Utility of aspirin in hospitalized COVID-19 patients

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A recent paper published in Anesthesia & Analgesia Journal evaluated the possible benefits of using aspirin in hospitalized COVID-19 patients [1].

COVID-19 disease is associated with hypercoagulability and increased thrombotic risk in critically ill patients. So far no studies have evaluated whether aspirin use could be associated with reduced risk of mechanical ventilation, intensive care unit admission, and in-hospital mortality. A retrospective, observational cohort study of adult patients admitted with COVID-19 to multiple hospitals in the United States was performed between March 2020 and July 2020. Four hundred twelve patients were included in the study. Three hundred fourteen patients (76.3%) did not receive aspirin, while 98 patients (23.7%) received aspirin within 24 hours of admission or 7 days prior to admission.

Aspirin use had a crude association with less mechanical ventilation (35.7% aspirin vs. 48.4% non-aspirin, p=0.03) and intensive care unit admission (38.8% aspirin vs. 51.0% non-aspirin, p=0.04), but no crude association with in-hospital mortality (26.5% aspirin vs. 23.2% non-aspirin, p=0.51) was found.

This study concluded that aspirin use may be associated with improved outcomes in hospitalized COVID-19 patients. However, a sufficiently powered randomized controlled trial is needed to assess whether a causal relationship exists between aspirin use and reduced lung injury and mortality in COVID-19 patients.

The use of acetyl-salicylic acid (ASA) in patients with different types of infections has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality. However, safety issues related both to the risk of bleeding and to that of developing rare but serious liver and brain damage mostly among children (i.e., Reye’s syndrome) should be considered. Hence, whether ASA might be a safe and reasonable therapeutic candidate to be tested in clinical trials involving adults with COVID-19 deserves further attention. In a review article, authors provide a critical appraisal of current evidence on the anti-inflammatory, antithrombotic, and antiviral effects of ASA, from both a pre-clinical and a clinical perspective. In addition, the potential benefits and risks of use of ASA have been put in the context of the adult-restricted COVID-19 population.

The long-lasting use of ASA as an anti-inflammatory and antithrombotic agent has been documented over decades. In addition to the anti-inflammatory and antiplatelet effects of ASA, much solid evidence from in vitro and experimental models supports the potency of ASA to reduce replication, propagation, and infectivity of several RNA-enveloped viruses, including human CoV-229E and MERS-CoV [2]. Also, ASA improved survival among patients with different types of infections, the latter conditions being characterized by overactivation of the inflammation cascade and enhanced platelet reactivity [3].

Altogether, these data, along with the recognized ability of ASA to mitigate several symptoms related to common viral infections, might support the notion to include ASA among the drugs deserving to be tested in patients with COVID-19. Overall, a critical appraisal of the clinical effects derived from testing ASA in adults with COVID-19 would add much to a still incomplete knowledge base and, hopefully, improve our ability to mitigate the disastrous clinical consequences of SARS-CoV-2 infection [4].

Aspirin and cyclodextrins

The pharmaceutical application of cyclodextrin aspirin formulations and complexes has been a subject of over 100 papers and patents. Most of the published data are related to the effect of different CDs on chemical stability, hydrolysis of acetylsalicylic acid.

The stability of the aspirin in HPBCD solution between pH 1.3-8 showed to be enhanced by a factor of 5-7. The complex association constant has been estimated to be about 101 M-1. Moreover, the solubility of the aspirin also showed to be enhanced [5].

Cyclodextrin-enabled aspirin was found to provide the possibility to administer this drug transdermally, aiming at the avoidance of its well-known gastrointestinal side effects. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery in particular during long-term use. A study reports on embedding aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximal enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent [6].

  1. Jonathan H. Chow, MD Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19 Anesthesia & Analgesia Journal  2020. DOI: 10.1213/ANE.0000000000005292
  2. Müller C, et al .  d,l-Lysine acetylsalicylate + glycine impairs coronavirus replication. J Antivir Antiretrovir.2016;8 (4):142–150. https://www.longdom.org/abstract/d-llysine-acetylsalicylate-glycine-impairs-coronavirus-replication-15312.html
  3. Speir E, et al. Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. Circ Res. 1998;83:210–216. DOI: 10.1161/01.res.83.2.210
  4. V. Bianconi et al. Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19 ? Drugs. 2020; 80(14): 1383–1396. DOI: 10.1007/s40265-020-01365-1
  5. Choudhury, S., Mitra, A.K. Kinetics of Aspirin Hydrolysis and Stabilization in the Presence of 2-Hydroxypropyl-β-Cyclodextrin. Pharm Res 10, 156–159 (1993). https://doi.org/10.1023/A:1018953920081
  6. Ammar, H. O.; Ghorab, M.; El-Nahhas, S. A.; Kamel, R.  Design of a transdermal delivery system for aspirin as an antithrombotic drug. International Journal of Pharmaceutics, 2006;327(1-2):81-88. DOI: 10.1016/j.ijpharm.2006.07.054


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