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A few responses:
1. It isn't just about deaths (from TTS or COVID) as both can cause long term health sequelae - eg stroke from CVST, extensive intestinal resection after splanchnic vein thrombosis, clotting after COVID. There are also the benefits that are harder to quantify (eg protection of close contacts, contributing to the community, reduced anxiety about getting COVID). The other endpoints (hospitalisation, ICU) also have limitations - people are hospitalised with COVID for reasons other than severity (eg where a nursing home is evacuated), and few people >80 are admitted to ICU due to advance care directives.
2. As I noted, all the three data sources (EMA, UK/MHRA and Australian data) have their limitations - EMA don't use a case definition (if an adverse event report mentioned "platelet" it would included, even if it wasn't TTS), under- and over-ascertainment possible in both EMA and UK, and relatively smaller numbers in Australian dataset particularly <50 years.
3. Mortality estimates in the cited risk benefit document were based on last year (as indicated in the footnote - Australian first wave and Victorian second wave) where no people in the 20s died. Obviously this may be different with delta (as might vaccine effectiveness and age specific incidence/severity). But the largest source of uncertainty is the risk of COVID over the period of time between now (when AZ is available) and whenever Pfizer/Moderna/Novavax is widely available to all (Sept-Nov).
Op COVID SHIELD National COVID Vaccine Campaign Plan (health.gov.au)
4. Worth re-emphasising that we carefully used the word "prefer" and are trying to respect patient autonomy, recognising that how those <40 perceive risk and benefit is a personal decision. I saw a tweet from a younger person saying that there were happy to have AZ as she had been on the pill for acne since she was 15 and had done illicit drugs off a toilet seat (I'm paraphrasing). That's not to say that all young people would concur, but I suppose that puts a 1:20000-40000 risk of TTS into perspective for that person (although if I were her GP I might be considering a few non-judgmental words about risk taking and life choices).
The problem for a Victorian outsider is that the epidemic has been steadily spreading in size and geographic spread in Sydney and NSW. As correct as statements made by Ken about the risk of getting COVID19 are in certain parts of Sydney today and subsequently dying, there seems to be a big risk to assume that this situation will continue over the next few months. Further long-COVID may well be a life time condition so this compounds the risk of irreversible damage from COVID. So I personally hope ATAGI does not change the current advice - but then I've had COVID so this may bias my view.
I have worked through some of this. Using the EEA data the incidence in 20-29 is about 2.5 times the Australian TGA rate. So you can take the mortality rate that the TGA found of 3% and that gives 1.6 deaths per million. Similarly for 30-49 it is about double, giving 1.1 deaths per million. Then, you look at the NEJM paper and you see a death rate of 22%. The EEA paper has 52/269=19%. So have they only found more severe patients? Probably, yes. The UK adverse events reporting is known to be very poor. Most of the cases in the EEA actually come from the UK, but are not the subjects in the NEJM paper which is for a later time period. An interesting question is why the EEA has information on the age distribution of vaccination while the NEJM article doesn't? Maybe BREXIT mess. Anyway, if I apply a death rate of 19% to the EEA paper I get 10 deaths per million in 20-29 and 8 deaths per million in 30-49.
Compared to the mortality in the Victoria wave from last year, they look good. Now the difficult part. In Sydney most cases are in South Western Sydney and vaccination is a good idea. If someone is in one of the more affluent areas, the cumulative case rate is 1 in 1,000 or less, so assuming that doesn't differ too much across ages, the fatality rate is 2 in a million, using 2 deaths per 1,000 cases in 20-29 from Ian Marschner's paper. Much better to follow the social distancing rules rather than be vaccinated.
I feel that this really needs another look at the TGA and ATAGI data updated until now, and broken down by all the age groups under 50, and including deaths. I believe there has already been one death in the 30-39 group so it would be worthwhile. By October these age groups will probably be opened to Pfizer or Moderna anyway.
Article in NEJM today https://www.nejm.org/doi/full/10.1056/NEJMoa2109908 talks about mortality in VITT
As there are more under 60s currently being vaccinated with AstraZeneca and more data becomes available, the risk estimates (of severe TTS and death) will become more precise and less prone to bias from the early younger vaccinated group. My question is, are the people currently giving informed consent to take AstraZeneca, being informed by data that is appropriate to their age group? Especially the under 50s. Even if they are given a range rather than a point estimate like "Risk of death is 1 in a million".
Just to note that there have been three sources of data to estimate the rate of TTS following AZ vaccine.
1. The UK are using their own case definition but it is likely that early cases may not have been recognised or fully investigated; this is evident in the high mortality rate (initially 25%). However, they have administered >24m first doses of AZ allowing more precise estimates of risk to be made, particularly in younger age groups.
2. Australia is using the UK case definition but the preferential recommendation against AZ in those <50 (now <60) was made relatively early, so there are few cases from which to estimate risk in the younger age group from. The available data does suggest that the incidence and severity of TTS in those <60 is higher, albeit with considerable uncertainty.
3. The EMA are not using a case definition and have made estimates from a database search of the EU adverse event reporting. It is likely that there is overascertainment of TTS cases using this method, but the rates reported are similar to that observed in Australia (noting also that there may have been under-reporting of TTS before there was widespread awareness)
We did consider whether to use some sort of meta-analytical method to combine these sources of data. However, neither the UK or EMA provided sufficient information to permit this (ie numerators and denominators by age group). Additionally, a pooled estimate is rather difficult to explain to the public and we felt that it was better to report observed Australian notes, particularly as we were more confident in the assessment process and the rate is higher than what had been reported elsewhere.
The other major criticism that has been made is that the comparison between risks and benefits isn't solely quantitative and based only on severe TTS vs severe COVID - benefits such as contributing to community protection (and reducing the need for lockdowns), reducing transmission to close contacts and reducing anxiety about contracting COVID are valid, although someone subjective and hard to quantify.
Finally, just to note that TTS isn't only about mortality (and neither is COVID). TTS is a distinct syndrome from "usual" DVTs or PEs - the tier 1 cases (which are roughly half of those <60 years) mainly involve clots in the cerebral venous sinuses (ie stroke) or abdominal veins (often requiring extensive surgery). However, this needs to be weighed against the benefit of not getting COVID, which also causes clotting as well as a range of other complications.
There may be newer data by now, but there’s quite a detailed EMA assessment report from 24 March:
There is an analysis by age on p.19, actually looks like quite a strong association.
There have been about 4,000 cases in a population of close to 6 million in the lockdown area, so about 7 cases per 10,000. This will probably end up at about 3 times the current, if the residents of Canterbury-Bankstown decide to obey the rules. So about 2 per 1000. A consideration is that most of these cases are in a region of Sydney with a population of about 2 million, so they will have about 6 per 1000. A lot of Sydney will have less than 1 in a 1000 cases. I would be very surprised if it was sensible for young patients to have Astra Zeneca.
In the ATAGI risk calculations they have not included any confidence intervals. They comment that the numbers under 50 are small but don't actually say how small. These were special classes of patient, I think mainly health practitioners who were in Phase 1. You can however find the numbers in https://www.tga.gov.au/periodic/covid-19-vaccine-weekly-safety-report-17-06-2021 which is 1 for under thirties and 1 for 30-39. So for under thirties we have 1 case in 53,000 (working backwards) which gives a rate per 100,000 of 1.9 with a 95% CI of 0 to 10.5. For 30-39 we have 1 case per 63,000 which gives a rate of 1.6 per 100,000 with 95% CI of 0 to 8.8. In other words nobody has any idea what the rate is in under 40 year olds. It could be that the rate peaks in 40-49 year olds but it may also have a nice logistic relationship. Maybe someone should investigate the data from other countries.
I have to comment on the mortality risk from the AstraZeneca vaccine. Across all age groups there have been 6 deaths from approximately 6 first doses, so an incidence of 1 in a million, which is what is being reported in the media.
However, if you look at the 30-49 age group, who are currently being urged to receive AZ instead of waiting for Pfizer, a different picture emerges
According to the latest TGA and ATAGI reports, the incidence of TTS in <50s is 3.4 in 100,000, or 1 in 30,000. In the 30-49 year old age group, there have been 8 Tier 1 (serious) clots and 4 deaths (1/2 in 30-39, 3/6 in 40-49). So among those who contract TTS in this age group, there's a death rate of 50%, leading to an overall death rate of 1 in 60,000 first AZ doses, or 1.7 TTS deaths per 100,000. This is higher than the expected deaths in this age group from COVID-19 in a low or medium risk scenario in this risk-benefit document. It's only when the scenario changes to high risk (3,544 cases per 100,000 in 16 week period) that there is a clear benefit from the vaccine. Is this where NSW or the other states with outbreaks are at the moment?
There isn't a gender breakdown of the TTS incidence, but I expect the mortality rate would be even higher in women, since they have had 3/4 deaths in this age group (5/6 deaths in all age groups have been women).
Admittedly there have only been a small number of deaths and I haven't calculated confidence intervals, but this incidence rate is 16.7 times higher than 1 in one million.
For some reason I often don't get notifications of the posts. Anyway, I had a look at the data, and Sydney is basically 2 cities. One where the original outbreak started of Waverley, Woollahra and Randwick, which shows the epidemic being controlled, and western and south-western Sydney where it isn't and the main cause of this has been mentioned by public health as lack of compliance. This is changing, and now Fairfield is showing similar reduction in cases. I've attached a graph showing all the LGA in the lockdown area, except Manly, Mossman and Shellharbour which have had no cases since lockdown.
So essentially modelling doesn't work if you have not been lucky enough to guess compliance correctly. I thought that Melbourne's compliance last year was poor, but Sydney has been worse. The error that was made in NSW was trying to get contact tracing to work on its own, which allowed the virus to move into areas that were likely to comply poorly.
I've attached the code as .txt, because the forum software won't allow me to upload R files.
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