Abstract
Taken from the largest U.S. cohort of patients with SARS-CoV2, our results demonstrate the association of even partial vaccination with lower risk of MACE after SARS-CoV-2 infection.
What is the clinical question being addressed?
How does vaccination impact the occurrence of MACE in patients developing SARS-CoV-2 infection?
What is the main finding?
Either partial or complete vaccination is associated with a lower risk of MACE after SARS-CoV-2 infection.
SARS-CoV-2 infection increases the risk of major adverse cardiac events (MACE) and long-term cardiovascular sequelae after recovery.1 However, the association of vaccination on cardiovascular outcomes following infection has not been elucidated in the United States. We investigate association between vaccination and MACE among patients with prior SARS-CoV-2 infection.
Using data from the National COVID Cohort Collaborative (N3C), we included patients aged 18 to 90 years who were initially infected with SARS-CoV-2 between March 1, 2020, and February 1, 2022.2 Starting from the first day following initial infection, the follow-up time was 180 days. We considered mRNA vaccines by Pfizer-BioNTech and Moderna and viral vector vaccines by Johnson and Johnson. Individuals were classified as fully vaccinated if they received ≥2 mRNA vaccines or 1 Johnson and Johnson vaccine ≥14 days before SARS-CoV-2 infection and as partially vaccinated if they received only 1 mRNA vaccine or their second mRNA or 1 Johnson and Johnson vaccine within 14 days of infection. Previous work suggests that COVID-19 vaccination may be associated with cardiovascular events within a few days.3 Although causality is unclear,4 we assess risk of MACE 14 days following last recorded vaccination to address this possibility and mitigate survivor bias. We excluded patients with ≥5 vaccine doses. We defined MACE by a composite set of diagnostic codes (OMOP codeset ID: 516422864). This study was approved by the Institutional Review Board at Mount Sinai.
We compared characteristics between individuals with and without MACE through the chi-square test. We used Cox proportional hazards to assess vaccination association with MACE. We adjusted for demographic characteristics, months since January 20, 2020 (first U.S. COVID-19 case), and comorbidities, classified by ≥2 entries on separate calendar days in patients’ electronic health record, that were significant in univariate analyses to calculate adjusted HRs (aHR) and 95% CIs.
Among 1,934,294 patients, mean age was 45.2 years, and 55.9% were women. In total, 1,573,036 (81.3%) were White, 45,723 (2.4%) were Asian, 300,031 (15.5%) were Black, 12,324 (0.6%) were “other,” and 3,180 (0.2%) were Native Hawaiian or Pacific Islander. A total of 195,136 (10.1%) patients were fully vaccinated, 22,707 (1.2%) were partially vaccinated, and 1,716,451 (88.7%) were not vaccinated. Overall, MACE was observed among 13,948 patients (0.7%): 12,733 cases occurred among nonvaccinated patients (0.7% of these patients), 160 in partially vaccinated patients (0.7%), and 1,055 in fully vaccinated patients (0.5%).
From index infection, median time to MACE was 17 days (IQR: 3-67 days) (Figure 1A ). In total, 3,175 patients died following MACE. Patients with and without MACE had significant differences in comorbidities including previous MACE (29.1% vs 0.9%; P < 0.001), type II diabetes (33.9% vs 7.5%; P < 0.001), hyperlipidemia (50.7% vs 14.4%; P < 0.001), ischemic heart disease (40.6% vs 3.9%; P < 0.001), liver disease (4.0% vs 0.8%; P < 0.001), and obesity (29.4% vs 16.4%; P < 0.001). Cox proportional hazards model showed full (aHR of 0.59; 95% CI: 0.55-0.63) and partial (aHR of 0.76; 95% CI: 0.65-0.89) vaccination were associated with reduced risk of MACE (Figure 1B). Median time from last vaccination to MACE is 212 days (IQR: 133-293 days). Risk of MACE significantly increased with male sex; age, notably among patients ≥66 years of age; and comorbidities, especially previous MACE.
Figure 1.
Kaplan-Meier Curve and HRs for Subgroups Stratified by Vaccination Status
(A) Kaplan-Meier curve for patients with COVID-19, stratified by full (red), partial (green), and no (blue) vaccination. (B) Forest plot with subgroup analysis. MACE = major adverse cardiac events.
Our results are concordant with Kim et al,5 who analyzed data from the Korean registry and found full vaccination was associated with decreased risk of myocardial infarction and ischemic stroke after COVID-19. However, the distinguishing strength of our work is that it draws from the largest open U.S. database of COVID-19–positive cases and control subjects, with greater size and racial diversity. We also investigated partial vaccination and included Johnson and Johnson vaccines, whereas previous work considered mRNA only.
Limitations include unmeasured confounding variables and inability to factor in vaccines beyond those distributed in the United States. However, although this would increase the number of vaccinated individuals, included vaccines comprise most U.S. vaccinations. We also did not consider SARS-CoV-2 reinfections following index illness, because patients may present with positive tests for varying periods. Finally, we could not account for different SARS-CoV-2 variants underlying infection.
Footnotes
The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave covid.cd2h.org/enclave and supported by CD2H - The National COVID Cohort Collaborative (N3C) IDeA CTR Collaboration 3U24TR002306-04S2 NCATS U24 TR002306. Dr Chan has consultancy agreements with Vifor Pharma, Inc; has received research funding from the National Institutes of Health; has received honoraria from Fresenius; and is supported in part by National Institute of Diabetes and Digestive and Kidney Diseases career development grant K23DK124645. Dr Oh is supported by NIDDK Institutional National Research Service award T32DK007757. Dr Nadkarni has consultancy agreements with AstraZeneca, BioVie, GLG Consulting, Pensieve Health, Reata, Renalytix, Siemens, and Variant Bio; has received research funding from Goldfinch Bio and Renalytix; has received honoraria from AstraZeneca, BioVie, Lexicon, and Reata; has patents or royalties with Renalytix; owns equity and stock options in Pensieve Health as a cofounder and Renalytix; has received financial compensation as a scientific board member and advisor to Renalytix; serves on the advisory board of Neurona Health; and serves in an advisory or leadership role for Pensieve Health and Renalytix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. This research was possible because of the patients whose information is included within the data from participating organizations (covid.cd2h.org/dtas) and the organizations and scientists (covid.cd2h.org/duas) who have contributed to the on-going development of this community resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the N3C program.
Fabio Lima, MD, MPH, served as Guest Associate Editor for this paper. Athena Poppas, MD, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Xie Y., Xu E., Bowe B., Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28:583–590. doi: 10.1038/s41591-022-01689-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Haendel M.A., Chute C.G., Bennett T.D., et al. The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment. J Am Med Inform Assoc. 2021;28:427–443. doi: 10.1093/jamia/ocaa196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hana D., Patel K., Roman S., Gattas B., Sofka S. Clinical cardiovascular adverse events reported post-COVID-19 vaccination: are they a real risk? Curr Probl Cardiol. 2022;47 doi: 10.1016/j.cpcardiol.2021.101077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Shimabukuro T.T., Nguyen M., Martin D., DeStefano F. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS) Vaccine. 2015;33:4398–4405. doi: 10.1016/j.vaccine.2015.07.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kim Y.-E., Huh K., Park Y.-J., Peck K.R., Jung J. Association between vaccination and acute myocardial infarction and ischemic stroke after COVID-19 infection. JAMA. 2022;328(9):887–889. doi: 10.1001/jama.2022.12992. [DOI] [PMC free article] [PubMed] [Google Scholar]