment of ACS. Regarding platelet aggregability/activation, lower platelet aggregability (at 5 and 20 min) and lower level of TXB2 (at 20 min) were seen, following IV aspirin administration. Although no difference was seen in platelet aggregability and platelet CD-62p level was quite lower at 1 week, no difference was seen with AA- and ADP-induced platelet aggregability at 1 week. Findings from healthy volunteers, PK-PD studies, also confirm more consistent inhibition of platelet inhibition following IV administration.
Similarly, no difference was found between the two arms in comparison to composite cardiovascular death, stroke, and MI up to 30 days; any cause mortality, cardiovascular mortality, occurrence of stroke, and occurrence of MI at 24 h and 7 days. Regarding adverse effects, no significant difference was seen between the two therapies (serious adverse event and risk of bleeding across different TIMI bleeding criteria). Although IV aspirin showed some benefits in terms of platelet activation biomarkers (5 min, 20 min, and 1 week), no difference was seen in terms of important clinical end points. However, in most cases, the certainty of the evidence was of moderate to very low grade. Moderate-grade evidence was found in the case of platelet aggregability biomarkers at 20 min and any cause mortality on the 1st day. For the rest of the end points, the certainty of the evidence was of low grade. Hence, the possible benefit (if at all it exists) is either absent or may be present, but not detected due to less number of RCTs and small sample size. Regarding safety, IV aspirin was comparable to oral aspirin in terms of the occurrence of serious adverse events and the occurrence of different TIMI category bleeding. The strengths of our study include an in-depth comprehensive search of different literature databases and including only RCTs for high-quality evidence per standard methodology using. The limitation of our study is concomitant therapy with other drugs was allowed in both studies which could give rise to drug interactions that might affect the bioavailability, safety, and efficacy of aspirin particularly with oral formulations. Follow-up duration was variable between the two studies.
| » Conclusion|| |
Hence, to summarize, IV aspirin showed some advantages in terms of platelet aggregability biomarkers at 20 min (AA-induced platelet aggregability) and 1 week (platelet CD-62p level), with comparable safety to oral aspirin with no difference in mortality or MI/reinfarction. We need more studies to address this issue and to generate high-quality data on the same.
Financial support and sponsorship
This was a self-funded study.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Layne K, Ferro A. Antiplatelet therapy in acute coronary syndrome. Eur Cardiol 2017;12:33-7.
Kumar A, Cannon CP. Acute coronary syndromes: Diagnosis and management, part I. Mayo Clin Proc 2009;84:917-38.
Rocca B, Petrucci G. Variability in the responsiveness to low-dose aspirin: Pharmacological and disease-related mechanisms. Thrombosis 2012;2012:376721.
Slattery DE, Pollack CV. Balancing potency of platelet inhibition with bleeding risk in the early treatment of acute coronary syndrome. West J Emerg Med 2009;10:163-75.
Nagelschmitz J, Blunck M, Kraetzschmar J, Ludwig M, Wensing G, Hohlfeld T. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers. Clin Pharmacol 2014;6:51-9.
Bhatt DL, Grosser T, Dong JF, Logan D, Jeske W, Angiolillo DJ, et al.
Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus. J Am Coll Cardiol 2017;69:603-12.
Gitt AK, Betriu A. Antiplatelet therapy in acute coronary syndromes. Eur Heart J Suppl 2008;10 Suppl-A:A4-12.
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al.
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119-77.
Fuchs I, Spiel AO, Frossard M, Derhaschnig U, Riedmüller E, Jilma B. Platelet hyperfunction is decreased by additional aspirin loading in patients presenting with myocardial infarction on daily aspirin therapy. Crit Care Med 2010;38:1423-9.
Nordt SP, Clark RF, Castillo EM, Guss DA. Comparison of three aspirin formulations in human volunteers. West J Emerg Med 2011;12:381-5.
Cochrane Handbook for Systematic Reviews of Interventions. Available from: https://handbook
. [Last accessed on 2019 Aug 09].
Zeymer U, Hohlfeld T, Vom Dahl J, Erbel R, Münzel T, Zahn R, et al.
Prospective, randomised trial of the time dependent antiplatelet effects of 500 mg and 250 mg acetylsalicylic acid i. v. and 300 mg p. o. in ACS (ACUTE). Thromb Haemost 2017;117:625-35.
Zhao Y, Shen L, Yang M, Cui J, Gao K, Sun Y, et al
. Feasibility of intravenous administration of aspirin in acute coronary syndrome. Journal of Geriatric Cardiology December. 2008;5:212.