Let's take a close look at PARADIGM-HF

10 years later here is the original un-redacted debate between Milt Packer and myself

Ten years ago this September, I was a 3rd year fellow and read Paradigm HF. I knew immediately the trial was flawed.

Remember, the trial’s purpose was to get the novel drug sacubitril— a neprylsin inhibitor—approved. In a good trial, you would have taken patients with HFrEF (reduced EF) who happened to be on an ARBs and randomize them to the addition of sacubitril vs. placebo. A clean test of the new drug. That’s not what happened.

First, the sponsor tested a combo of 160mg BID of valsartan + sacubitril (Entresto) vs. Enalapril 10mg BID. The ARB was the maximal FDA approved dose, but the Ace-i was given at half maximal dosing.

Second, the trial employed an double drug in period. Entresto was given for twice as long (4 wks vs 2 wks enalapril), and ~20% of people fell off during run-in, limiting generalizability and removing people idiosyncratically intolerant to this hefty dose. No other cardiology registration trial ever did this.

Three, the control arm had to stop their medication and switch, while the intervention arm did not. Any penalty from switching (exacerbations b/c of changes) happened to the control arm.

Immediately afterwards, I circulated my criticism via email, and was asked to submit it to the CardioExchange website, which was run by Mass Med Society.

There was a fierce debate. Milt Packer, the trial principal investigator, argued with me. He made some interesting points. One was that in prior trials, the achieved dose of Enalapril was never the max dose. And that pushing the max dose didn’t offer that much benefit. But the mistake he made was ignoring the double drug run in period. If you ran in the max dose of Enalapril, you would guarantee everyone could take it, because those who couldn’t, wouldn’t be in the study. And in this group, we don’t know the impact of being on less than the max dose.

Milt also strayed from pure scientific criticism. He said a few times that I didn’t understand the literature very well, and he imagined a scenario where I had heart failure, and demanded to know if I would take sacubitril-valsartan.

The editoral team at CardioExchange deleted the original comments, and posted a summarized and edited version, which I can still find online. My original post appears to have disappeared entirely from the internet, but is on the way-back machine.

At the time, I agreed they could clean up the comments because I had not yet secured a faculty job, but now, 10 years later, I am a professor, so I would never agree. Things should remain on the internet, uncensored. In that spirit, I would like to make available the original argument, un-redacted. Feel free to save the PDF attached because lots of people want it to disappear.

But I also have a point to make about the difference in dialog from 2014 to 2024, read on. First, consider, some Packer highlights from 2014.

At the end, I replied

Now, you might expect me to say that had Milt Packer, a trial PI, responded to a fellow like this in 2024, the cancel culture mob would be out to get him, saying he engaged in punching down, and the like. And, I suspect there is truth to this. But that is not the point I want to make.

The point I want to make was that in 2014, the PI of a multimillion dollar study and a potential billion dollar drug took the time to debate a fellow posting a blog. The debate was spirited and went back and forth for days. That would never happen in 2024.

It wouldn’t happen because the company would leash the PI and say he can’t respond to comments, it would jeopardize their launch and discussions with regulators. It wouldn’t happen because the PI— aware of the cancel culture mob— would not even risk debating, even if infinitely civil and polite, lest it be misconstrued. The internet mob famously thought John Ioannidis was attacking Gideon-M-K, an epi student, in a paper when he described him as having big glasses and holding a cat, but those of us who know John understand that not in a million years would he criticize someone’s appearance— it is not his nature— instead, he was merely describing the gentleman’s photo. And yet, the mob came for him. PIs knowing the mob is out there are incredibly reluctant to take a chance.

Finally, the internet is more siloed. 10 years ago, there was just one space for doctors to speak, but now there are many forums, and many groupthink bubbles. Packer v. Prasad would never happen today because the Packers of the world and the Prasads don’t mix.

10 years ago, when I replied to an oncology PI saying incorrect things about their marginal drug, they would debate me in the comments, and to some degree that formed the basis of my early reputation as a faculty member.

But, 10 years later, they don’t debate. They mute and move on. They pick discussants at the conference who will cheerlead. Milt Packer wished (not really, wink wink) I had heart failure and had to take Entresto. So what? At least he had the courage to argue for his trial. To stand up and with a straight face and pretend a double drug run in period with unequal dosing is a-OK. I give him credit, and wish more were like him.

We would all be better off with a little thicker skin and a little more debate, rather than the current culture in medicine which eschews debate because feelings might be hurt or it might offended the weakest person in the audience.

Now, 10 years later, it is clear Packer is wrong. Death rates among those diagnosed with heart failure has increased from 2012 to 2021, and a new meta-analysis suggests that Entresto only works when the ace-i dosing is suboptimal. But the gold standard is a new trial. Someday one of us will be proven correct, I suppose.

I ended my post 10 years ago thanking Packer for participating. 10 years later, I feel the same way.

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PS: I am coming to debate Carlos Del Rio at Emory on Monday. Book your tickets here.

Paradigm Hf Original Thread

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