Why calculating the risk of the AstraZeneca vaccine is so difficult

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Both the European Medicines Agency and the UK Medicines and Health Products Regulatory Authority have concluded that there is a possible link between the AstraZeneca vaccine and rare forms of blood clotting. However, the reactions of different countries to these results varied widely.

Denmark has withdrawn the vaccine entirely. In Germany, the vaccine is only given to those over 60, while France has decided that children under 55 should receive a different COVID vaccine for their second dose. In the UK, however, the authorities have not ordered any action. All they said was that it would be preferable to offer an alternative vaccine to children under the age of 30 whenever possible.

These are very different positions. So how can we understand them? How risky is the vaccine? Unfortunately, it is difficult to come to a final conclusion and this may explain some of these differences between countries. Here’s why it’s so challenging.

Calculate risk

Two specific coagulation disorders have been linked to the AstraZeneca vaccine: cerebral venous sinus thrombosis (CVST), in which clots form in the veins that drain blood from the brain, and splanchnic vein thrombosis (SVT), in which clots form form in the abdominal veins. They coincided with people with low platelet counts (thrombocytopenia), with CVST being more common.

To determine the risk of the vaccine, the key question is: do a higher percentage of people develop these rare clots after receiving the vaccine than they normally do? The following is known so far.

As of April 4, 34 million doses of AstraZeneca had been administered in Europe, with 169 cases of CVST and 53 cases of SVT reported. In the UK, 20 million doses had been administered by the end of March, including 54 CVST and 25 SVT cases. Taken together, this equates to about one case of CVST per 240,000 doses and one case of SVT per 690,000 doses.

A commonly cited estimate for the background incidence of CVST is about one case per 200,000 people per year. Given the higher CVST rate after vaccination and the introduction of the rollout for only a few months, this indicates an increased risk of coagulation.

To put this into context, if every person in Ireland (5 million residents) were to receive the vaccine, for example, we could expect around 21 cases of CVST. That would probably be on top of the 25 cases we would expect each year without vaccination anyway. So the overall risk is very low.

However, the comparison of such estimates is subject to significant limitations.

First, post-vaccination CVST appears specifically to coincide with low platelet counts. This is a novel phenomenon that has been given a specific name: vaccine-induced immune thrombotic thrombocytopenia. Usually CVST is not associated with immune-related thrombocytopenia. As a result, it may not be appropriate to compare CVST to what happens after vaccination – the conditions may be entirely different.

In addition, CVST is rare, which in itself makes background estimates uncertain. While the above background rate is frequently referred to, others exist and some are significantly higher. The incidence of CVST can also vary with age, gender, and other risk factors. For example, the oral contraceptive pill has been linked to a seven-fold increase in the risk of CVST in women aged 15 to 50.

This may be particularly relevant as the AstraZeneca vaccine has been disproportionately administered to younger female populations in some countries. In Germany, for example, the vaccine has been offered to medical staff and teachers, who are usually female. Some of the risk of CVST seen with the vaccine could be due to a higher underlying risk in the recipients.

Another potential problem is that COVID-19 itself has also been linked to an increased risk of clotting and low platelets (in fact, early research pending review by other scientists suggests the risk of developing CVST after COVID-19 could be eight to ten times it is after vaccination). Therefore, the pandemic can also increase the underlying risk of these rare blood clots.

It is also possible that the vaccine could trigger CVST in patients who have an underlying predisposition to developing the disease, which means that some post-vaccination cases will occur in patients who would have developed the disease anyway. All of these factors make the risk assessment of the vaccine uncertain.

What to do?

In the meantime, a pragmatic approach could be to compare the potential risk of these rare blood clots with the risk of COVID-19.

All approved vaccines, including the AstraZeneca vaccine, provide excellent protection against both severe and fatal COVID-19. The risk of severe COVID-19 is lower in young people and also decreases for everyone when the amount of virus circulating in the population is lower. Even so, the UK government calculates that in almost all cases the risk-benefit ratio still favors the use of the AstraZeneca vaccine. Only when the risk of exposure to the virus is low is there any benefit to those under the age of 30 not ingesting it.

It’s also worth noting that COVID-19 can still kill among the young. In the UK, it is estimated that one in 2,500 people aged 25 to 44 who receive COVID-19 will die – 400 times the death rate from vaccine-related blood clots in the UK. If you are at a higher risk of contracting the virus, possibly because of your work, then taking the vaccine makes sense.

Also, be aware that other COVID-19 vaccines can also carry risks that may not arise until after broader use. For example, anaphylaxis has been reported after one in 90,000 Pfizer vaccine doses, and the Johnson & Johnson vaccine can also cause blood clots.

If the association between coagulation events and these vaccines is confirmed and it is shown that this risk is predominantly in specific groups, the use of alternatives in risk groups would be appropriate. In the meantime, remember that no decision is safe and that not taking a COVID-19 vaccine is also a risk.

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