COVID-19 Linked to Long-Term Risk of MACE, Especially Among Adults with non-O Blood Types

New data suggest adults with prior SARS-CoV-2 infection, especially those requiring hospitalization, are at an increased risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke, or all-cause mortality, for up to 3 years after infection, even without a history of cardiovascular disease (CVD).¹

A large analysis of UK Biobank data that included more than 10 000 adults infected with SARS-CoV-2 before vaccines were available showed that the risk of MACE was more than 2-times higher among those who had COVID-19 and nearly 4-times greater among those hospitalized with COVID-19 compared with individuals with no history of COVID-19 infection during the nearly 3-year follow-up.¹

In addition, findings published today in Arteriosclerosis, Thrombosis, and Vascular Biology, showed that an increased risk of MI or stroke among individuals hospitalized with COVID-19 “resulted from a genetic interaction with the ABO locus and was more pronounced in subjects with non-O blood types,” lead author James Hilser, MPH, a PhD-candidate at the University of Southern California Keck School of Medicine in Los Angeles, and colleagues said.¹

“Worldwide, over a billion people have already experienced COVID-19 infection. The findings reported are not a small effect in a small subgroup,” cosenior author Stanley Hazen, MD, PhD, chair of cardiovascular and metabolic sciences in Cleveland Clinic’s Lerner Research Institute, said in an American Heart Association (AHA) press release.² “The results included nearly a quarter million people and point to a finding of global health care importance that may translate into an explanation for a rise in cardiovascular disease around the world.”

Although it is known that COVID-19 is associated with acute risk of serious cardiovascular complications, such as MI and stroke, it is still unclear how long that risk lasts or what factors modulate this risk.¹

“Furthermore, whether certain subgroups of COVID-19 patients are at greater increased risk of adverse CVD events is not entirely clear, and whether or not any of these subgroups rise to the level of a coronary artery disease (CAD) risk equivalent has not been explored,” Hilser and colleagues explained.¹

Investigators identified 10 005 individuals from the UK Biobank with either a positive PCR test for SARS-CoV-2 or a hospital-based ICD-10 code for COVID-19 between February 1, 2020, and December 31, 2020. Vaccinated individuals were excluded from the analysis. Risk for MI and stroke following infection and hospitalization in the cohort was compared to risk among population controls already in the UK Biobank who never received a positive PCR test for SARS-CoV-2 or were never assigned a COVID-19 ICD-10 code during the study period (n = 217 730) and another propensity-matched cohort (n = 38 860) to reduce confounding due to preexisting risk factors. COVID-19 as a CAD-equivalent risk factor was also evaluated over 1000 days of follow-up, according to the study.¹

Findings¹

COVID-19 and risk for MACE. Researchers observed that SARS-CoV-2 infection at all levels of severity was associated with significantly higher risk of MI, stroke, or all-cause mortality over 1003 days of follow-up (HR 2.09, 95% CI 1.94-2.25; P < . 005) compared with those without SARS-CoV-2, and was especially higher among people hospitalized with COVID-19 (HR 3.85, 95% CI 3.51-4.24; P<.005). The association between MACE and COVID-19-associated hospitalization was consistent when compared with propensity-matched controls (HR 3.65, 95% CI 3.3-4.05; P < .0005).

Investigators noted that the risk for MACE remained elevated out to 1000 days follow-up among those hospitalized with COVID-19, even among those without CVD at the time of hospitalization (HR 7.04, 95% CI 6.25–7.92; P < .005).Compared with patients with CVD and no history of SARS-CoV-2 infection, those without CVD who were hospitalized with COVID-19 had an approximately 20% increased risk for MACE during follow-up (HR 1.21, 95% CI 1.08-1.37; P < .005), according to the results.

“Given the observation that COVID-19 represented a CAD equivalent, we next explored whether thrombotic risk could be modulated by the use of antiplatelet agents,” Hilser and colleagues noted. They found that thrombotic risk stayed elevated among primary prevention participants without known CVD who were hospitalized with COVID-19 and not on antiplatelet agents at the time of enrollment in the UK Biobank (HR 1.98, 95% CI 1.39-2.82; P < .005). By comparison, researchers added, the risk of MI or stroke was not significantly increased among primary prevention COVID-19 patients who were receiving antiplatelet agents.

“Taken together, these results demonstrate that, in the context of our UK Biobank data set, hospitalization for COVID-19 increased the risk of MACE among primary prevention subjects to the same degree as in COVID-19 negative subjects with preexisting CAD equivalent risk factors,” Hilser et al wrote. “Furthermore, our data suggest that thrombotic risk can potentially be mitigated by the use of antiplatelet agents.”

Genetic interaction with blood type. To assess whether thrombosis risk after SARS-CoV-2 infection was affected via interaction with genetic susceptibility factors, researchers analyzed the ABO blood type locus. They reported a significant genetic interaction between the ABO locus and hospitalization for COVID-19 (P_interaction = .01), with the risk of thrombotic events higher among individuals with non-O blood types (HR 1.65, 95% CI 1.29-2.09; P = .000048 compared with those with blood type O (HR 0.96, 95% CI 0.66-1.39; P = .82; P_interaction = .01).

“The results of our study highlight the long-term cardiovascular effects of COVID-19 infection. Given the increased risk of heart attack, stroke and death, the question is whether or not severe COVID-19 should be considered as another risk factor for CVD, much like Type 2 diabetes or peripheral artery disease, where treatment focused on CVD prevention may be valuable,” cosenior study author Hooman Allayee, PhD, a professor of population and public health sciences at the University of Southern California Keck School of Medicine, said in the AHA release.² “The results suggest that people with prior COVID infection may benefit from preventive care for cardiovascular disease.”

References:

1. Hilser JR, Spencer NJ, Afshari K, et al. COVID-19 is a coronary artery disease risk equivalent and exhibits a genetic interaction with ABO blood type. Arterioscler Thromb Vasc Biol. Published online October 9, 2024. doi:10.1161/ATVBAHA.124.321001
2. COVID-19 infection appeared to increase risk of heart attack & stroke up to 3 years later. News release. American Heart Association. October 9, 2024. Accessed October 9, 2024. https://newsroom.heart.org/news/covid-19-infection-appeared-to-increase-risk-of-heart-attack-stroke-up-to-3-years-later