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Aspirin for COVID-19: real-time meta analysis of 76 studies

@CovidAnalysis, December 2024, Version 67V67
 
0 0.5 1 1.5+ All studies 9% 76 187,919 Improvement, Studies, Patients Relative Risk Mortality 10% 65 161,240 Ventilation 5% 15 54,773 ICU admission 3% 15 35,339 Hospitalization -1% 10 12,578 Progression 11% 12 30,120 Recovery 9% 3 16,018 Cases 5% 7 10,749 Viral clearance 9% 2 710 RCTs 5% 7 23,015 RCT mortality 5% 6 22,735 Peer-reviewed 9% 68 171,966 Prophylaxis 5% 41 146,429 Early 67% 1 280 Late 15% 34 41,210 Aspirin for COVID-19 c19early.org December 2024 after exclusions Favorsaspirin Favorscontrol
Abstract
Significantly lower risk is seen for mortality and progression. 28 studies from 26 independent teams in 11 countries show significant benefit.
Meta analysis using the most serious outcome reported shows 9% [3‑15%] lower risk. Early treatment is more effective than late treatment.
0 0.5 1 1.5+ All studies 9% 76 187,919 Improvement, Studies, Patients Relative Risk Mortality 10% 65 161,240 Ventilation 5% 15 54,773 ICU admission 3% 15 35,339 Hospitalization -1% 10 12,578 Progression 11% 12 30,120 Recovery 9% 3 16,018 Cases 5% 7 10,749 Viral clearance 9% 2 710 RCTs 5% 7 23,015 RCT mortality 5% 6 22,735 Peer-reviewed 9% 68 171,966 Prophylaxis 5% 41 146,429 Early 67% 1 280 Late 15% 34 41,210 Aspirin for COVID-19 c19early.org December 2024 after exclusions Favorsaspirin Favorscontrol
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, comparable with the mortality results of all studies, 10% [4‑16%], and the 16% improvement in the REMAP-CAP RCT.
No treatment is 100% effective. Protocols combine safe and effective options with individual risk/benefit analysis and monitoring. Other treatments are more effective. All data and sources to reproduce this analysis are in the appendix.
4 other meta analyses show significant improvements with aspirin for mortality1-3, mechanical ventilation1, and progression4.
Evolution of COVID-19 clinical evidence Meta analysis results over time Aspirin p=0.0045 Acetaminophen p=0.00000029 2020 2021 2022 2023 2024 Lowerrisk Higherrisk c19early.org December 2024 100% 50% 0% -50%
Aspirin for COVID-19 — Highlights
Aspirin reduces risk with very high confidence for mortality, progression, and in pooled analysis, and low confidence for recovery and viral clearance. Benefit may be more likely without coadministered anticoagulants.
Real-time updates and corrections with a consistent protocol for 112 treatments. Outcome specific analysis and combined evidence from all studies including treatment delay, a primary confounding factor.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ ACTIV-4B Connors (DB RCT) 67% 0.33 [0.01-7.96] hosp. 0/144 1/136 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.5 Early treatment 67% 0.33 [0.01-7.96] 0/144 1/136 67% lower risk Alamdari -28% 1.28 [0.67-2.43] death 9/53 54/406 Improvement, RR [CI] Treatment Control Husain 80% 0.20 [0.01-3.55] death 0/11 3/31 Goshua (PSM) 35% 0.65 [0.42-0.98] death 319 (n) 319 (n) Meizlish (PSM) 48% 0.52 [0.34-0.81] death 319 (n) 319 (n) Liu (PSM) 75% 0.25 [0.07-0.87] death 2/28 11/204 Mura (PSM) 15% 0.85 [0.69-1.01] death 527 (n) 527 (n) Chow 47% 0.53 [0.31-0.90] death 26/98 73/314 Haji Aghajani 25% 0.75 [0.57-0.99] death 336 (n) 655 (n) Elhadi (ICU) 10% 0.90 [0.67-1.21] death 22/40 259/425 ICU patients Sahai (PSM) 13% 0.87 [0.56-1.34] death 33/248 38/248 Pourhoseingholi -32% 1.32 [1.02-1.71] death 71/290 268/2,178 Vahedian-Azimi 22% 0.78 [0.33-1.74] death 13/337 28/250 Abdelwahab -8% 1.08 [0.15-3.82] ventilation 11/31 6/36 Karruli (ICU) 46% 0.54 [0.09-3.13] death 1/5 22/27 ICU patients Al Harthi (ICU) 27% 0.73 [0.56-0.97] death 98/176 107/173 ICU patients Kim (PSM) 34% 0.66 [0.36-1.23] death 14/124 23/135 Zhao 43% 0.57 [0.41-0.78] death 121/473 140/473 RECOVERY RECOVERY Co.. (RCT) 4% 0.96 [0.89-1.04] death 7,351 (n) 7,541 (n) Mustafa 44% 0.56 [0.21-1.51] death 4/66 41/378 REMAP-CAP Bradbury (RCT) 16% 0.84 [0.70-1.00] death 165/563 170/521 Chow (PSW) 13% 0.87 [0.81-0.93] death population-based cohort Santoro (PSM) 38% 0.62 [0.42-0.92] death 360 (n) 2,949 (n) RESIST Ghati (RCT) 22% 0.78 [0.31-1.98] death 11/442 7/219 Karimpour-Razke.. -123% 2.23 [1.26-3.38] death 39/90 64/363 ACT inpatient Eikelboom (RCT) -5% 1.05 [0.86-1.28] death 193/1,063 186/1,056 CT​1 ACT outpatient Eikelboom (RCT) -9% 1.09 [0.48-2.46] death 12/1,945 11/1,936 Ali (ICU) 40% 0.60 [0.51-0.72] death 152/660 202/530 ICU patients Aidouni (ICU) 31% 0.69 [0.54-0.88] death 202/712 165/412 ICU patients Singla (RCT) 57% 0.43 [0.04-3.27] death 3/49 5/49 CT​1 Shamsi 96% 0.04 [0.00-7.20] death 0/13 24/170 Mehrizi 16% 0.84 [0.82-0.86] death population-based cohort Lewandowski -70% 1.70 [1.08-2.70] death 430 (all patients) Vinod 14% 0.86 [0.48-1.52] death 128 (n) 248 (n) Azimi Pirsaraei -97% 1.97 [1.28-3.04] death 28/184 50/647 Tau​2 = 0.02, I​2 = 78.3%, p < 0.0001 Late treatment 15% 0.85 [0.78-0.92] 1,230/17,041 1,957/23,739 15% lower risk Holt -34% 1.34 [0.98-1.84] death/ICU 35/116 129/573 Improvement, RR [CI] Treatment Control Wang 58% 0.42 [0.01-1.98] death 1/9 13/49 Lodigiani -21% 1.21 [0.73-2.01] ICU 17/94 44/294 Yuan 4% 0.96 [0.47-1.72] death 11/52 29/131 Ramos-Rincón -29% 1.29 [1.05-1.51] death 132/264 253/526 Osborne (PSM) 59% 0.41 [0.35-0.48] death 272/6,300 661/6,300 Merzon 28% 0.72 [0.53-0.99] cases 73/1,621 589/8,856 Bejan 1% 0.99 [0.61-1.63] ventilation 1,899 (n) 7,330 (n) Mulhem -14% 1.14 [0.93-1.40] death 300/1,354 216/1,865 Reese (PSM) -61% 1.61 [1.31-1.99] death 4,921 (n) 4,921 (n) Drew 22% 0.78 [0.49-1.24] progression n/a n/a Pan -13% 1.13 [0.70-1.82] death 239 (n) 523 (n) Oh 1% 0.99 [0.65-1.50] death n/a n/a Son (PSM) 11% 0.89 [0.53-1.47] death case control Ma (PSM) 9% 0.91 [0.82-1.02] death Chow (PSM) 19% 0.81 [0.76-0.87] death 1,280/6,781 2,271/10,566 Kim (PSM) -700% 8.00 [1.07-59.6] death 6/15 1/20 Basheer -13% 1.13 [1.05-1.21] death 45/140 29/250 Sisinni -7% 1.07 [0.89-1.29] death 93/253 251/731 Pérez-Segura -49% 1.49 [1.20-1.80] death 66/155 183/608 Formiga (PSM) -3% 1.03 [0.94-1.13] death 1,000/3,291 874/2,885 Sullerot (PSW) -10% 1.10 [0.81-1.49] death 101/301 224/746 Monserrat .. (PSM) -31% 1.31 [1.01-1.71] death n/a n/a Levy 26% 0.74 [0.49-1.10] death/hosp. 29/159 178/690 Nimer 4% 0.96 [0.69-1.33] hosp. 83/427 136/1,721 Gogtay -6% 1.06 [0.51-1.89] death 12/38 21/87 Campbell (PSW) 3% 0.97 [0.95-1.00] death 419 (n) 20,311 (n) Lal 11% 0.89 [0.82-0.97] death 4,691 (n) 16,888 (n) Botton -4% 1.04 [0.98-1.10] death/int. population-based cohort Malik 14% 0.86 [0.39-1.80] death 15/87 24/223 Abul 33% 0.67 [0.47-0.95] death 46/511 201/1,176 Loucera 18% 0.82 [0.74-0.92] death 2,127 (n) 13,841 (n) Morrison (PSM) 8% 0.92 [0.73-1.18] death 1,667 (n) 1,667 (n) Ali 28% 0.72 [0.51-1.03] death 481 (n) 1,164 (n) Zadeh 37% 0.63 [0.30-1.29] death n/a n/a Azizi 0% 1.00 [0.53-1.87] death 17/131 17/131 Aweimer -10% 1.10 [0.90-1.34] death 34/44 74/105 Intubated patients Tse (PSM) 67% 0.33 [0.18-0.59] death/int. 2,664 (all patients) Prieto-Campo -13% 1.13 [0.86-1.48] death case control Ware (PSM) 46% 0.54 [0.53-0.56] death population-based cohort Sakamaki -37% 1.37 [1.31-1.44] severe case population-based cohort Tau​2 = 0.07, I​2 = 95.2%, p = 0.31 Prophylaxis 5% 0.95 [0.86-1.05] 3,668/38,587 6,418/105,178 5% lower risk All studies 9% 0.91 [0.85-0.97] 4,898/55,772 8,376/129,053 9% lower risk 76 aspirin COVID-19 studies c19early.org December 2024 Tau​2 = 0.05, I​2 = 93.0%, p = 0.0045 Effect extraction pre-specified(most serious outcome, see appendix) 1 CT: study uses combined treatment Favors aspirin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ ACTIV-4B Connors (DB RCT) 67% hospitalization Improvement Relative Risk [CI] Tau​2 = 0.00, I​2 = 0.0%, p = 0.5 Early treatment 67% 67% lower risk Alamdari -28% death Husain 80% death Goshua (PSM) 35% death Meizlish (PSM) 48% death Liu (PSM) 75% death Mura (PSM) 15% death Chow 47% death Haji Aghajani 25% death Elhadi (ICU) 10% death ICU patients Sahai (PSM) 13% death Pourhoseingholi -32% death Vahedian-Azimi 22% death Abdelwahab -8% ventilation Karruli (ICU) 46% death ICU patients Al Harthi (ICU) 27% death ICU patients Kim (PSM) 34% death Zhao 43% death RECOVERY RECOVERY C.. (RCT) 4% death Mustafa 44% death REMAP-CAP Bradbury (RCT) 16% death Chow (PSW) 13% death Santoro (PSM) 38% death RESIST Ghati (RCT) 22% death Karimpour-Razk.. -123% death ACT inpatient Eikelboom (RCT) -5% death CT​1 ACT outpatient Eikelboom (RCT) -9% death Ali (ICU) 40% death ICU patients Aidouni (ICU) 31% death ICU patients Singla (RCT) 57% death CT​1 Shamsi 96% death Mehrizi 16% death Lewandowski -70% death Vinod 14% death Azimi Pirsaraei -97% death Tau​2 = 0.02, I​2 = 78.3%, p < 0.0001 Late treatment 15% 15% lower risk Holt -34% death/ICU Wang 58% death Lodigiani -21% ICU admission Yuan 4% death Ramos-Rincón -29% death Osborne (PSM) 59% death Merzon 28% case Bejan 1% ventilation Mulhem -14% death Reese (PSM) -61% death Drew 22% progression Pan -13% death Oh 1% death Son (PSM) 11% death Ma (PSM) 9% death Chow (PSM) 19% death Kim (PSM) -700% death Basheer -13% death Sisinni -7% death Pérez-Segura -49% death Formiga (PSM) -3% death Sullerot (PSW) -10% death Monserrat.. (PSM) -31% death Levy 26% death/hosp. Nimer 4% hospitalization Gogtay -6% death Campbell (PSW) 3% death Lal 11% death Botton -4% death/intubation Malik 14% death Abul 33% death Loucera 18% death Morrison (PSM) 8% death Ali 28% death Zadeh 37% death Azizi 0% death Aweimer -10% death Intubated patients Tse (PSM) 67% death/intubation Prieto-Campo -13% death Ware (PSM) 46% death Sakamaki -37% severe case Tau​2 = 0.07, I​2 = 95.2%, p = 0.31 Prophylaxis 5% 5% lower risk All studies 9% 9% lower risk 76 aspirin C19 studies c19early.org December 2024 Tau​2 = 0.05, I​2 = 93.0%, p = 0.0045 Protocol pre-specified/rotate for details1 CT: study uses combined treatment Favors aspirin Favors control
B
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Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix. B. Timeline of results in aspirin studies.
SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological injury5-16 and cognitive deficits8,13, cardiovascular complications17-19, organ failure, and death. Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factorsA,20-25, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 8,000 compounds may reduce COVID-19 risk26, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
We analyze all significant controlled studies of aspirin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, Randomized Controlled Trials (RCTs), and higher quality studies.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
regular treatment to prevent or minimize infectionstreat immediately on symptoms or shortly thereafterlate stage after disease progressionexposed to virusEarly TreatmentProphylaxisTreatment delayLate Treatment
Figure 2. Treatment stages.
2 In Vitro studies support the efficacy of aspirin27,28.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 show forest plots for 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.
Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, after exclusions, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval. * p<0.05  **** p<0.0001.
Improvement Studies Patients Authors
All studies9% [3‑15%]
**
76 187,919 1,096
After exclusions13% [6‑18%]
***
66 180,765 1,004
Peer-reviewed studiesPeer-reviewed9% [3‑15%]
**
68 171,966 985
Randomized Controlled TrialsRCTs5% [-2‑11%]7 23,015 235
Mortality10% [4‑16%]
**
65 161,240 969
VentilationVent.5% [-5‑15%]15 54,773 222
ICU admissionICU3% [-11‑16%]15 35,339 225
HospitalizationHosp.-1% [-6‑4%]10 12,578 128
Recovery9% [-1‑18%]3 16,018 112
Cases5% [-5‑14%]7 10,749 65
Viral9% [-0‑17%]2 710 16
RCT mortality5% [-2‑11%]6 22,735 208
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval. * p<0.05  **** p<0.0001.
Early treatment Late treatment Prophylaxis
All studies67% [-696‑99%]15% [8‑22%]
****
5% [-5‑14%]
After exclusions67% [-696‑99%]20% [14‑25%]
****
7% [-3‑16%]
Peer-reviewed studiesPeer-reviewed67% [-696‑99%]16% [9‑23%]
****
4% [-5‑12%]
Randomized Controlled TrialsRCTs67% [-696‑99%]5% [-2‑11%]
Mortality15% [8‑22%]
****
5% [-6‑15%]
VentilationVent.8% [-14‑25%]2% [-2‑7%]
ICU admissionICU3% [-35‑30%]2% [-16‑17%]
HospitalizationHosp.67% [-696‑99%]17% [-19‑42%]-1% [-7‑4%]
Recovery9% [-1‑18%]
Cases5% [-5‑14%]
Viral-2% [-61‑36%]10% [0‑18%]
*
RCT mortality5% [-2‑11%]
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Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
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Figure 4. Random effects meta-analysis for all studies. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for progression.
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Figure 10. Random effects meta-analysis for recovery.
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Figure 11. Random effects meta-analysis for cases.
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Figure 12. Random effects meta-analysis for viral clearance.
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Figure 13. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below. Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses including 114 trials.
Figure 14 shows a comparison of results for RCTs and non-RCT studies. Figure 15 and 16 show forest plots for random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. RCT results are included in Table 1 and Table 2.
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Figure 14. Results for RCTs and non-RCT studies.
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Figure 15. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
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Figure 16. Random effects meta-analysis for RCT mortality results.
RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases31, and analysis of double-blind RCTs has identified extreme levels of bias32. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, reporting, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 112 treatments we have analyzed, 65% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments. They may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. RCTs for aspirin are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
For COVID-19, observational study results do not systematically differ from RCTs, RR 1.00 [0.92‑1.08] across 112 treatments34.
Evidence shows that observational studies can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. analyzed reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. We performed a similar analysis across the 112 treatments we cover, showing no significant difference in the results of RCTs compared to observational studies, RR 1.00 [0.92‑1.08]. Similar results are found for all low-cost treatments, RR 1.02 [0.92‑1.12]. High-cost treatments show a non-significant trend towards RCTs showing greater efficacy, RR 0.92 [0.82‑1.03]. Details can be found in the supplementary data. Lee et al. showed that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or remote survey bias may have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see38,39.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 60% have been confirmed in RCTs, with a mean delay of 7.1 months (68% with 8.2 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be more likely to be RCTs, and more likely to be large trials that dominate meta analyses.
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 can be easily influenced by potential bias, may ignore or underemphasize serious issues not captured in the checklists, and may overemphasize issues unlikely to alter outcomes in specific cases (for example certain specifics of randomization with a very large effect size and well-matched baseline characteristics).
The studies excluded are as below. Figure 17 shows a forest plot for random effects meta-analysis of all studies after exclusions.
Alamdari, substantial unadjusted confounding by indication likely.
Aweimer, unadjusted results with no group details.
Azimi Pirsaraei, unadjusted results with no group details.
Azizi, age matching based on only two categories, matching may be very poor given the relationship between age and COVID-19 risk; inconsistent data.
Elhadi, unadjusted results with no group details.
Holt, unadjusted results with no group details.
Karimpour-Razkenari, substantial unadjusted confounding by indication likely.
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.
Shamsi, unadjusted results with no group details.
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Figure 17. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. For details see the appendix.
Heterogeneity in COVID-19 studies arises from many factors including:
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 hours50,51. Baloxavir marboxil studies for influenza also show that treatment delay is critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir marboxil for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases52
<24 hours-33 hours symptoms53
24-48 hours-13 hours symptoms53
Inpatients-2.5 hours to improvement54
Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 112 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Figure 18. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 112 treatments.
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, for example as in López-Medina et al.
Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk varies significantly across variants56, for example the Gamma variant shows significantly different characteristics57-60. Different mechanisms of action may be more or less effective depending on variants, for example the degree to which TMPRSS2 contributes to viral entry can differ across variants61,62.
Effectiveness may depend strongly on the dosage and treatment regimen.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams et al. analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu et al. analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic65-76, therefore efficacy may depend strongly on combined treatments.
Across all studies there is a strong association between different outcomes, for example improved recovery is strongly associated with lower mortality. However, efficacy may differ depending on the effect measured, for example a treatment may be more effective against secondary complications and have minimal effect on viral clearance.
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 early treatment is very effective. All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. 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 results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
For COVID-19, delay in clinical results translates into additional death and morbidity, as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity, improved recovery, and lower mortality, and the significance may be very high when combining the results. "The studies reported different outcomes" is not a good reason for disregarding results. Pooling the results of studies reporting different outcomes allows us to use more of the available information. Logically we should, and do, use additional information when evaluating treatments—for example dose-response and treatment delay-response relationships provide additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
We present both specific outcome and pooled analyses. In order to combine the results of studies reporting different outcomes we use the most serious outcome reported in each study, based on the thesis that improvement in the most serious outcome provides comparable measures of efficacy for a treatment. A critical advantage of this approach is simplicity and transparency. There are many other ways to combine evidence for different outcomes, along with additional evidence such as dose-response relationships, however these increase complexity.
Trials with high-risk patients may be restricted due to ethics for treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe outcomes as a proxy for more serious outcomes allows faster and safer collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, which follows from a reduction in PCR positivity. We can directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from all 112 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Figure 19 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly, Figure 20 shows that improved recovery is very strongly associated with lower mortality (p < 0.000000000001). Considering the extremes, Singh et al. show an association between viral clearance and hospitalization or death, with p = 0.003 after excluding one large outlier from a mutagenic treatment, and based on 44 RCTs including 52,384 patients. Figure 21 shows that improved viral clearance is strongly associated with fewer serious outcomes. The association is very similar to Singh et al., with higher confidence due to the larger number of studies. As with Singh et al., the confidence increases when excluding the outlier treatment, from p = 0.00000042 to p = 0.00000002.
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Figure 19. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 20. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 19. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.1 months. When restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months. Figure 22 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 22. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral clearance may show no efficacy if most studies only examine viral clearance. In practice, it is rare for a non-antiviral treatment to report viral clearance and to not report clinical outcomes; and in practice other sources of heterogeneity such as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average. However, as with all meta analyses, it is important to review the different studies included. We also present individual outcome analyses, which may be more informative for specific use cases.
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 results78-81.
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.
Figure 23 shows a scatter plot of results for prospective and retrospective studies. 38% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 30% of prospective studies, consistent with a bias toward publishing positive results. The median effect size for retrospective studies is 12% improvement, compared to 13% for prospective studies, showing similar results.
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Figure 23. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-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 24 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 < 0.0582-89. 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.
Log Risk Ratio Standard Error 1.406 1.055 0.703 0.352 0 -3 -2 -1 0 1 2 A: Simulated perfect trials p > 0.05 Log Risk Ratio Standard Error 1.433 1.074 0.716 0.358 0 -4 -3 -2 -1 0 1 2 B: Simulated perfect trials with varying treatment delay p < 0.0001
Figure 24. Example funnel plot analysis for simulated perfect trials.
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.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses for specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.
Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. 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.
Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials with conflicts of interest may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone65-76. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.
No treatment or intervention is 100% available and effective for all current and future variants. Efficacy may vary significantly with different variants and within different populations. All treatments have potential side effects. Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized advice, and provide details of risks and benefits based on individual medical history and situations.
2 of 76 studies combine treatments. The results of aspirin alone may differ. 2 of 7 RCTs use combined treatment. 4 other meta analyses show significant improvements with aspirin for mortality1-3, mechanical ventilation1, and progression4.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors20-25, providing many therapeutic targets. Over 8,000 compounds have been predicted to reduce COVID-19 risk26, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Figure 25 shows an overview of the results for aspirin in the context of multiple COVID-19 treatments, and Figure 26 shows a plot of efficacy vs. cost for COVID-19 treatments.
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Figure 25. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of random effects meta-analysis. 0.6% of 8,000+ proposed treatments show efficacy90.
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Figure 26. Efficacy vs. cost for COVID-19 treatments.
Significantly lower risk is seen for mortality and progression. 28 studies from 26 independent teams in 11 countries show significant benefit. Meta analysis using the most serious outcome reported shows 9% [3‑15%] lower risk. 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, comparable with the mortality results of all studies, 10% [4‑16%], and the 16% improvement in the REMAP-CAP RCT.
4 other meta analyses show significant improvements with aspirin for mortality1-3, mechanical ventilation1, and progression4.
Ventilation -8% Improvement Relative Risk Aspirin  Abdelwahab et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 67 patients in Egypt Study underpowered to detect differences c19early.org Abdelwahab et al., Clinical Drug Inves.., Jul 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 225 hospitalized patients in Egypt, showing significantly lower thromboembolic events with aspirin treatment, but no significant difference in the need for mechanical ventilation. Submit Corrections or Updates.
Mortality, day 56 33% Improvement Relative Risk Mortality, day 30 40% Hospitalization 20% Aspirin for COVID-19  Abul et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 1,687 patients in the USA (December 2020 - September 2021) Lower mortality with aspirin (p=0.025) c19early.org Abul et al., medRxiv, August 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 31% Improvement Relative Risk Ventilation 10% Aspirin for COVID-19  Aidouni et al.  ICU PATIENTS Is very late treatment with aspirin beneficial for COVID-19? Prospective study of 1,124 patients in Morocco (Mar 2020 - Mar 2022) Lower mortality with aspirin (p=0.003) c19early.org Aidouni et al., Research Square, November 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Prospective study of 1,124 COVID-19 ICU patients, showing lower mortality with aspirin treatment. Submit Corrections or Updates.
Mortality 27% Improvement Relative Risk Mortality (b) 14% ICU time 5% Aspirin for COVID-19  Al Harthi et al.  ICU PATIENTS Is very late treatment with aspirin beneficial for COVID-19? PSM retrospective 351 patients in Saudi Arabia Lower mortality with aspirin (p=0.03) c19early.org Al Harthi et al., J. Intensive Care Me.., Sep 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality -28% Improvement Relative Risk Aspirin for COVID-19  Alamdari et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 459 patients in Iran Higher mortality with aspirin (not stat. sig., p=0.52) c19early.org Alamdari et al., The Tohoku J. Experim.., Sep 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 459 patients in Iran, 53 treated with aspirin, showing no significant difference with treatment. Submit Corrections or Updates.
Mortality 28% Improvement Relative Risk Aspirin for COVID-19  Ali et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 1,645 patients in the USA Lower mortality with aspirin (not stat. sig., p=0.067) c19early.org Ali et al., Chest, November 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 1,645 hospitalized patients in the USA, showing lower mortality with aspirin use, without statistical significance. Submit Corrections or Updates.
Mortality 40% Improvement Relative Risk ARDS 37% Aspirin for COVID-19  Ali et al.  ICU PATIENTS Is very late treatment with aspirin beneficial for COVID-19? Retrospective 1,190 patients in Egypt Lower mortality (p<0.0001) and ARDS (p=0.0011) with aspirin c19early.org Ali et al., Egyptian J. Anaesthesia, Oct 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 1,190 ICU patients in Egypt, showing lower mortality with aspirin treatment. 150mg daily. Submit Corrections or Updates.
Mortality -10% Improvement Relative Risk Aspirin  Aweimer et al.  INTUBATED PATIENTS Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 149 patients in Germany (March 2020 - August 2021) No significant difference in mortality c19early.org Aweimer et al., Scientific Reports, Mar 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 149 patients under invasive mechanical ventilation in Germany showing no significant difference in mortality with aspirin prophylaxis in unadjusted results. Submit Corrections or Updates.
Mortality -97% Improvement Relative Risk Aspirin  Azimi Pirsaraei et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 831 patients in Iran (March - June 2020) Higher mortality with aspirin (p=0.002) c19early.org Azimi Pirsaraei et al., Cureus, August 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 831 hospitalized COVID-19 patients showing higher mortality with aspirin treatment in unadjusted results. Submit Corrections or Updates.
Mortality 0% Improvement Relative Risk Aspirin for COVID-19  Azizi et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 262 patients in Iran No significant difference in mortality c19early.org Azizi et al., J. Nephropharmacology, Feb 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 131 COVID-19 patients with aspirin use and 131 matched controls in Iran, showing no significant difference in outcomes, however age matching used only two categories, 40-60 and 60+, therefore matching may be very poor given the relationship between age and COVID-19 risk. The percentages given for the control group death/recovery outcomes do not match the reported counts. Submit Corrections or Updates.
Mortality -13% Improvement Relative Risk Aspirin for COVID-19  Basheer et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 390 patients in Israel Higher mortality with aspirin (p=0.0003) c19early.org Basheer et al., Metabolites, October 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 390 hospitalized patients in Israel, showing higher risk of mortality with prior aspirin use. Details of the analysis are not provided. Submit Corrections or Updates.
Ventilation 1% Improvement Relative Risk Aspirin for COVID-19  Bejan et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 9,229 patients in the USA No significant difference in ventilation c19early.org Bejan et al., Clinical Pharmacology & .., Feb 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 9,748 COVID-19 patients in the USA showing no signficant difference with aspirin use. Submit Corrections or Updates.
Death/intubation -4% Improvement Relative Risk Hospitalization -3% Aspirin for COVID-19  Botton et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 31,072,642 patients in France No significant difference in outcomes seen c19early.org Botton et al., Research and Practice i.., Jun 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 31 million people without cardiovascular disease in France, showing no significant difference in hospitalization or combined intubation/death with low dose aspirin prophylaxis. Submit Corrections or Updates.
Mortality 16% Improvement Relative Risk Discharge 17% Progression 21% Progression (b) 5% primary Aspirin  REMAP-CAP  LATE TREATMENT  RCT Is late treatment with aspirin beneficial for COVID-19? RCT 1,084 patients in multiple countries (October 2020 - June 2021) Lower progression with aspirin (p=0.018) c19early.org Bradbury et al., JAMA, March 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
RCT 1,557 critical patients, showing significantly lower mortality with aspirin, with 97.5% posterior probability of efficacy. Submit Corrections or Updates.
Mortality, day 60 3% Improvement Relative Risk Mortality, day 30 2% Aspirin for COVID-19  Campbell et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 20,730 patients in the USA (March - December 2020) No significant difference in mortality c19early.org Campbell et al., PLOS ONE, May 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 19% Improvement Relative Risk Ventilation 3% Aspirin for COVID-19  Chow et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 17,347 patients in the USA Lower mortality with aspirin (p=0.005) c19early.org Chow et al., J. Thrombosis and Haemost.., Aug 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
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. Submit Corrections or Updates.
Mortality 13% Improvement Relative Risk Aspirin for COVID-19  Chow et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 112,070 patients in the USA Lower mortality with aspirin (p=0.00004) c19early.org Chow et al., JAMA Network Open, March 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 112,269 hospitalized COVID-19 patients in the USA, showing lower mortality with aspirin treatment. Submit Corrections or Updates.
Mortality 47% Improvement Relative Risk Ventilation 44% ICU admission 43% Aspirin for COVID-19  Chow et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 412 patients in the USA Lower mortality (p=0.02) and ventilation (p=0.007) with aspirin c19early.org Chow et al., Anesthesia & Analgesia, Apr 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 412 hospitalized patients, 98 treated with aspirin, showing lower mortality, ventilation, and ICU admission with treatment. Submit Corrections or Updates.
Hospitalization 67% Improvement Relative Risk Progression 19% Progression (b) 6% primary Aspirin  ACTIV-4B  EARLY TREATMENT  DB RCT Is early treatment with aspirin beneficial for COVID-19? Double-blind RCT 280 patients in the USA (September 2020 - June 2021) Lower hospitalization with aspirin (not stat. sig., p=0.49) c19early.org Connors et al., JAMA, October 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
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). Submit Corrections or Updates.
Progression 22% Improvement Relative Risk Case -3% Aspirin for COVID-19  Drew et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective study in multiple countries (March - May 2020) Lower progression with aspirin (not stat. sig., p=0.3) c19early.org Drew et al., medRxiv, May 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 2,736,091 individuals in the U.S., U.K., and Sweden, showing lower risk of hospital/clinic visits with aspirin use. Submit Corrections or Updates.
Mortality -9% Improvement Relative Risk Progression 20% primary Hospitalization 17% Aspirin  ACT outpatient  LATE TREATMENT  RCT Is late treatment with aspirin beneficial for COVID-19? RCT 3,881 patients in Canada (August 2020 - February 2022) Lower progression (p=0.21) and hospitalization (p=0.31), not sig. c19early.org Eikelboom et al., The Lancet Respirato.., Oct 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Late (5.4 days) outpatient RCT showing no significant difference in outcomes with aspirin treatment. Submit Corrections or Updates.
Mortality -5% Improvement Relative Risk Progression 8% Progression (b) 11% Aspirin  ACT inpatient  LATE TREATMENT  RCT Is late treatment with aspirin + rivaroxaban beneficial for COVID-19? RCT 2,119 patients in multiple countries (October 2020 - February 2022) No significant difference in outcomes seen c19early.org Eikelboom et al., The Lancet Respirato.., Oct 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
RCT very late stage (baseline SpO2 77%) patients, showing no significant differences with rivaroxaban and aspirin treatment. Submit Corrections or Updates.
Mortality 10% Improvement Relative Risk Aspirin for COVID-19  Elhadi et al.  ICU PATIENTS Is very late treatment with aspirin beneficial for COVID-19? Prospective study of 465 patients in Libya (May - December 2020) No significant difference in mortality c19early.org Elhadi et al., PLOS ONE, April 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Prospective study of 465 COVID-19 ICU patients in Libya showing no significant differences with treatment. Submit Corrections or Updates.
Mortality -3% Improvement Relative Risk Ventilation -3% ICU admission -4% Aspirin for COVID-19  Formiga et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 20,641 patients in the USA (Mar 2020 - May 2021) No significant difference in outcomes seen c19early.org Formiga et al., Internal and Emergency.., Nov 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 20,641 hospitalized patients in Spain, showing no significant difference in outcomes with existing aspirin use. Submit Corrections or Updates.
Mortality 22% Improvement Relative Risk Mortality (b) 58% Ventilation 9% Ventilation (b) 50% Progression 30% primary Progression (b) 60% primary Aspirin  RESIST  LATE TREATMENT  RCT Is late treatment with aspirin beneficial for COVID-19? RCT 661 patients in India (July 2020 - January 2021) Lower progression with aspirin (not stat. sig., p=0.46) c19early.org Ghati et al., BMC Infectious Diseases, Jul 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
RCT hospitalized patients in India, 224 treated with atorvastatin, 225 with aspirin, and 225 with both, showing lower serum interleukin-6 levels with aspirin, but no statistically significant changes in other outcomes. Low dose aspirin 75mg daily for 10 days. Submit Corrections or Updates.
Mortality -6% Improvement Relative Risk Ventilation 50% ICU admission 49% Aspirin for COVID-19  Gogtay et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 125 patients in the USA (March - April 2020) Lower ventilation (p=0.16) and ICU admission (p=0.41), not sig. c19early.org Gogtay et al., World J. Critical Care .., Mar 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 125 COVID+ hospitalized patients in the USA, showing no significant differences with aspirin prophylaxis. Submit Corrections or Updates.
Mortality 35% Improvement Relative Risk Ventilation -49% ICU admission -45% Aspirin for COVID-19  Goshua et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 2,785 patients in the USA Lower mortality (p=0.044) and higher ventilation (p=0.037) c19early.org Goshua et al., Blood, November 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 2,785 hospitalized patients in the USA, showing lower mortality and higher ventilation and ICU admission with aspirin treatment. Submit Corrections or Updates.
Mortality 25% Improvement Relative Risk Aspirin  Haji Aghajani et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 991 patients in Iran Lower mortality with aspirin (p=0.043) c19early.org Haji Aghajani et al., J. Medical Virol.., Apr 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 991 hospitalized patients in Iran, showing lower mortality with aspirin treatment. Submit Corrections or Updates.
Death/ICU -34% Improvement Relative Risk Aspirin for COVID-19  Holt et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 689 patients in Denmark (March - April 2020) Higher death/ICU with aspirin (not stat. sig., p=0.094) c19early.org Holt et al., J. Hypertension, May 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 689 hospitalized COVID-19 patients in Denmark, showing higher risk of ICU/death with aspirin use in unadjusted results subject to confounding by indication. Submit Corrections or Updates.
Mortality 80% Improvement Relative Risk Recovery 65% Complications 96% Aspirin for COVID-19  Husain et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 42 patients in Bangladesh Lower mortality (p=0.55) and improved recovery (p=0.4), not sig. c19early.org Husain et al., ResearchGate, October 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 42 patients in Bangladesh, 11 treated with aspirin, showing fewer complications with treatment. Submit Corrections or Updates.
Mortality -123% Improvement Relative Risk Aspirin  Karimpour-Razkenari et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 478 patients in Iran (February - May 2020) Higher mortality with aspirin (p=0.008) c19early.org Karimpour-Razkenari et al., J. Pharmac.., Oct 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 478 moderate to severe hospitalized patients in Iran, showing higher mortality with aspirin treatment. Authors note confounding by indication for aspirin treatment. Submit Corrections or Updates.
Mortality 46% Improvement Relative Risk Aspirin for COVID-19  Karruli et al.  ICU PATIENTS Is very late treatment with aspirin beneficial for COVID-19? Retrospective 32 patients in Italy (March - May 2020) Study underpowered to detect differences c19early.org Karruli et al., Microbial Drug Resista.., Sep 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 32 ICU patients showing lower mortality with aspirin treatment, without statistical significance. Submit Corrections or Updates.
Mortality -700% Improvement Relative Risk Ventilation -433% ICU admission -433% Case 33% Mortality (b) 34% Ventilation (b) -102% ICU admission (b) -91% Aspirin for COVID-19  Kim et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 272 patients in South Korea Higher mortality with aspirin (p=0.027) c19early.org Kim et al., Medicina, September 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective database analysis of 22,660 patients tested for COVID-19 in South Korea. There was no significant difference in cases according to aspirin use. Aspirin use before COVID-19 was related to an increased death rate and aspirin use after COVID-19 was related to a higher risk of oxygen therapy.

Results for late treatment are listed separately91. Submit Corrections or Updates.
Mortality 34% Improvement Relative Risk Ventilation -102% ICU admission -91% Aspirin for COVID-19  Kim et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 259 patients in South Korea Lower mortality (p=0.22) and higher ventilation (p=0.16), not sig. c19early.org Kim et al., Medicina, September 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective database analysis of 22,660 patients tested for COVID-19 in South Korea. There was no significant difference in cases according to aspirin use. Aspirin use before COVID-19 was related to an increased death rate and aspirin use after COVID-19 was related to a higher risk of oxygen therapy.

Results for prophylaxis are listed separately92. Submit Corrections or Updates.
Mortality 11% Improvement Relative Risk ICU admission 22% Progression 9% Aspirin for COVID-19  Lal et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 21,579 patients in the USA (February 2020 - September 2021) Lower mortality (p=0.01) and ICU admission (p<0.0001) c19early.org Lal et al., Archivos de Bronconeumología, May 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 21,579 hospitalized COVID-19 patients mostly in the USA, showing lower risk of mortality and severity with existing aspirin use. Submit Corrections or Updates.
Death/hospitalization 26% Improvement Relative Risk Aspirin for COVID-19  Levy et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 849 patients in Israel Lower death/hosp. with aspirin (not stat. sig., p=0.13) c19early.org Levy et al., Gerontology, January 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 849 COVID-19+ patients in skilled nursing homes, showing lower risk of combined hospitalization/death with aspirin prophylaxis, not reaching statistical significance. Submit Corrections or Updates.
Mortality -70% Improvement Relative Risk Aspirin  Lewandowski et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 430 patients in Poland Higher mortality with aspirin (p=0.023) c19early.org Lewandowski et al., Biomedicines, March 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 430 hospitalized COVID-19 patients with type 2 diabetes in Poland showing lower mortality with metformin and higher mortality with remdesivir, convalescent plasma, and aspirin in univariable analysis. These results were not statistically significant except for aspirin, and no baseline information per treatment is provided to assess confounding. Submit Corrections or Updates.
Mortality 75% Improvement Relative Risk Mortality (b) 81% Time to viral- -2% Aspirin for COVID-19  Liu et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 232 patients in China Lower mortality with aspirin (p=0.03) c19early.org Liu et al., Medicine, February 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective PSM analysis of 232 hospitalized patients, 28 treated with aspirin, showing lower mortality with treatment. There was no significant difference in viral clearance. Submit Corrections or Updates.
ICU admission -21% Improvement Relative Risk Aspirin for COVID-19  Lodigiani et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 388 patients in Italy (February - April 2020) Higher ICU admission with aspirin (not stat. sig., p=0.52) c19early.org Lodigiani et al., Thrombosis Research, Jul 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 388 hospitalized COVID-19 patients in Italy showing higher use of aspirin in ICU patients, without statistical significance. Submit Corrections or Updates.
Mortality 18% Improvement Relative Risk Aspirin for COVID-19  Loucera et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 15,968 patients in Spain (January - November 2020) Lower mortality with aspirin (p=0.0004) c19early.org Loucera et al., Virology J., August 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments. Submit Corrections or Updates.
Mortality 9% Improvement Relative Risk Hospitalization 2% Symp. case -9% Case -7% Aspirin for COVID-19  Ma et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 77,221 patients in the United Kingdom No significant difference in outcomes seen c19early.org Ma et al., Drugs & Aging, August 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
UK Biobank retrospective 77,271 patients aged 50-86, showing no significant differences with aspirin use. Matching lead to different results for the gender vs. overall analysis, for example the overall result for cases was OR 1.07, however both gender results are lower OR 0.97 and 1.02. Submit Corrections or Updates.
Mortality 14% Improvement Relative Risk ICU admission 28% ARDS 25% Hospitalization 2% Aspirin for COVID-19  Malik et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 310 patients in the USA (March - December 2020) Lower ICU admission (p=0.17) and ARDS (p=0.39), not sig. c19early.org Malik et al., Health Science Reports, Jul 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 539 patients in the USA, showing lower mortality, ICU admission, and ARDS with aspirin treatment, without statistical significance. Submit Corrections or Updates.
Mortality 16% Improvement Relative Risk Aspirin for COVID-19  Mehrizi et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 917,198 patients in Iran (February 2020 - March 2022) Lower mortality with aspirin (p<0.000001) c19early.org Mehrizi et al., Frontiers in Public He.., Dec 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective study of 917,198 hospitalized COVID-19 cases covered by the Iran Health Insurance Organization over 26 months showing that antithrombotics, corticosteroids, and antivirals reduced mortality while diuretics, antibiotics, and antidiabetics increased it. Confounding makes some results very unreliable. For example, diuretics like furosemide are often used to treat fluid overload, which is more likely in ICU or advanced disease requiring aggressive fluid resuscitation. Hospitalization length has increased risk of significant confounding, for example longer hospitalization increases the chance of receiving a medication, and death may result in shorter hospitalization. Mortality results may be more reliable.

Confounding by indication is likely to be significant for many medications. Authors adjustments have very limited severity information (admission type refers to ward vs. ER department on initial arrival). We can estimate the impact of confounding from typical usage patterns, the prescription frequency, and attenuation or increase of risk for ICU vs. all patients.

Submit Corrections or Updates.
Mortality 48% Improvement Relative Risk Aspirin for COVID-19  Meizlish et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 638 patients in the USA Lower mortality with aspirin (p=0.004) c19early.org Meizlish et al., American J. Hematology, Jan 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 638 matched hospitalized patients in the USA, 319 treated with aspirin, showing lower mortality with treatment. Submit Corrections or Updates.
Case 28% Improvement Relative Risk Mortality 62% Time to viral- 10% Time to viral- (b) 15% Aspirin for COVID-19  Merzon et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 10,477 patients in Israel Fewer cases (p=0.041) and faster viral clearance (p=0.045) c19early.org Merzon et al., The FEBS J., February 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 10,477 patients in Israel, showing lower risk of COVID-19 cases with existing aspiring use. Submit Corrections or Updates.
Mortality -31% Improvement Relative Risk Aspirin  Monserrat Villatoro et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective study in Spain Higher mortality with aspirin (p=0.038) c19early.org Monserrat Villatoro et al., Pharmaceut.., Jan 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 3,712 hospitalized patients in Spain, showing lower mortality with existing use of azithromycin, bemiparine, budesonide-formoterol fumarate, cefuroxime, colchicine, enoxaparin, ipratropium bromide, loratadine, mepyramine theophylline acetate, oral rehydration salts, and salbutamol sulphate, and higher mortality with acetylsalicylic acid, digoxin, folic acid, mirtazapine, linagliptin, enalapril, atorvastatin, and allopurinol. Submit Corrections or Updates.
Mortality 8% Improvement Relative Risk Ventilation -1% ICU admission -12% Hospitalization -18% Aspirin for COVID-19  Morrison et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 13,585 patients in the USA (Mar 2020 - Mar 2021) Higher hospitalization with aspirin (p=0.045) c19early.org Morrison et al., PLOS ONE, October 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 13,585 COVID+ patients in the USA, showing higher hospitalization with aspirin use, and no significant difference for mortality, ventilation, and ICU admission. Submit Corrections or Updates.
Mortality -14% Improvement Relative Risk Aspirin for COVID-19  Mulhem et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 3,219 patients in the USA No significant difference in mortality c19early.org Mulhem et al., BMJ Open, April 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time. Submit Corrections or Updates.
Mortality 15% Improvement Relative Risk Mortality (b) 37% Aspirin for COVID-19  Mura et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 1,054 patients in multiple countries Lower mortality with aspirin (not stat. sig., p=0.081) c19early.org Mura et al., Signal Transduction and T.., Mar 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective TriNetX database analysis of 1,379 severe COVID-19 patients requiring respiratory support, showing lower mortality with aspirin (not reaching statistical significance) and famotidine, and improved results from the combination of both. Submit Corrections or Updates.
Mortality 44% Improvement Relative Risk Aspirin for COVID-19  Mustafa et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 444 patients in Pakistan Lower mortality with aspirin (not stat. sig., p=0.28) c19early.org Mustafa et al., Exploratory Research i.., Dec 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 444 hospitalized patients in Pakistan, showing lower mortality with aspirin treatment in unadjusted results, not reaching statistical significance. Submit Corrections or Updates.
Hospitalization 4% Improvement Relative Risk Severe case -18% Aspirin for COVID-19  Nimer et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 2,148 patients in Jordan (March - July 2021) Higher severe cases with aspirin (not stat. sig., p=0.28) c19early.org Nimer et al., Bosnian J. Basic Medical.., Feb 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 2,148 COVID-19 recovered patients in Jordan, showing no significant differences in the risk of severity and hospitalization with aspirin prophylaxis. Submit Corrections or Updates.
Mortality 1% Improvement Relative Risk Case 12% Aspirin for COVID-19  Oh et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective study in South Korea Fewer cases with aspirin (p=0.041) c19early.org Oh et al., Yonsei Medical J., June 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective database analysis of 328,374 adults in South Korea, showing lower risk of COVID-19 cases with aspirin use, but no difference in mortality for COVID-19 patients. Submit Corrections or Updates.
Mortality 59% Improvement Relative Risk Mortality (b) 60% Aspirin for COVID-19  Osborne et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 13,628 patients in the USA Lower mortality with aspirin (p<0.000001) c19early.org Osborne et al., PLOS ONE, February 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective PSM analysis of pre-existing aspirin use in the USA, showing lower mortality with treatment. Submit Corrections or Updates.
Mortality -13% Improvement Relative Risk Death/intubation -2% Aspirin for COVID-19  Pan et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 762 patients in the USA (March - April 2020) No significant difference in outcomes seen c19early.org Pan et al., Heart & Lung, May 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 762 COVID+ hospitalized patients in the USA, 239 on antiplatelet medication (199 aspirin), showing no significant differences in outcomes.

For more discussion see93. Submit Corrections or Updates.
Mortality -32% Improvement Relative Risk Aspirin  Pourhoseingholi et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Prospective study of 2,468 patients in Iran (Feb - Jul 2020) Higher mortality with aspirin (p=0.036) c19early.org Pourhoseingholi et al., Research Square, May 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Prospective study of 2,468 hospitalized COVID-19 patients in Iran, showing higher mortality with aspirin treatment. IR.MUQ.REC.1399.013. Submit Corrections or Updates.
Mortality -13% Improvement Relative Risk Hospitalization 3% Progression 0% Case 8% Aspirin for COVID-19  Prieto-Campo et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective study in Spain Fewer cases with aspirin (p=0.015) c19early.org Prieto-Campo et al., Revista Española .., Jan 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Population-based case-control study of 86,602 people in Spain, shower lower risk of COVID-19 cases with low-dose aspirin, but no significant difference for severity, hospitalization, or mortality. Submit Corrections or Updates.
Mortality -49% Improvement Relative Risk Aspirin for COVID-19  Pérez-Segura et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 763 patients in multiple countries Higher mortality with aspirin (p=0.00012) c19early.org Pérez-Segura et al., Medicina Clínica, Oct 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 770 COVID-19 patients with cancer, showing increased mortality with aspirin use in unadjusted results. Submit Corrections or Updates.
Mortality -29% Improvement Relative Risk Aspirin for COVID-19  Ramos-Rincón et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 790 patients in Spain (March - May 2020) Higher mortality with aspirin (p=0.02) c19early.org Ramos-Rincón et al., Research Square, Dec 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 790 hospitalized type 2 diabetes patients ≥80 years old in Spain, showing higher mortality with existing aspirin use. Submit Corrections or Updates.
Mortality 4% Improvement Relative Risk Mortality (b) 17% Ventilation 5% Discharge 6% Discharge (b) 16% Hospitalization time 11% no CI Aspirin  RECOVERY  LATE TREATMENT  RCT Is late treatment with aspirin beneficial for COVID-19? RCT 14,892 patients in multiple countries (November 2020 - March 2021) Higher discharge with aspirin (p=0.0062) c19early.org RECOVERY Collaborative Group, The Lancet, Nov 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
RCT 14,892 late stage patients, 7,351 treated with aspirin, showing slightly improved discharge and hospitalization time, and no significant difference for mortality.

Results are limited due to low dose (150mg daily), very late treatment (9 days post symptom onset), and 96% concurrent use of low molecular weight heparin. Greater benefits were seen for non-LMWH patients, and for very late (<= 7 days from onset) vs. extremely late (>7 days) treatment. For more discussion see94. Submit Corrections or Updates.
Mortality -61% Improvement Relative Risk Severe case -309% Aspirin for COVID-19  Reese et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 9,842 patients in the USA Higher mortality (p<0.0001) and severe cases (p<0.0001) c19early.org Reese et al., medRxiv, April 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
N3C retrospective 250,533 patients showing significantly higher mortality with aspirin use. Note that aspirin results were not included in the journal version or v2 of this preprint. Submit Corrections or Updates.
Mortality 13% Improvement Relative Risk Aspirin for COVID-19  Sahai et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 496 patients in the USA Lower mortality with aspirin (not stat. sig., p=0.53) c19early.org Sahai et al., Vascular Medicine, May 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 1,994 PCR+ patients in the USA, not showing a significant difference in mortality with aspirin treatment. Submit Corrections or Updates.
Severe case -37% Improvement Relative Risk Aspirin for COVID-19  Sakamaki et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 650,317 patients in Japan (January 2020 - December 2022) Higher severe cases with aspirin (p<0.000001) c19early.org Sakamaki et al., Discover Public Health, Sep 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 650,317 COVID-19 patients in Japan showing higher risk of severe COVID-19 with low-dose apirin use. Although cardiovascular disease should have been adjusted for (details of adjustments are not provided), there may be significant residual confounding because aspirin use might indicate more severe or complex cardiovascular issues not fully captured by the adjustment. Submit Corrections or Updates.
Mortality 38% Improvement Relative Risk Aspirin for COVID-19  Santoro et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? PSM retrospective 7,824 patients in multiple countries (Jan - May 2020) Lower mortality with aspirin (p=0.017) c19early.org Santoro et al., J. the American Heart .., Jun 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
HOPE-COVID-19 PSM retrospective 7,824 patients, comparing prophylactic anticoagulation with and without additional treatment with aspirin in hospitalized patients, showing lower mortality with aspirin treatment. Submit Corrections or Updates.
Mortality 96% Improvement Relative Risk Aspirin for COVID-19  Shamsi et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 183 patients in Iran (March 2020 - August 2021) Lower mortality with aspirin (not stat. sig., p=0.22) c19early.org Shamsi et al., Canadian J. Infectious .., Jul 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 183 hospitalized pediatric COVID-19 patients in Iran, showing no significant difference in mortality with aspirin in unadjusted results. Submit Corrections or Updates.
Mortality, day 28 57% Improvement Relative Risk Mortality, day 14 15% Ventilation 20% ICU admission 29% Progression 33% Progression, resp. failure 76% Progression, AKI 44% Progression, DIC 86% Progression, liver dysfunct.. 25% Aspirin  Singla et al.  LATE TREATMENT  RCT Is late treatment with aspirin + dipyridamole beneficial for COVID-19? RCT 98 patients in the USA (October 2020 - April 2021) Lower mortality with aspirin + dipyridamole (not stat. sig., p=0.44) c19early.org Singla et al., PLOS ONE, January 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
RCT 98 hospitalized patients in the USA, 49 treated with aspirin and dipyridamole, showing improved results with treatment, but without statistical significance. Submit Corrections or Updates.
Mortality -7% Improvement Relative Risk Death or respiratory sup.. 30% Aspirin for COVID-19  Sisinni et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 984 patients in Italy Lower death/intubation with aspirin (p=0.012) c19early.org Sisinni et al., Int. J. Cardiology, Oct 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 984 COVID-19 patients, 253 taking aspirin prior to admission, showing lower risk of respiratory support upgrade with treatment. Submit Corrections or Updates.
Mortality 11% Improvement Relative Risk Mortality (b) 24% Progression -7% Progression (b) 9% Case -11% Case (b) -1% Aspirin for COVID-19  Son et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 21,669 patients in South Korea No significant difference in outcomes seen c19early.org Son et al., Medicine, July 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective case control study in South Korea, showing a trend towards lower mortality, but no significant differences with aspirin use. Submit Corrections or Updates.
Mortality -10% Improvement Relative Risk ICU admission -110% Hospitalization time -10% Aspirin for COVID-19  Sullerot et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 1,047 patients in multiple countries (Mar - Dec 2020) Higher ICU admission (p=0.007) and longer hospitalization (p=0.024) c19early.org Sullerot et al., GeroScience, January 2022 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 1,047 pneumonia patients in 5 COVID-19 geriatric units in France and Switzerland, significantly higher ICU admission and longer hospital stays with existing aspirin treatment. Numbers in this study appear to be inconsistent, for example the abstract says 147 of 301 aspirin patients died, shown as 34.3%, while Table 1 shows 104 of 301 (34.6%). Submit Corrections or Updates.
Death/intubation 67% Improvement Relative Risk Aspirin for COVID-19  Tse et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 2,664 patients in China (January - December 2020) Lower death/intubation with aspirin (p=0.00027) c19early.org Tse et al., Heart, June 2023 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 2,664 COVID-19 hospitalized patients receiving steroids/antiviral therapy in Hong Kong, showing lower risk of combined death/intubation with aspirin use. Submit Corrections or Updates.
Mortality 22% primary Improvement Relative Risk ICU admission -10% Aspirin  Vahedian-Azimi et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 587 patients in Iran Lower mortality with aspirin (not stat. sig., p=0.56) c19early.org Vahedian-Azimi et al., Identification .., Jul 2021 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 587 COVID+ hospitalized patients in Iran, showing no significant differences in outcomes with aspirin treatment. Submit Corrections or Updates.
Mortality 14% Improvement Relative Risk Ventilation 30% Hypoxia 40% Readmisson -6% DVT/PE 18% Aspirin for COVID-19  Vinod et al.  LATE TREATMENT Is late treatment with aspirin beneficial for COVID-19? Retrospective 376 patients in the USA (March - October 2020) Lower ventilation with aspirin (not stat. sig., p=0.24) c19early.org Vinod et al., Cardiology Research, Jun 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 376 hospitalized COVID-19 patients in the United States showing no significant differences with aspirin. Mortality, mechanical ventilation, and hypoxia were lower with treatment, without statistical significance. Submit Corrections or Updates.
Mortality 58% Improvement Relative Risk Aspirin for COVID-19  Wang et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? Retrospective 58 patients in the USA Lower mortality with aspirin (not stat. sig., p=0.43) c19early.org Wang et al., J. Hematology & Oncology, Jul 2020 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
Retrospective 58 multiple myeloma COVID-19 patients in the USA, showing no significant difference with aspirin treatment. Submit Corrections or Updates.
Mortality 46% Improvement Relative Risk Aspirin for COVID-19  Ware et al.  Prophylaxis Is prophylaxis with aspirin beneficial for COVID-19? PSM retrospective 334,374 patients in the USA (Mar 2020 - Jun 2022) Lower mortality with aspirin (p=0.001) c19early.org Ware et al., medRxiv, April 2024 Favorsaspirin Favorscontrol 0 0.5 1 1.5 2+
PSM retrospective 334,374 COVID-19 patients showing decreased risk of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, but increased risk of arterial thromboembolic disorders, including ischemic stroke and acute ischemic heart disease, with aspirin use prior to COVID-19 diagnosis. The increased risk of arterial disease may be associated with preexisting cardiovascular disease for which aspirin was already prescribed. All cause mortality was lower in the aspirin group, however authors do not discuss this result. Submit Corrections or Updates.