iiinova — where your digital self keeps evolving

Richard Buka @richardbuka.bsky.social · 16/05/2025

Wonderful! Thank you. Scots is such a fascinating thing to listen to - just a beautiful illustration of how new languages develop

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Richard Buka @richardbuka.bsky.social · 09/03/2025

The latest episode of Don't Just Read the Abstract with is now up! We discuss the APPOINT-PNH trial of ictacopan, a proximal complement inhibitor and the first oral therapy for PNH. Available now on all podcast platforms.

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Richard Buka @richardbuka.bsky.social · 05/03/2025

Hugely excited for this webinar from Saskia Middledorp lead on sooo many pivotal studies in H&T. Part of HaemSTAR's research-focused 2 monthly webinar series hosted by the limbic Tues 25th March 08:15 - 09:00 GMT. thelimbic.com/uk/haematolo...

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Richard Buka @richardbuka.bsky.social · 07/02/2025

Extremely interesting! Antibodies against COVID-19 receptor binding domain are also anti-PF4/heparin antibodies - frequently platelet activating. 1st report I know of showing this phenomenon. Well done to authors @versitiresearch.bsky.social, reviewers, & editors @bloodportfolio.bsky.social

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Richard Buka @richardbuka.bsky.social · 03/02/2025

**NEW EPISODE** Pleased to release the latest episode of Don't Just Read the Abstract with Pip Nicolson. We discuss Kuhne et al.'s study in @bloodportfolio.bsky.social on the treatment of TTP without the use of plasma exchange. There will be a follow-up episode with an author interview.

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Richard Buka @richardbuka.bsky.social · 28/01/2025

Very cool study in @nature.com showing transfer of mutated mitochondria from cancer cells into tumour infiltrating T cells --> impaired T cell function and association with poor response to checkpoint inhibition. www.nature.com/articles/s41...

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Richard Buka @richardbuka.bsky.social · 07/01/2025

Thanks to @profmakris.bsky.social for invitation and editorial input and thank you to insightful, thoughtful reviewers who helped to improve the piece substantially. #andexanetalfa

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Richard Buka @richardbuka.bsky.social · 07/01/2025

7/ I conclude - some patients likely to benefit but we don't know who they are - probably those treated early. At the moment, lack of evidence for net clinical benefit makes me sceptical of all the options available.

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Richard Buka @richardbuka.bsky.social · 07/01/2025

6/ Thrombosis rates are high with andexanet alfa - statistically increased risk of thrombosis vs usual care. No mortality or disability benefit was shown (study underpowered for these) so we cannot know if there is net benefit.

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Richard Buka @richardbuka.bsky.social · 07/01/2025

5/ However, the lack of blinding & usual care control --> bias especially in context of surrogate endpoints - particularly the need for rescue therapy (which was part of the primary outcome). Need for rescue therapy was significantly better with andexanet in whole cohort analysis

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Richard Buka @richardbuka.bsky.social · 07/01/2025

4/ With a usual care control arm, blinding patients and physicians is impractical - given different methods of administration for PCC and andexanet, and the chaotic, time pressured situation. These trials are hard enough to run and recruit to.

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Richard Buka @richardbuka.bsky.social · 07/01/2025

3/ I argue that the usual care control arm is reasonable as evidence for PCC is scanty and is not licensed for FXa DOAC reversal.

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Richard Buka @richardbuka.bsky.social · 07/01/2025

2/ 530 patients, most with intracerebral haemorrhage randomised to andexanet or usual care in ANNEXA-I. Showed improved haemostatic efficacy with andexanet - a surrogate endpoint composed of haematoma expansion <35% at 12h, need for rescue therapy and change in NIHSS <7.

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Richard Buka @richardbuka.bsky.social · 07/01/2025

Pleased to share this perspective on andexanet alfa, now published in @rpth.bsky.social #openaccess🔓 rpthjournal.org/article/S2475-… I cover blinding, surrogate endpoints, clinical outcomes and thrombosis. A brief 🧵

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Richard Buka @richardbuka.bsky.social · 31/12/2024

Maybe the best option is going to be B-cell delivered FVIII gene therapy. Excited to see how this goes.

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Richard Buka @richardbuka.bsky.social · 12/12/2024

Making a mirror image of organisms doesn't sound like a good idea... Organisms made out of left handed DNA and right handed amino acids could evade our immune systems and have profound effects on the survival of life on earth. www.science.org/doi/10.1126/...

science.org

Confronting risks of mirror life

Broad discussion is needed to chart a path forward.

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Richard Buka @richardbuka.bsky.social · 09/12/2024

Sitting at the front for the Ernest Butler prize lectures at #ASH24. Spent last 10 reading about this remarkable physician scientist who discovered G6PD deficiency, X inactivation, Gaucher disease, pioneered BMT and coded reference manager software en.m.wikipedia.org/wiki/Ernest_...

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Richard Buka @richardbuka.bsky.social · 09/12/2024

They're planning on a pre-surgical trial against standard of care (which will be a messy control arm) so not going up against andexanet initially

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Richard Buka @richardbuka.bsky.social · 09/12/2024

Re antibodies, given it's a one off treatment for most, maybe not too worried although one would also worry about spreading of antibodies to endogenous FXa (although clearly unlikely and not seen with andexanet)

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Richard Buka @richardbuka.bsky.social · 09/12/2024

I think this is a promising agent but it's very different showing no thrombosis signals with d-dimer etc... than when you start giving it to real patients. The lack of effect on TFPI is reassuring though.

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Reposted by Richard Buka

Ben Samelson-Jones, MD, PhD @samelsonjones.bsky.social · 07/12/2024

#Ash24 #hemesky Very large datasets suggest factor 12 haploinsufficiency substantially reduce venous #thrombosis. Suggest intravascular pathological clot formation is molecularly different than extra vascular hemostatic clot formation?

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Reposted by Richard Buka

International Society on Thrombosis and Haemostasis @isth.org · 03/12/2024

Abstract submission for #ISTH2025 is OPEN! Tag someone who should definitely submit an abstract below⏬

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Reposted by Richard Buka

ProfMakris @profmakris.bsky.social · 28/11/2024

A large prospective study from Austria shows that bleeding is more frequent and is of more relevance than generally assumed. Paper is behind a pay wall. tinyurl.com/2tf8kfv6 #cancer #bleeding

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Thanks for reading. Check out Don't Just Read the Abstract podcast (on all major platforms). We have done a a two-part podcast on the ANNEXA-I trial.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Remember, the FAST trial of rFVIIa in spontaneous, non-anticoagulated intracerebral haemorrhage also found reduction in haematoma expansion, but no functional benefit and increased the risk of thrombosis. Tellingly, this is standard of care!

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Also, earlier data about andexanet showed thrombin generation being boosted to much higher than the baseline with andexanet. I wonder whether the TFPI effect is actually partly responsible for the effect on haematoma expansion - giving supranormal haemostasis.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Andexanet definitely reverses anti-FXa activity - very well. And gives improved thrombin generation compared to PCC. But look at the TFPI effect - sustained for many many hours, and likely the cause for excess thrombosis.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Reasons? (1) Just statistical noise - mRS was a post-hoc analysis and study was not powered for this. (2) Andexanet may “delay” rather than prevent deterioration – think tortoise and hare – they end up in the same place (3) stroke risk offsetting benefit of ⬇️haematoma expansion.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

You can see that in responding patients with mRS 0-3 at presentation, andexanet patients were more likely than usual care patients to have a worse mRS at 30 days. The p-values are mine (Fisher's exact test) - and are a bit naughty given this is a post-hoc analysis.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

In the published paper, there was no difference in mRS at 30 days. Next, we see some interesting data in the FDA (n=404) dataset. This analysis looks only at patients who those who were responders (patients with <35% haematoma expansion at 30 days).

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Richard Buka @richardbuka.bsky.social · 28/11/2024

So, whilst I agree that expansion is correlated with outcomes, it's not linear. Also, ANNEXA-I uses % change rather than absolute. There are issues relating to bleed volume etc... that I won't go into but long story short the stat above is a simplification.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

This is based on Delcourt et al. 2012 – a subanalysis of the INTERACT1 study - so these are hypertensive patients who are not anticoagulated. In this study, haematoma expansion was measured at 24h rather than 12.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

There were +++ comments about hematoma expansion being strongly correlated with outcomes. Often quoted is the statistic: every 1 mL expansion corresponds to a 5% increased risk of death/dependency at 90 days.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

Data not new but Kaplan Meier is useful. All cause mortality: 28% vs 26%, death due to index bleeding event: 5% vs 7% Many point out that 30 days is too short to look for survival effects of acute interventions but this is all we have to go on.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

First AZ presented (mostly) published trial data. Andexanet showed significant improvement in all parameters making up haemostatic efficacy but the only significant component was haematoma expansion. The visual representation is quite useful but nothing new here.

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Richard Buka @richardbuka.bsky.social · 28/11/2024

The other day, I summarised the new data on thrombotic events with andexanet alfa, presented to/by the FDA. Now, let's focus on new efficacy data A🧵

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Richard Buka @richardbuka.bsky.social · 25/11/2024

In the next couple of days, I’ll go over the new efficacy data - lots of stuff on mRS - and try to bring together lots of other thoughts on the subject. If you want to watch the whole FDA meeting, it's here: t.co/CLge9YUd28

t.co

https://www.youtube.com/live/xztpe5-d9eY

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Richard Buka @richardbuka.bsky.social · 25/11/2024

Thoughts: 1) Thrombotic events very concerning. FDA data -⬆️ rates and happen very early 2) If you give andexanet, strongly consider early (~24h) thromboprophylaxis 3) Avoid high dose andexanet (? give low dose instead) 4) Avoid in pts with hx of stroke, MI, or heart failure

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Richard Buka @richardbuka.bsky.social · 25/11/2024

Thrombosis rates are much higher in patients receiving high dose andexanet (as are death rates - more on efficacy in next thread)

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Richard Buka @richardbuka.bsky.social · 25/11/2024

Patients with history of heart failure, stroke or MI are at particularly high risk of thrombotic events.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

Interestingly, thrombosis rate in patients who did not receive any haemostatic treatment had a high thrombosis rate – 4/33 (12.1%) vs 11/232 (4.8%). May just be statistical noise or could be related to thrombotic risk factors and reasons why physicians did not give anything.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

In case you’re wondering – as expected rate of oral anticoagulation restart was low – ~10% by day 30 – might reflect treatment of patients with thrombotic events.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

At the 5-day mark, only 50% patients were on some kind of anticoagulation. This is probably reasonable as we know that 81% patients were mRS 0-3 at baseline (moderate disability) so a good proportion should be able to mobilise.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

Could thromboprophylaxis, prevent thrombotic events after andexanet? Firstly, I would not expect LMWH to prevent ARTERIAL events. Nevertheless, AHA guidelines recommend thromboprophylaxis in non-ambulatory patients after 1-4 days (2015 guideline), and 24-48h (2022 guideline).

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Richard Buka @richardbuka.bsky.social · 25/11/2024

To my mind, NOPE! The reason we see this pattern is because the events caused by andexanet happen really early - median 3.5 days vs 16 days with usual care. With andexanet, 17/35 events were in the first 3 days vs 1/16 with usual care.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

AZ presented striking data on thrombotic events and re-anticoagulation (refers to thromboprophylaxis). Suggests that if you give thromboprophylaxis, you can prevent andexanet-induced events. Is this correct?

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Richard Buka @richardbuka.bsky.social · 25/11/2024

FDA's own review of thrombotic events reported 12 extra cases – 9 in andexanet & 3 in usual care – that were not assigned as thrombotic by blinded committee. Sorry, I don’t have more info on this! Final figures (based on n=471 FDA safety set): 14.6% vs 6.9%, stroke 5% vs 0.4%.

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Richard Buka @richardbuka.bsky.social · 25/11/2024

The most important new data is on thrombotic events. In the published ANNEXA-I data, cases were adjudicated by a blinded committee – who said whether events were or were not thrombotic according to prespecified criteria.

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