Dr Marc Sabatine from the Brigham and Woman's hospital just presented the FOURIER trial at the American College of Cardiology (ACC) 2017 Scientific Sessions[1].

The FOURIER investigators asked simple but important questions: Does the LDL lowering from the PCSK9 inhibitor evolocumab (Repatha, Amgen)) lead to better outcomes? And if so, how much better?

We already knew—from an Amgen press release—that top-line results of FOURIER were positive. Dr Sabatine told us the details.

Now we have to translate these results to the bedside. Every medical decision is a gamble. How will we explain this gamble to our patients? Deborah Brauser from heartwire on Medscape has excellent news coverage of the results.

Here are my initial (fast-writing) thoughts.

1. First, a general point on the current state of cardiology: the law of diminishing returns may be the biggest impediment to progress in our field—which is both good and bad news. Good in that our background medical therapy and interventional techniques are impressive. Humans do not live forever, and thus, the bad news is that it's hard for any new therapy to make what is great, greater.

Now to the details of FOURIER.

2. The investigators deserve congratulations for completing an impressive trial. With more than 13,700 patients in two randomized groups, FOURIER provides high-grade clinical evidence to the decision on whether or not to add PCSK9 drugs to baseline medical therapy in patients with established blood-vessel disease.

3. The observation that evoculumab reduced nonfatal cardiac events strengthens LDL-C as surrogate marker of heart disease. Recall that the 2013 ACC/AHA guidelines did away with titrating drugs to a lower LDL. This was controversial because a generation of doctors were taught that lower LDL-C was better. The results of FOURIER vindicate those who opposed the treat-to-risk idea, and it probably brings back the practice of micromanagement of LDL-C levels.

4. The baseline characteristics of FOURIER were notable in that they were young (mean age 62), mostly white men. One in three patients in each group were taking moderate-intensity statins. The remaining two-thirds were on high-intensity statins. This could have affected the results. A higher percentage of patients on high-dose statin might have blunted the small evolocumab effect.

5. Evolocumab resulted in significant (59% relative reduction) and sustained LDL-C reductions. LDL-C levels went from a mean of 92 to a mean of 30. A remarkable 42% of patients on evolocumab maintained LDL-C below 25 mg/dL. The trialists noted no diabetes, cataracts, or neurocognitive effects. But a median follow-up of 26 months is not long. Are there long-term problems of living a decade or more with cholesterol levels that low?

6. Evolocumab reduced both the primary and secondary composite end points. But the absolute risk reduction was modest, at 1.5%. The authors estimate that 74 patients would need to take evolocumab to prevent a cardiovascular death, MI, or stroke.

7. The benefits of evolocumab came in the prevention of nonfatal events: stroke was lower by 0.4%,, myocardial infarction lower by 1.2%, and coronary revascularization by 1.5%.

8. Evolocumab did not reduce cardiovascular or death from any cause. There was not even a trend for improvement. This is important. See point number 10.

9. The shortness of follow-up of FOURIER deserves mention. On the upside, the Kaplan Meier curves for both the primary and secondary end points looked to be separating over time. This makes sense biologically, as the benefits of exposure to LDL would accrue over time. But so would potential side effects, such as diabetes and neurocognitive effects. The mean age of patients in FOURIER was 63 years; LDL lowering is not a 2-year proposition. The heart and blood vessels are not the only important parts of the body.

10. We can't afford PCSK9 inhibitors at their current price. By we, I mean either individuals or our healthcare system. If our model of healthcare is pay for value, 1% to 2% reductions in nonfatal events are worth something. But they are not worth many thousands of dollars per year. And no, we don't need a complex modeling study to tell us the cost of this drug will have to come down.



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