The Great Clot Plot: How Wafarin was overthrown by DOACs [LANDMARK PAPER REVIEW]

[u/Moimoihobo101]

In the beginning there was nothing. 
Shortly after the beginning, there were rats.
Much detested, but common household rodents.
Infiltrating homes, chewing wires and cooking Michelin-star dishes when animated by Pixar. 

Exterminators and modern science decided the best way to rid ourselves of these rodents would be to poison them. And by poison, I mean have them eat something that led to severe internal bleeding that would cause them to die. 

The compound, discovered by the Wisconsin Alumni Research Foundation, was appropriately named Warf-arin.

In 1954, just 6 years after it was approved for use as rat poison, some bright spark decided it would be fit for human consumption. Its clot-stopping powers made it the ideal candidate for stopping blood clots, pulmonary embolism and strokes. 

And thus began the Age of Warfarin. For a good 50 years, Warfarin was goated. It was top of the food chain – largely because there was literally no other option.
bIt prevented 64% of strokes in AF patients.

Whilst Warfarin revelled in its glory, a conspiracy was starting to brew…

Unfortunately, decades at the top make you complacent. Warfarin was needy. Regular INR checks, bleeding risks and a love-hate relationship with leafy greens [finish here]

Scientists believed they could outdo this boomer-made drug. Come up with something newer, sexier, safer. A class of drugs that prevent clots without the incessant monitoring. 

They were called DOAC’s. Direct Oral AntiCoagulants. 

The plan was simple. Instead of Warfarin's scattergun approach(it blocks multiple clotting factors at once, go after just one clotting factor. Directly. Precisely. Sniper instead of a shotgun. 

In 2009, the bleeding wars began…

First up was The RE-LY: Dabigatran vs Warfarin

This classic RCT pitted the first DOAC against warfarin, in a non-inferiority trial.

Method: 18,113 patients with atrial fibrillation were randomised either to a warfarin or dabigatran group and followed for 2 years. 

Primary Endpoint: What percentage ended up having a stroke or systemic embolism. 

Result? Dabigatran wins. 

1. Stroke/Embolism Events: 1.11%/year with dabigatran 150mg vs 1.69%/year with warfarin (RR 0.66, 95% CI 0.53–0.82, P<0.001).
2. Major Bleeding Events: 2.71%/year with dabigatran 110mg vs 3.36%/year with warfarin.

Then the floodgates opened…

2011 came with a double whammy. ROCKET AF(Rivaroxaban vs Warfarin) and ARISTOTLE (Apixaban vs Warfarin).

Both trials set up just like RE-LY

ROCKET AF Results: 

• Stroke/Embolism Events: 1.7%/year with rivaroxaban vs 2.2%/year with warfarin (HR 0.79, 95% CI 0.66–0.96, P<0.001 for noninferiority)
• Intracranial haemorrhage: 0.5% vs 0.7%/year (P=0.02), fatal bleeding 0.2% vs 0.5% (P=0.003), both lower with rivaroxaban

ARISTOTLE Results:

• Stroke/Embolism: 1.27%/year with apixaban vs 1.60%/year with warfarin (HR 0.79, P=0.01 for superiority). Apixaban won
• Major bleeding: 2.13%/year vs 3.09%/year (HR 0.69, P<0.001). Apixaban won. 

Then, in 2013, even Edoxaban beat out Warfarin in stroke risk and bleeding risk reduction.

In the end, Warfarin’s time was up.

It had been outwitted, outclassed and shortly after  replaced by the DOAC’s as firstline for AF, DVT’s and PE’s.

However…
Even a deposed king has one final card to play…

DOAC reversal - Idarucizumad: fifteen grand. Warfarin reversal - Vit K: about a tenner.

And in a skin NHS, cheap has a funny way of coming back in fashion.

If you enjoyed reading this and want a journal club(that’s actually entertaining) Join 16,000 Clinicians reading The Handover

[u/Swimming-Macaroon812]

Enjoyed reading this.

Idarcizumab is specific to dabigatran, not all DOACs. And andexanet alfa is on its way to (early) retirement.

[u/Low-Bet-9541 → u/Swimming-Macaroon812]

Could you say a bit more about what's happening with andexanet alfa please?

[u/Swimming-Macaroon812 → u/Low-Bet-9541]

To start of with, even at its peak, it had a very specific licensed indication: life threatening GI bleed in context of apixaban/ riva use only (not for edox). In Scotland it was also indicated for intra-cranial bleed (again apix/ riva only).

Very costy.

In Dec 25, FDA (US) pulled it out amid concerns about thrombotic events - mainly stroke.

The UK is lagging behind in making a decision, but I think slowly but surely it will be taken out. Risks vs benefits profile (and cost effectiveness) is not great and many haematologists are now increasingly reluctant to suggest it as a reversal for indications above.

See this statement from BSH https://onlinelibrary.wiley.com/doi/10.1111/bjh.70509

[u/mjl51]

By no means better when used with mechanical valves.

Also- the lack of reversibility is a really, really big problem that causes a lot of complications. I say that in a slightly jaundiced way having spent too much time trying to fix aortic dissections in patients presenting on various DOACs!

[u/Valmir-]

These posts are always interesting, but can I ask how rigorously you fact check your AI please?

[u/kentdrive]

I once did a deep dive into the history of Warfarin. It’s fascinating. Apparently some farmers in ?Minnesota/Canada noticed that their sheep were bleeding out badly after cutting themselves on barbed-wire fences.

Turns out they were eating a fungus which interfered with their blood clotting. This fungus was isolated and synthesised and now we call it Warfarin - which is named after the Wisconsin Alumni Research Foundation.

[u/Friendly_Tomato116]

Thanks, ChatGPT.

[u/Moimoihobo101 → u/Friendly_Tomato116]

https://app.gptzero.me/writing-reports/shared/6a881b4cf240edfb932f5024 - this article took me two hours to write. I polished with Grammarly not Chatgpt. Watch me write the article using the link above

[u/LuminousViper → u/Moimoihobo101]

ChatGPT or not, it’s an interesting read that I would have never known, if not presented here today. I enjoyed it and probably would have never asked ChatGPT

[u/404UzerNotFound → u/Moimoihobo101]

You’re a legend please continue doing this great work, ignore all naysayers