Thread by @holmanm

1/16 A mainstream Cardiologist who is aware of how essentially all lipid lowering trials have bombed and that Statins, whatever small benefit they show in drug company funded 2nd prevention trials, probably don't work by LDL lowering.

The letter, shows some Cardiologists care:

2/16 Dear FDA: Resist the Urge on PCSK9 Drugs

Last week, an FDA advisory committee recommended approval of two (PCSK9)–inhibitor drugs. A formal decision is expected later this summer. The FDA usually follows the advice of its advisory committees, but not always.

3/16 This is a big moment in Cardiology. It is also a huge gamble for the FDA.

I believe the FDA should break with its advisory committee and say NO !!.

Not yet. It's too early to unleash these drugs on American patients and doctors.

Here are four reasons.

Target Confusion

4/16 The first reason the FDA should say no (not yet) is the target. PCSK9 drugs lower LDL cholesterol. That fact is clear. But our target is not a LAB VALUE; it's HEART disease

These factors, which affect individuals in genetically varied ways, accumulate over years, not months

5/16 LDL-C may be important, or very important, but it is just one risk factor. Even in patients with Familial Hypercholesterolemia, LDL-C may be one of many risk factors.

6/16 The stunning LDL-C lowering from PCSK9 drugs might prevent future heart attacks, strokes, and deaths. The key word in that sentence is MIGHT. We don't know. The biology of these drugs is beautiful, but that beauty should not obscure the current state of knowledge.

7/16 What we know now is that PCSK9 drugs are effective at LDL-C lowering. That is it. Period ! The OSLER[1] and ODYSSEY[2] trials were not powered to look at outcomes. Those data are forthcoming in the FOURIER trial, which has completed enrollment of 27,000 subjects,

8/16 and results are expected in 2017. Why not wait?

Do No Harm

(We did wait ! More patients died in the treatment arm than in the placebo arm of the trial)

9/16 The second reason the FDA should hold off is the risk. The mission statement of the FDA says its charge is to "protect the public health by [ensuring] the safety, efficacy, and security of human and veterinary drugs.

10/16 What I read into that is harm avoidance. In this way, I see the FDA's role as similar to a physician's. Yes, we want to benefit our patients, but the guiding principle must be to avoid harm. This is especially critical when treating people

11/ 16 for something (an MI, stroke, or death) that has yet to happen. Having a high risk for a disease is not the same as having a disease.

It is true; in the OSLER and ODYSSEY studies, evolocumab (Repatha/Amgen) and alirocumab (Praluent, Sanofi/Regeneron) looked reasonably

12/ 16 safe. But follow-up was only 11 months in OSLER and 78 weeks in ODYSSEY. That's too short. Heart-disease prevention is not a 2-year endeavor. !!!

In both studies, more patients on the PCSK9 inhibitor reported neurocognitive effects. That may be significant.

13/16 Is it implausible to think cholesterol might be important for brain cells? Here, let's also be mindful of euphemism. "Neurocognitive function" is a fancy way to say "think." Thinking is what makes us human. So if we think of this issue from a patient-centered standpoint,

14/16 How many humans would trade a dull mind for a possible benefit 2 to 10 years in the future???

The third reason the FDA should say no is historical. The use of surrogate markers for cardiac drugs has proven to be a bad gamble. We can point to niacin, fibrates and

15/ 16 cholesteryl ester transfer protein inhibitors as evidence of that failure. The case of ezetimibe is hardly supportive of the LDL-C hypothesis. In the IMPROVE-IT trial, the tiny absolute benefit of ezetimibe (composite end point) was achieved against Simvastatin

16/16 A straw-man comparator if there ever was one.

Distractions—Benefits Missed 🤬

@migib20 you may like this thread !