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A new study that systematically monitored rates of vascular and thromboembolic events in people receiving the AstraZeneca COVID-19 vaccine has found it to be associated with a rate of cerebral venous sinus thrombosis (CVST) of 1 in 40,000.
Using national health records, the researchers identified rates of arterial and venous events in a cohort of 282,572 people aged 18-65 years within 28 days of receiving a first dose of the AstraZeneca vaccine in Denmark and Norway from February 2021 through to March 11, 2021 and compared these with expected rates in the general population of the same age and sex.
Results showed seven cases of CVST in the vaccinated cohort.
“If we monitored this number of people in this age range over 28 days, we would expect to see 0.3 cases of CVST. We found a rate 20 times higher than that, which translates to 1 excess case in every 40,000 people vaccinated,” lead author Anton Pottegård, PhD, told Medscape Medical News.
“When we first saw this figure, it was much higher than the estimates being reported from spontaneous reporting systems with the vaccine,” Pottegård, who is professor of pharmacoepidemiology and clinical pharmacy at the University of Southern Denmark, Odense, commented.
“But now actually the most recent rates of this adverse effect from spontaneous reports are not so out of line with our figures. The official European Medicines Agency (EMA) rates are now about 1 in 50,000 for individuals aged 20 to 49,” he added.
Pottegård explained that spontaneous reporting systems are useful to find a signal of an adverse event, but they are not reliable for an accurate risk quantification as the adverse events are often underreported and there are usually delays in events being reported. “Our estimate will be more reliable as we are systematically collecting data on this,” he said.
“Early on, we thought CVST was a very rare occurrence — with figures of 3 or 4 in a million being reported, but now it looks like our estimate of 1 in 40,000 is more realistic,” he added.
The study was published online May 5 in BMJ.
Risk/Benefit Varies
Whether or not the risk of CVST outweighs the benefit of the vaccine depends on transmission rates of COVID-19 in each individual country and each individual’s own risk of a poor COVID outcome, Pottegård said. “The benefit of the vaccine will still likely outweigh the risk for most people when transmission rates are high,” he added.
Noting that Denmark is no longer using the AstraZeneca vaccine, Pottegård explained the decision was made in the context of a low rate of COVID-19 transmission. “We have vaccinated all high-risk groups and frontline workers and we still have quite strict restrictions in place, so there is a low rate of virus transmission. In this situation, the value of the vaccine is lower, so it makes less sense to risk a serious adverse effect like this. But in countries where there is a high rate of transmission that decision may be different,” he commented.
In the current study, all seven cases of CVST identified after administration of the AstraZeneca vaccine occurred in women. But Pottegård pointed out that the vaccine was mainly used in healthcare workers and 80% of the population vaccinated in this study were women. “As such, we cannot yet conclude whether this risk is or is not related to sex,” he said.
He noted that all the initial cases of CVST with the Janssen/Johnson & Johnson vaccine reported in the United States have also been in women, but latest data from spontaneous reporting in the UK (which has the highest use of the AstraZeneca vaccine) have shown 209 cases of CVST linked to the vaccine of which 87 occurred in men.
In an accompanying editorial, Rafael Perera, DPhil, professor of medical statistics at the University of Oxford, UK, and John Fletcher, MB BChir associate editor of BMJ, say that interpretation of the findings as either reassuring or concerning “depends critically on the type of comparisons.”
Pointing out that all vaccines against COVID-19 reduce mortality from COVID-19 substantially, and while the absolute magnitude of this benefit varies with the proportion of people exposed to infection over time, the editorialists state, “we do know from vaccine trials that mortality reduction far outweighs any risk of adverse events.
“We also know that COVID-19 is itself associated with cerebral venous thrombosis — an estimated 4.3 events per 100,000 infections, which is higher than the 2.5 per 100,000 reported by Pottegård and colleagues,” they add.
They say that comparing vaccine adverse event rates to background population rates is appropriate for rare diseases, as most people are never exposed to the disease but are exposed to risk of adverse events if vaccinated. But they add that the situation is different in a pandemic: most people are at risk of serious harm from infection, so comparisons with an unexposed population are less appropriate.
The editorialists also make the point that too few adverse events were observed in the study for a definitive answer. “While subgroup analyses hinted at particularly high risk of thromboembolic events among women younger than 45, lack of a discernible effect in other groups, including men, might be due to the study’s lack of power,” they write.
“The choice we nearly all face is between eventual SARS-CoV-2 infection or vaccination,” they conclude. “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.”
In an accompanying opinion piece, Paul R. Hunter, MB ChB, MD, professor of medicine at the University of East Anglia, Norwich, UK, says the new study “does not change the conclusions of both the EMA and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) that the benefits of the Oxford-AstraZeneca vaccine far outweigh its risks for most age groups.”
He states: “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.
“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,” Hunter concludes.
Other results from the study showed no increased rate of arterial events after the AstraZeneca vaccine, but there was an increased risk of venous thromboembolic events, equivalent to 11 excess events per 100,000 vaccinations.
Subgroup analysis suggested a higher excess of venous thromboembolic events in younger people: 13 excess events per 100,000 vaccinations among those aged 18-44 years versus 9 excess events per 100,000 vaccinations among those aged 45-65 years.
The researchers also found a lower death rate in the vaccinated population than would be expected based on the general population mortality rates, a finding the authors attribute to bias in that individuals with severe comorbidities or known terminal illnesses would not generally have received the AstraZeneca vaccine in Denmark or Norway.
There was no funding for this study. The authors have reported no conflicts of interest related to this work. Hunter has reported funding from the National Institute for Health Research (NIHR) Health Protection Research Unit in Emergency Preparedness and Response at King’s College London, in partnership with Public Health England and collaboration with the University of East Anglia. Perera has reported part funding from the NIHR, NIHR Oxford Biomedical Research Centre, NIHR Oxford and Thames Valley Applied Research Collaborative, NIHR Oxford Medtech and In Vitro Diagnostics Co-operative, and the Oxford Martin School.
BMJ. Published online May 5, 2021. Full text, Editorial, Opinion
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