Aspirin for COVID-19: real-time analysis of all 23 studies

Aspirin for COVID-19: real-time meta analysis of 23 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, recovery, and cases. 12 studies from 6 different countries show statistically significant improvements in isolation (9 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 21% [8‑33%] improvement. Results are similar after exclusions and similar for peer-reviewed studies.

• Benefits may only be evident without the use of other 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 from all studies, 19% [5‑31%].

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. None of the aspirin studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments are more effective. There has been no early treatment studies to date.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

• All data to reproduce this paper and sources are in the appendix.

	Studies	Late treatment	Prophylaxis	Patients	Authors
All studies	23	27% [13‑39%]	15% [-12‑36%]	66,304	274
With exclusions	20	28% [14‑41%]	18% [-11‑40%]	62,182	250
Peer-reviewed	21	27% [10‑41%]	8% [-22‑31%]	65,955	244
RCTs	1	4% [-4‑11%]		14,892	1
Percentage improvement with aspirin treatment

Covid Analysis et al., 1/5/2022, preprint, 1 author.

Pattern of medication utilization in hospitalized patients with COVID-19 in three District Headquarters Hospitals in the Punjab province of Pakistan

Mustafa et al., Exploratory Research in Clinical and Social Pharmacy, doi:10.1016/j.rcsop.2021.100101 (Peer Reviewed)

Retrospective 444 hospitalized patients in Pakistan, showing lower mortality with aspirin treatment in unadjusted results, not reaching statistical significance.

risk of death, 44.1% lower, RR 0.56, p = 0.28, treatment 4 of 66 (6.1%), control 41 of 378 (10.8%), NNT 21.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Mustafa et al., 12/29/2021, retrospective, Pakistan, South Asia, peer-reviewed, 7 authors.

Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

RECOVERY Collaborative Group, The Lancet, doi:10.1016/S0140-6736(21)01825-0 (Peer Reviewed)

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 see [1].

[1] twitter.com/Covid19Crusher/status/1461272964675031042

risk of death, 4.0% lower, RR 0.96, p = 0.35, treatment 7,351, control 7,541.

risk of death, 17.0% lower, RR 0.83, p = 0.35, treatment 7,351, control 7,541, non-LMWH.

risk of mechanical ventilation, 5.0% lower, RR 0.95, p = 0.32, treatment 7,351, control 7,541.

risk of no hospital discharge, 5.7% lower, RR 0.94, p = 0.006, treatment 7,351, control 7,541.

risk of no hospital discharge, 16.0% lower, RR 0.84, p = 0.04, treatment 7,351, control 7,541, non-LMWH.

hospitalization time, 11.1% lower, relative time 0.89, treatment 7,351, control 7,541.

RECOVERY et al., 11/18/2021, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 1 author, 1 November, 2020 - 21 March, 2021.

Antiplatelet therapy and outcome in patients with COVID-19. Results from a multi-center international prospective registry (HOPE-COVID19)

Santoro et al., European Heart Journal, doi:10.1093/eurheartj/ehab724.3002 (Peer Reviewed)

Retrospective database analysis of 7,824 patients in the HOPE-COVID19 registry, 730 receiving antiplatelet therapy including aspirin, showing lower mortality with treatment. Authors do not provide results restricted to aspirin.

risk of death, 71.0% lower, RR 0.29, p < 0.001, treatment 730, control 7,094, antiplatelet therapy, multivariable.

Santoro et al., 10/14/2021, retrospective, multiple countries, multiple regions, peer-reviewed, 6 authors.

Prognostic factors at admission on patients with cancer and COVID-19: Analysis of HOPE registry data

Pérez-Segura et al., Medicina Clínica, doi:10.1016/j.medcle.2021.02.010 (Peer Reviewed)

Retrospective 770 COVID-19 patients with cancer, showing increased mortality with aspirin use in unadjusted results.

risk of death, 49.1% higher, RR 1.49, p < 0.001, treatment 66 of 155 (42.6%), control 183 of 608 (30.1%), OR converted to RR.

Pérez-Segura et al., 10/4/2021, retrospective, multiple countries, multiple regions, peer-reviewed, 23 authors.

Pre-admission acetylsalicylic acid therapy and impact on in-hospital outcome in COVID-19 patients: The ASA-CARE study

Sisinni et al., International Journal of Cardiology, doi:10.1016/j.ijcard.2021.09.058 (Peer Reviewed)

Retrospective 984 COVID-19 patients, 253 taking aspirin prior to admission, showing lower risk of respiratory support upgrade with treatment.

risk of death, 7.1% higher, RR 1.07, p = 0.65, treatment 93 of 253 (36.8%), control 251 of 731 (34.3%).

risk of death or respiratory support upgrade, 30.3% lower, RR 0.70, p = 0.01, treatment 253, control 731, multivariate.

Sisinni et al., 10/4/2021, retrospective, Italy, Europe, peer-reviewed, 18 authors.

Clinical Predictors of Mortality and Critical Illness in Patients with COVID-19 Pneumonia

Basheer et al., Metabolites, doi:10.3390/metabo11100679 (Peer Reviewed)

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

risk of death, 13.0% higher, RR 1.13, p < 0.001, treatment 45 of 140 (32.1%), control 29 of 250 (11.6%), adjusted, OR converted to RR, group sizes approximated (only percentages provided).

Basheer et al., 10/2/2021, retrospective, Israel, Middle East, peer-reviewed, 4 authors.

Treatments Associated with Lower Mortality among Critically Ill COVID-19 Patients: A Retrospective Cohort Study

Zhao et al., Anesthesiology, doi:10.1097/ALN.0000000000003999 (Peer Reviewed)

Retrospective 2,070 hospitalized patients in the USA, showing lower mortality with aspirin treatment.

risk of death, 43.0% lower, RR 0.57, p < 0.001, treatment 121 of 473 (25.6%), control 140 of 473 (29.6%), NNT 25, adjusted, PSM.

risk of death, 28.0% lower, RR 0.72, p = 0.03, treatment 473, control 1,597, adjusted, multivariable.

Zhao et al., 10/1/2021, retrospective, USA, North America, peer-reviewed, 6 authors.

Aspirin Is Related to Worse Clinical Outcomes of COVID-19

Kim et al., Medicina, doi:10.3390/medicina57090931 (Peer Reviewed)

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.

risk of death, 700.0% higher, RR 8.00, p = 0.03, treatment 6 of 15 (40.0%), control 1 of 20 (5.0%), PSM, prior aspirin use.

risk of mechanical ventilation, 433.3% higher, RR 5.33, p = 0.14, treatment 4 of 15 (26.7%), control 1 of 20 (5.0%), PSM, prior aspirin use.

risk of ICU admission, 433.3% higher, RR 5.33, p = 0.14, treatment 4 of 15 (26.7%), control 1 of 20 (5.0%), PSM, prior aspirin use.

risk of case, 33.4% lower, RR 0.67, p = 0.29, treatment 15 of 136 (11.0%), control 20 of 136 (14.7%), NNT 27, adjusted, OR converted to RR, PSM, logistic regression, prior aspirin use.

risk of death, 33.7% lower, RR 0.66, p = 0.22, treatment 14 of 124 (11.3%), control 23 of 135 (17.0%), NNT 17, PSM, aspirin treatment after diagnosis.

risk of mechanical ventilation, 102.2% higher, RR 2.02, p = 0.16, treatment 13 of 124 (10.5%), control 7 of 135 (5.2%), PSM, aspirin treatment after diagnosis.

risk of ICU admission, 90.5% higher, RR 1.91, p = 0.36, treatment 7 of 124 (5.6%), control 4 of 135 (3.0%), PSM, aspirin treatment after diagnosis.

Kim et al., 9/4/2021, retrospective, propensity score matching, South Korea, Asia, peer-reviewed, 7 authors.

Evaluation of low-dose aspirin use among COVID-19 critically ill patients: A Multicenter Propensity Score Matched Study

Al Harthi et al., Research Square, doi:10.21203/rs.3.rs-872891/v1 (Preprint)

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.

risk of death, 27.0% lower, RR 0.73, p = 0.03, treatment 98 of 176 (55.7%), control 107 of 173 (61.8%), NNT 16, adjusted, in-hospital mortality, multivariable Cox proportional hazards.

risk of death, 14.0% lower, RR 0.86, p = 0.30, treatment 95 of 176 (54.0%), control 97 of 175 (55.4%), NNT 69, adjusted, day 30, multivariable Cox proportional hazards.

Al Harthi et al., 9/3/2021, retrospective, propensity score matching, Saudi Arabia, Middle East, preprint, 20 authors.

Association of Pre-Hospital Antiplatelet Therapy with Survival in Patients Hospitalized with COVID-19: A Propensity Score-Matched Analysis

Chow et al., Journal of Thrombosis and Haemostasis, doi:10.1111/jth.15517 (Peer Reviewed)

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.

risk of death, 19.0% lower, RR 0.81, p < 0.005, treatment 1,280 of 6,781 (18.9%), control 2,271 of 10,566 (21.5%), NNT 38, adjusted, Kaplan Meier.

risk of mechanical ventilation, 2.8% lower, RR 0.97, p = 0.21, treatment 2,122 of 6,781 (31.3%), control 3,403 of 10,566 (32.2%), NNT 109.

Chow et al., 8/29/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 12 authors.

Acetylsalicylic Acid Compared with Enoxaparin for the Prevention of Thrombosis and Mechanical Ventilation in COVID-19 Patients: A Retrospective Cohort Study

Abdelwahab et al., Clinical Drug Investigation, doi:10.1007/s40261-021-01061-2 (Peer Reviewed)

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

risk of mechanical ventilation, 7.8% higher, RR 1.08, p = 0.93, treatment 11 of 31 (35.5%), control 6 of 36 (16.7%), adjusted, OR converted to RR.

Abdelwahab et al., 7/30/2021, retrospective, Egypt, Africa, peer-reviewed, 17 authors.

Effect of aspirin on short-term outcomes in hospitalized patients with COVID-19

Sahai et al., Vascular Medicine, doi:10.1177/1358863X211012754 (Peer Reviewed)

PSM retrospective 1,994 PCR+ patients in the USA, not showing a significant difference in mortality with aspirin treatment.

risk of death, 13.2% lower, RR 0.87, p = 0.53, treatment 33 of 248 (13.3%), control 38 of 248 (15.3%), NNT 50.

Sahai et al., 5/19/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 18 authors.

3219 hospitalised patients with COVID-19 in Southeast Michigan: a retrospective case cohort study

Mulhem et al., BMJ Open, doi:10.1136/bmjopen-2020-042042 (Peer Reviewed)

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.

risk of death, 13.9% higher, RR 1.14, p = 0.21, treatment 300 of 1,354 (22.2%), control 216 of 1,865 (11.6%), adjusted, OR converted to RR, Table S1, logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mulhem et al., 4/7/2021, retrospective, database analysis, USA, North America, peer-reviewed, 3 authors.

Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019

Chow et al., Anesthesia & Analgesia, doi:10.1213/ANE.0000000000005292 (Peer Reviewed)

Retrospective 412 hospitalized patients, 98 treated with aspirin, showing lower mortality, ventilation, and ICU admission with treatment.

risk of death, 47.0% lower, RR 0.53, p = 0.02, treatment 26 of 98 (26.5%), control 73 of 314 (23.2%), adjusted, Cox proportional hazards.

risk of mechanical ventilation, 44.0% lower, RR 0.56, p = 0.007, treatment 35 of 98 (35.7%), control 152 of 314 (48.4%), NNT 7.9, adjusted, Cox proportional hazards.

risk of ICU admission, 43.0% lower, RR 0.57, p = 0.007, treatment 38 of 98 (38.8%), control 160 of 314 (51.0%), NNT 8.2, adjusted, Cox proportional hazards.

Chow et al., 4/1/2021, retrospective, USA, North America, peer-reviewed, 38 authors.

Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients

Mura et al., Signal Transduction and Targeted Therapy, doi:10.1038/s41392-021-00689-y (preprint 3/31/2021) (Peer Reviewed)

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.

risk of death, 15.4% lower, RR 0.85, p = 0.08, treatment 527, control 527, OR converted to RR, aspirin only, control prevalence approximated with treatment prevalence, propensity score matching.

risk of death, 37.3% lower, RR 0.63, p = 0.001, treatment 305, control 305, OR converted to RR, famotidine and aspirin, control prevalence approximated with treatment prevalence, propensity score matching.

Mura et al., 3/31/2021, retrospective, database analysis, multiple countries, multiple regions, peer-reviewed, 6 authors.

The use of aspirin for primary prevention of cardiovascular disease is associated with a lower likelihood of COVID-19 infection

Merzon et al., The FEBS Journal, doi:10.1111/febs.15784 (Peer Reviewed)

Retrospective 10,477 patients in Israel, showing lower risk of COVID-19 cases with existing aspiring use.

risk of case, 27.6% lower, RR 0.72, p = 0.04, treatment 73 of 1,621 (4.5%), control 589 of 8,856 (6.7%), NNT 47, adjusted, OR converted to RR.

risk of death, 62.4% lower, RR 0.38, p = 0.51, treatment 1 of 21 (4.8%), control 6 of 91 (6.6%), NNT 55, adjusted, OR converted to RR.

time to viral-, 9.6% lower, relative time 0.90, p = 0.04, treatment 73, control 589, time to 2nd negative test.

time to viral-, 14.8% lower, relative time 0.85, p = 0.005, treatment 73, control 589, time to 1st negative test.

Merzon et al., 2/23/2021, retrospective, Israel, Middle East, peer-reviewed, 8 authors.

Effect of low-dose aspirin on mortality and viral duration of the hospitalized adults with COVID-19

Liu et al., Medicine, doi:10.1097/MD.0000000000024544 (Peer Reviewed)

Retrospective PSM analysis of 232 hospitalized patients, 28 treated with aspirin, showing lower mortality with treatment. There was no significant difference in viral clearance.

risk of death, 75.0% lower, RR 0.25, p = 0.03, treatment 2 of 28 (7.1%), control 11 of 204 (5.4%), adjusted, 60 days, KM, PSM.

risk of death, 81.0% lower, RR 0.19, p = 0.02, treatment 1 of 28 (3.6%), control 9 of 204 (4.4%), NNT 119, adjusted, 30 days, KM, PSM.

time to viral-, 1.9% higher, relative time 1.02, p = 0.94, treatment 24, control 24, PSM.

Liu et al., 2/12/2021, retrospective, propensity score matching, China, Asia, peer-reviewed, 8 authors.

Association of mortality and aspirin prescription for COVID-19 patients at the Veterans Health Administration

Osborne et al., PloS ONE, doi:10.1371/journal.pone.0246825 (Peer Reviewed)

Retrospective PSM analysis of pre-existing aspirin use in the USA, showing lower mortality with treatment.

risk of death, 59.4% lower, RR 0.41, p < 0.001, treatment 272 of 6,300 (4.3%), control 661 of 6,300 (10.5%), NNT 16, OR converted to RR, 30 days, PSM.

risk of death, 60.5% lower, RR 0.40, p < 0.001, treatment 170 of 6,814 (2.5%), control 427 of 6,814 (6.3%), NNT 27, OR converted to RR, 14 days, PSM.

Osborne et al., 2/11/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 6 authors.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis

Meizlish et al., American Journal of Hematology, doi:10.1002/ajh.26102 (Peer Reviewed)

Retrospective 638 matched hospitalized patients in the USA, 319 treated with aspirin, showing lower mortality with treatment.

risk of death, 47.8% lower, RR 0.52, p = 0.004, treatment 319, control 319, PSM.

Meizlish et al., 1/21/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 22 authors.

Mortality and pre-hospitalization use of low-dose aspirin in COVID-19 patients with coronary artery disease

Yuan et al., Journal of Cellular and Molecular Medicine, doi:10.1111/jcmm.16198 (Peer Reviewed)

Retrospective 183 hospitalized patients in China, 52 taking low-dose aspirin prior to hospitalization, showing no significant difference with treatment.

risk of death, 4.4% lower, RR 0.96, p = 0.89, treatment 11 of 52 (21.2%), control 29 of 131 (22.1%), NNT 102, OR converted to RR, mutivariate.

Yuan et al., 12/18/2020, retrospective, China, Asia, peer-reviewed, 6 authors.

Mortality Risk Factors among Hospitalized COVID-19 Patients in a Major Referral Center in Iran

Alamdari et al., Tohoku J. Exp. Med., 2020, 252, 73-84, doi:10.1620/tjem.252.73 (Peer Reviewed)

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

risk of death, 27.7% higher, RR 1.28, p = 0.52, treatment 9 of 53 (17.0%), control 54 of 406 (13.3%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Alamdari et al., 9/9/2020, retrospective, Iran, Middle East, peer-reviewed, 14 authors.

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Wang et al., Journal of Hematology & Oncology, doi:10.1186/s13045-020-00934-x (Peer Reviewed)

Retrospective 58 multiple myeloma COVID-19 patients in the USA, showing no significant difference with aspirin treatment.

risk of death, 57.7% lower, RR 0.42, p = 0.43, treatment 1 of 9 (11.1%), control 13 of 49 (26.5%), NNT 6.5, OR converted to RR.

Wang et al., 7/14/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

Association of previous medications with the risk of COVID-19: a nationwide claims-based study from South Korea

Huh et al., medRxiv, doi:10.1101/2020.05.04.20089904 (Preprint)

Retrospective database analysis of 65,149 in South Korea, showing significantly lower cases with existing aspirin treatment. The journal version of this paper does not present the aspirin results (only combined results for NSAIDs).

risk of case, 71.0% lower, RR 0.29, p = 0.001, treatment 8 of 543 (1.5%), control 5,164 of 64,606 (8.0%), NNT 15, adjusted.

Huh et al., 5/18/2020, retrospective, database analysis, South Korea, Asia, preprint, 10 authors.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption