VTE Risk Higher After Oxford/AstraZeneca COVID-19 Vaccine, Study Affirms

Venous thromboembolic (VTE) events are indeed increased after people get the COVID-19 vaccine from Oxford/AstraZeneca, but the absolute risk is low considering the proven effectiveness of vaccination and the continued spread of SARS-CoV-2 around the globe, researchers report in the BMJ.

After vaccination programs got underway, spontaneous reports of thrombotic events in people who had received the vaccine started coming in, with several European countries pausing its use in March due to the clots. The European Medicines Agency (EMA) examined the issue and concluded last month that there is a possible link between the Oxford/AstraZeneca vaccine and “very rare cases of unusual blood clots with low blood platelets,” a condition that has come to be known as vaccine-induced immune thrombotic thrombocytopenia (VITT). A similar signal has since been seen with the Janssen COVID-19 vaccine from Johnson & Johnson.

The EMA has said the benefits of vaccination outweigh the risks of side effects.

The current study aimed to quantify the potential risk in a more-systematic way using national registries from Denmark and Norway, finding an excess of 11 VTE events for every 100,000 vaccinations with the Oxford/AstraZeneca vaccine when compared with expected rates in the general population. There was no overall increase in rates of arterial events, but there were possible small increases in thrombocytopenia/coagulation disorders and bleeding.

This information was conveyed to regulators in the United States and Europe before publication in the BMJ, lead author Anton Pottegård, DMSc, PhD (University of Southern Denmark, Odense), told TCTMD. When addressing questions about the benefit-risk balance, Pottegård provided a nuanced perspective, saying that the answer has to consider many factors, such as the age of the person receiving the vaccine, the availability of other vaccines, and the COVID-19 situation in the country or local region.

In most scenarios, the first option will be the best option. Anton Pottegård

For instance, in Denmark, which has taken both the Oxford/AstraZeneca and Janssen shots out of its vaccination program, much of the elderly and high-risk population has already been immunized. There is currently a very low rate of SARS-CoV-2 transmission, and there are other vaccines available. In that case, it probably doesn’t make sense to take the VTE risks associated with the Oxford/AstraZeneca vaccine, Pottegård said. “But in very many other countries where rates of transmission are higher, where you are at higher risk of getting [COVID-19] and having a complicated course, this is not the case.”

He pointed out that the director-general of the Danish Health Authority has said that the benefit-risk balance might tip in favor of restarting use of the vaccine if there is a fresh wave of infections. “So this is highly context-dependent,” he explained.

Pottegård acknowledged that such a nuanced message can be difficult to convey to the public. “There is a very real risk that disseminating these findings does not add to health globally, but subtracts from health globally, which is obviously contrary to what we are trying to do as health researchers,” he said. “I really stress that this is new knowledge, or rather better quantifies the knowledge we have, but how this influences the risk-benefit profile is highly country- and context-dependent, and in very many cases this will still be an overall positive vaccine.”

Findings Beyond VTE ‘Largely Reassuring’

For the study, Pottegård et al used data from nationwide healthcare registries in Denmark and Norway. The analysis included 148,792 people in Denmark and 132,472 in Norway (median age 44 years; 78% women) who received a first dose of the Oxford/AstraZeneca vaccine between February 9 and March 11, 2021. Rates of arterial and VTE events, as well as thrombocytopenia/coagulation disorders and bleeding, were compared with expected rates derived from historical data from 2016 to 2019.

There were 59 VTE events observed versus 30 expected, for a standardized morbidity ratio (SMR) of 1.97 (95% CI 1.50-2.54). Cerebral venous thrombosis, which has been a focus of recent investigations around the Oxford/AstraZeneca and Janssen vaccines, was about 20 times more frequent than expected in the vaccinated cohort (SMR 20.25). The absolute risk was low, however, with 2.5 excess events per 100,000 vaccinations. In addition, there were significant increases in pulmonary embolism (3.4 excess events per 100,000) and “other” venous thrombosis (2.2 excess events per 100,000).

Overall arterial events were not increased in vaccinated people (SMR 0.97; 95% CI 0.77-1.20). There were no excesses in cardiac events or most cerebrovascular events, although there was significantly more intracerebral hemorrhage than expected (1.7 excess events per 100,000).

“For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients,” the investigators report.

There were fewer deaths than expected in the vaccinated cohort (15 vs 44), but Pottegård did not put too much stock in that finding, pointing to the likely influence of a “healthy vaccinee” bias. Generally, healthier individuals are offered vaccines, so the short-term risk of dying after getting one is low, as has been seen with flu shots. “Basically I don’t trust that finding very much,” Pottegård said.

Benefit-Risk Balance Still Tips in Favor of Getting the Shot

In an accompanying opinion piece, Paul Hunter, MBChB, MD (Norwich Medical School, University of East Anglia, Norwich, England), notes that the VTE risk estimates from this study are greater than those derived from pharmacovigilance reporting systems and delves into some of the reasons that might be the case.

The BMJ study depended on diagnostic codes to identify thrombotic events, so the researchers “have not been able to identify confirmed cases of thrombosis with thrombocytopenia, which is the syndrome specifically linked to vaccination,” he writes. “Similarly, Pottegård and colleagues would likely not have been able to identify thrombosis in people who had not had a vaccine and who were primarily admitted for COVID-19 and might not have been investigated for thrombotic events, or had those events recorded under a primary diagnosis of COVID-19.”

Even considering those issues, however, the results suggest the risk of thromboembolic events after receiving the Oxford/AstraZeneca vaccine is higher than indicated by pharmacovigilance reporting systems, Hunter says.

He stresses that that doesn’t change the conclusion “that the benefits of the Oxford/AstraZeneca vaccine far outweigh its risks for most age groups. It remains the case that for most age groups, the probability of surviving the year is much greater for people who accept any vaccine when offered than if they decline it. To decline a vaccine today because it is the Oxford/AstraZeneca or Johnson & Johnson vaccine in the hope of being able to get another vaccine sometime later carries a real risk of dying from COVID-19 before being able to get a preferred vaccine.”

And Hunter takes it a step further, saying that “those countries that delayed their own vaccination programs at a time of high transmission rates by declining to use available Oxford/AstraZeneca vaccines should know that their decision will have contributed to an increase in the number of avoidable deaths from COVID-19.”

Pottegård agreed that in most situations, people should not avoid getting the Oxford/AstraZeneca vaccine in the hopes of getting a shot from another manufacturer. “In most scenarios, the first option will be the best option.”

But this remains an active area of research, he said, pointing to the need for studies to assess thrombotic risks with the Janssen vaccine, to compare risks between different vaccines, and to explore how sex influences the likelihood of these events.

For now, Pottegård said, the message around the VTE risk associated with the Oxford/AstraZeneca vaccine should be: “We see a slightly higher rate of this than previously reported. Nevertheless, the absolute risk of this is very small, and whether this tips the balance of risk-benefit will be highly context- and country-dependent.”

Rafael Perera, DPhil (University of Oxford, England), and John Fletcher, MB BChir (The BMJ, London, England), who wrote an editorial accompanying the study, put the findings in context, pointing out that all of the available vaccines effectively reduce mortality from COVID-19. In addition, they note, COVID-19 itself is associated with a risk of cerebral venous thrombosis even greater than that observed in this study (an estimated 4.3 vs 2.5 excess events per 100,000 vaccinations).

In a pandemic scenario, Perera and Fletcher conclude, “the choice we nearly all face is between eventual SARS-CoV-2 infection or vaccination. The Oxford/AstraZeneca vaccine is clearly a good choice, despite the likely risks found by Pottegård and colleagues. Quantifying the comparative risk associated with other vaccines is now a research (and public health) priority.”