Risk of death and cardiovascular events following COVID-19 vaccination or positive SARS-CoV-2 test amongst adult Singaporeans during omicron transmission

Importance: Assessing population-wide risk-benefit ratio of COVID-19 vaccination remains relevant in the current era of Omicron endemicity and boosting. Assessments of mortality risk and cardiovascular events post-vaccination/infection were generally made prior to emergence of milder Omicron and booster rollout.

Methods: Retrospective cohort study from 6th January to 31st December 2022 (Omicron-predominant transmission), amongst adult Singaporeans aged ≥18 years. Cox regression models adjusted for demographics/comorbidities were used to estimate risk of all-cause mortality and cardiovascular events 0-180 days post-mRNA vaccination/SARS-CoV-2 infection, compared to >180 days post-mRNA vaccination. Risk periods post-vaccination were further stratified by presence/absence of SARS-CoV-2 infection in the preceding 180 days; similarly, risk periods post-infection were further stratified by vaccination in the 180 days preceding infection.

Results: 3,137,210 adults participated, with 2,047,008 vaccine doses administered (99 % being booster doses) and 1,189,846 infections. 23,028 deaths and 54,017 cardiac events were recorded. No elevated risk of all-cause mortality/cardiovascular events was observed across all age strata post-vaccination. Conversely, all-cause mortality post-infection remained elevated up to >180 days in older adults (≥60 years), compared to person-time > 180 days post-vaccination. For vaccine-breakthrough SARS-CoV-2 infection in older adults vaccinated <180 days prior, risk of mortality was only elevated up to 60 days post-infection, but not beyond. Elevated risk of cardiovascular events 1-2 months after any SARS-CoV-2 infection was observed across all age strata, with elevated risk observed in older adults >180 days post-infection (adjusted-hazards-ratio, aHR = 1.18, 95 %CI = 1.04-1.34). Preceding vaccination within 180 days prior to infection attenuated this risk, with no significantly elevated post-acute risk of cardiovascular events (>180 days: aHR = 1.10, 95 %CI = 0.95-1.07).

Conclusion: No increased risk of all-cause mortality or cardiovascular events was observed up to 180 days after any mRNA vaccination dose in the Omicron era; vaccination attenuated post-acute cardiovascular risk in older adults. The risk-benefit ratio of vaccination remained positive during Omicron.