Large Study Confirms Clot Risks With Oxford/AstraZeneca COVID-19 Vaccine

In line with prior studies, a new analysis based on data from three Nordic countries affirms that the adenovirus-based Oxford/AstraZeneca COVID-19 vaccine is associated with greater risks of thromboembolic events—particularly cerebral venous thrombosis (CVT)—and thrombocytopenia.

The mRNA-based vaccines from Pfizer/BioNTech and Moderna also were associated with higher rates of certain events, although the absolute risks were small and the relationships were not as consistent as seen with the Oxford/AstraZeneca shot, researchers led by Jacob Dag Berild, MD (Norwegian Institute of Public Health, Oslo), report.

“Confirmatory analysis on the two mRNA vaccines by other methods are warranted,” they write in a paper published online this week in JAMA Network Open.

In March 2021, a few months after the first COVID-19 vaccines started rolling out, there were reports of patients with thromboembolic events coupled with thrombocytopenia—a condition since named thrombosis with thrombocytopenia syndrome (TTS) or vaccine-induced immune thrombotic thrombocytopenia (VITT)—associated with the Oxford/AstraZeneca vaccine, leading several European countries to suspend its use.

Multiple studies have confirmed the association, which also has been seen with another adenovirus-based vaccine, Johnson & Johnson’s Janssen vaccine.

Anders Hviid, DrMedSci (University of Copenhagen, Denmark), senior author of the current analysis, said his research group has published two prior analyses exploring the same issues, one published last year in the BMJ and another published earlier this year in the Annals of Internal Medicine.

“We’ve done three studies [using] different data sources and three different methods which each have their own strengths, advantages, [and] also of course some limitations, but they complement each other well and they basically come to the same conclusion, which is reassuring,” Hviid told TCTMD, referring to the strong association between thromboembolic events and thrombocytopenia seen with the Oxford/AstraZeneca vaccine and the lack of robust relationships with the mRNA vaccines.

These outcomes are rare. . . . That’s the main takeaway. Anders Hviid

For the current analysis, the investigators examined individual patient-level data from national registries in Denmark, Finland, and Norway. They used a self-controlled case series design to compare the risk of CAD, coagulation disorders, and cerebrovascular disease in the 28 days following vaccination with the risk in a control period in 2020; each patient served as his or her own control.

Overall, there were 265,339 hospital contacts for the outcomes of interest between January 1, 2020, and May 16, 2021; 44% involved CAD, 35% cerebrovascular disease, and 21% coagulation disorders. During that time, more than 5.3 million people across the three countries were vaccinated with one or two doses of vaccine—80% Pfizer/BioNTech, 12% Oxford/AstraZeneca, and 8% Moderna.

During the 28-day postvaccination risk period, the rate of CAD was elevated for those receiving the Moderna vaccine (rate ratio 1.13; 95% CI 1.02-1.25), but not the Oxford/AstraZeneca (RR 0.92; 95% CI 0.82-1.03) or Pfizer (RR 0.96; 95% CI 0.92-0.99) shots.

Coagulation disorders were increased for all three vaccines: Oxford/AstraZeneca (RR 2.01; 95% CI 1.75-2.31), Pfizer/BioNTech (RR 1.12; 95% CI 1.07-1.19), and Moderna (RR 1.26; 95% CI 1.07-1.47). Similarly, rates of cerebrovascular disease were higher across shots: Oxford/AstraZeneca (RR 1.32; 95% CI 1.16-1.52), Pfizer/BioNTech (RR 1.09; 95% CI 1.05-1.13), and Moderna (RR 1.21; 95% CI 1.09-1.35).

The largest rate increases were seen among individuals receiving the Oxford-AstraZeneca shot—for CVT (RR 12.04; 95% CI 5.37-26.99) and thrombocytopenia (RR 4.29; 95% CI 2.96-6.20).

Even with that vaccine and for those events, however, these complications were rare, the authors indicate. “We estimated excess events per 100,000 doses for each outcome, demonstrating that although the RR is significantly increased, the absolute risk is low. For example, the excess number of thrombocytopenic and CVT events following [Oxford/AstraZeneca] vaccination are estimated to be 4.9 (95% CI 2.90-6.90) and 1.6 (95% CI 0.60-2.60) per 100,000 doses.”

Moreover, because the relative increases in the rates of various outcomes were smaller with the mRNA vaccines, not consistently observed across countries, and not robust across sensitivity analyses, those findings “should be interpreted with caution,” Berild et al write.

Speaking with TCTMD, Berild said about the mRNA vaccines that “we need to continue monitoring their safety profile.”

Indeed, he said, “this is only a part of the big puzzle. What we find here needs to be replicated in other countries with other designs in other populations before we can put all the pieces together and finally conclude on the safety.”

For now, both Berild and Hviid agreed that the risks identified in this study shouldn’t discourage anybody who hasn’t been vaccinated from doing so. “These outcomes are rare,” Hviid said, noting that the occurrence of myocarditis after receipt of one of the mRNA vaccines has been shown to be infrequent as well. “That’s the main takeaway.”

But as the pandemic continues, there’s a need to continue monitoring the safety of the vaccines, Hviid said, pointing to unknowns around third and fourth doses and effects in individuals with hybrid immunity from vaccination and a prior SARS-CoV-2 infection. “There’s still a lot to look at and keep vigilant about,” he said.