Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.

To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.

The studies excluded are as below. Figure 14 shows a forest plot for random effects meta-analysis of all studies after exclusions.

[Alamdari], substantial unadjusted confounding by indication likely.

[Elhadi], unadjusted results with no group details.

[Holt], unadjusted results with no group details.

[Mulhem], substantial unadjusted confounding by indication likely, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

[Mustafa], unadjusted results with no group details.

Heterogeneity in COVID-19 studies arises from many factors including:

Treatment delay.

The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours [McLean, Treanor]. Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 47 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.

Patient demographics.

Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in [López-Medina]).

Effect measured.

Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.

Variants.

There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics [Faria, Karita, Nonaka, Zavascki]. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective [Peacock, Willett].

Regimen.

Effectiveness may depend strongly on the dosage and treatment regimen.

Other treatments.

The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.

Medication quality.

The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. [Williams] analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. [Xu] analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.

Meta analysis.

The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though the treatment may be very effective when used earlier.

In general, by combining heterogeneous studies, as all meta analyses do, we run the risk of obscuring an effect by including studies where the treatment is less effective, not effective, or harmful.

When including studies where a treatment is less effective we expect the estimated effect size to be lower than that for the optimal case. We do not a priori expect that pooling all studies will create a positive result for an effective treatment. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present pooled results for all studies, we also present individual outcome and treatment time analyses, which are more relevant for specific use cases.

Publication bias.

Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results [Boulware, Meeus, Meneguesso]. For aspirin, there is currently not enough data to evaluate publication bias with high confidence.

One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.

44% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 33% of prospective studies, consistent with a bias toward publishing positive results. The median effect size for retrospective studies is 15% improvement, compared to 13% for prospective studies, showing similar results. Figure 19 shows a scatter plot of results for prospective and retrospective studies.

Funnel plot analysis.

Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 20 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 [Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley]. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.

Conflicts of interest.

Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. Aspirin for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 aspirin trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all aspirin trials represent the optimal conditions for efficacy.

Early/late vs. mild/moderate/severe.

Some analyses classify treatment based on early/late administration (as we do here), while others distinguish between mild/moderate/severe cases. We note that viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.

Notes.

Other meta analyses for aspirin can be found in [Banaser, Srinivasan], showing significant improvements for mortality and mechanical ventilation.

Aspirin is an effective treatment for COVID-19. Statistically significant improvement is seen for mortality. 23 studies from 21 independent teams in 9 different countries show statistically significant improvements in isolation (18 for the most serious outcome). Meta analysis using the most serious outcome reported shows 12% [6‑17%] improvement. Results are worse for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

Studies to date do not show a significant benefit for mechanical ventilation and ICU admission. Benefit may be more likely without coadministered anticoagulants. The RECOVERY RCT shows 4% [-4‑11%] lower mortality for all patients, however when restricting to non-LMWH patients there was 17% [-4‑34%] improvement, consistent with the mortality results of all studies, 12% [5‑18%], and the 16% improvement in the REMAP-CAP RCT.

Abdelwahab

[Abdelwahab] Retrospective 225 hospitalized patients in Egypt, showing significantly lower thromboembolic events with aspirin treatment, but no significant difference in the need for mechanical ventilation.

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Abul

[Abul] Retrospective 1,687 nursing home residents in the USA, showing significantly lower risk of mortality with chronic low-dose aspirin use. Low dose 81mg aspirin users had treatment ≥10 of 14 days prior to the positive COVID date, control patients had no aspirin use in the prior 14 days.

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Al Harthi

[Al Harthi] Retrospective 1,033 critical condition patients, showing lower in-hospital mortality with aspirin in PSM analysis. Patients receiving aspirin also had a higher risk of significant bleeding, although not reaching statistical significance. Authors note that the use of aspirin during an ICU stay should be tailored to each patient.

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Alamdari

[Alamdari] Retrospective 459 patients in Iran, 53 treated with aspirin, showing no significant difference with treatment.

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Basheer

[Basheer] Retrospective 390 hospitalized patients in Israel, showing higher risk of mortality with prior aspirin use. Details of the analysis are not provided.

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Botton

[Botton] Retrospective 31 million people without cardiovascular disease in France, showing no significant difference in hospitalization or combined intubation/death with low dose aspirin prophylaxis.

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Bradbury

[Bradbury] RCT 1,557 critical patients, showing significantly lower mortality with aspirin, with 97.5% posterior probability of efficacy.

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Campbell

[Campbell] Retrospective 28,856 COVID-19 patients in the USA, showing no significant difference in mortality for chronic aspirin use vs. sporadic NSAID use. Since aspirin is available OTC and authors only tracked prescriptions, many patients classified as sporadic users may have been chronic users.

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Chow

[Chow (C)] PSM retrospective 6,781 hospitalized patients ≥50 years old in the USA who were on pre-hospital antiplatelet therapy (84% aspirin), and 10,566 matched controls, showing lower mortality with treatment.

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Chow

[Chow] Retrospective 112,269 hospitalized COVID-19 patients in the USA, showing lower mortality with aspirin treatment.

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Chow

[Chow (B)] Retrospective 412 hospitalized patients, 98 treated with aspirin, showing lower mortality, ventilation, and ICU admission with treatment.

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Connors

[Connors] Early terminated RCT with 164 aspirin and 164 control patients in the USA with very few events, showing no significant difference with aspirin treatment for the combined endpoint of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, and hospitalization for cardiovascular or pulmonary indication. There was no mortality and no major bleeding events among participants that started treatment (there was one ITT placebo death). ACTIV-4B. NCT04498273.

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Drew