The eagerly awaited results of the FOURIER trial were recently presented at the Annual Meeting of the American College of Cardiology (ACC) in Washington DC and simultaneously published in the New England Journal of Medicine (1).
The goal of FOURIER was to evaluate the efficacy and safety of evolocumab (Repatha), a PCSK9 inhibitor, among subjects with elevated risk on statin therapy. Patients with established cardiovascular disease were randomized to evolocumab 140 mg subcutaneous every two weeks or 420 mg monthly versus placebo. The treatment was added on top of statin therapy.
The study found that evolocumab lowered LDL cholesterol levels by 59% compared with placebo. There was a 15% reduction in the risk of the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Furthermore, there was a 20% reduction in the key secondary end point of cardiovascular death, myocardial infarction, or stroke. There was no significant difference between evolocumab and placebo with regard to adverse events. The median duration of follow-up was 26 months.
The results have been embraced by many experts who regard FOURIER as a groundbreaking trial and final proof that reducing LDL cholesterol to extremely low levels will reduce risk. Dr. Peter Block MD who reported from the ACC meeting said: “this is an outstanding outcome from a trial that tells us that the lower the LDL, the better the outcomes.”
The New York Times reports (2): “Cholesterol-Slashing Drug Can Protect High-Risk Heart Patients, Study Finds.” The famous Harvard Medical School cardiologist Dr. Eugene Braunwald is quoted saying “This is like the era of the statins coming in. It’s a new ballgame.”
The article also quoted Dr. David Maron, director of preventive cardiology at Stanford saying the results were “incredibly important,” adding; The future looks brighter for patients with established coronary disease.”
The BBC writes (3). “Huge advance in fighting world’s biggest killer… An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors.“
But, media hype aside, when the dust has settled, and the hangover takes over, we will realize that despite the positive results, FOURIER fell short of expectations, and there are serious concerns when it comes to implementing the trial results into clinical practice.
A Few Thoughts on the Sample Size
FOURIER is one of the biggest randomized placebo-controlled trials on drug therapy so far performed. A total of 27.564 were randomized to either evolocumab (13.784) or placebo (13.780).
The calculation of the sample size was based on the postulated frequency of the key secondary end point. It was estimated that 1.630 such end-point events were required to provide a 90% power to detect a 15% relative reduction with evolocumab as compared with placebo.
The median follow-up period in FOURIER was originally planned to be approximately four years. However, an event rate that was approximately 50% higher than had been postulated led to a shorter required duration of follow-up.
Sample size calculation is an essential component of study design, and the sample size must be determined and specified in the study protocol before recruitment starts (4).
Obviously, if a pharmaceutical company plans to introduce a new drug, it will not take the risk of failing to demonstrate efficacy relative to placebo by using an excessively small sample size. Furthermore, for ethical and scientific reasons, it is equally unacceptable for a drug to be tested on too many patients. Such a study may be considered overpowered.
An overpowered study might find a therapeutic effect that is clinically and scientifically irrelevant albeit statistically significant.
Evolocumab reduced the primary and secondary composite end points by 15% and 20% respectively. However, the absolute risk reduction was modest, at 1.5% for both. The authors estimate that 74 patients would need to be treated with evolocumab for 2 years to prevent one cardiovascular death, myocardial infarction or stroke.
Interestingly, evolocumab did not reduce cardiovascular death rate or death from any cause. Indeed, there was no such trend.
The benefits of evolocumab were restricted to the reduction of the risk of stroke by 0.4%, myocardial infarction by 1.2%, and coronary revascularization by 1.5%.
The Duration of Follow-Up
The short duration of follow-up in the FOURIER trial is a concern.
The authors highlight the possibility that the full clinical benefit of evolocumab may take longer than 2-3 years to develop. They point out other research data suggesting a delay between the onset of LDL cholesterol lowering and the emergence of full clinical benefit.
In FOURIER, the magnitude of risk reduction with regard to the key secondary end point appeared to grow from 16% during the first year to 25% beyond 12 months. Although this may be a pure coincidence, the authors claim it suggests that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time.
On the other hand, the authors fail to mention that this may be true for adverse effects as well. Apparently, side effects such as diabetes and neurocognitive dysfunction may take longer than 2 years to develop.
The EBBINGHAUS Study
There have been concerns that forceful lowering of LDL cholesterol to very low levels may harm the brain and cause neurocognitive dysfunction.
The EBBINGHAUS study addressed neurocognitive function in almost 2.000 patients participating in FOURIER. The patients underwent a battery of neurocognitive tests, and neurocognitive adverse events were tracked. No differences were found between evolocumab and placebo.
It has been pointed out that most PCSK9 inhibitors are big molecules that don’t cross the intact blood brain barrier and therefore should not affect cholesterol metabolism within the brain.
However, patients were only followed for 20 months in EBBINGHAUS. What happens beyond this time is unknown. So, whether cognitive dysfunction may develop during long-term therapy with PCSK9 inhibitors is an unanswered question.
The Cost-Benefit Issue
A recent Biopharm Insight Report suggested that anything lower than 35 percent risk reduction in FOURIER may mean that the cost outweighs the treatment benefit (5). As previously mentioned, FOURIER was powered to detect a 15% risk reduction, which in this case may be far from cost-effective.
Evolocumab is estimated to cost approximately $14,350 per patient for a one-year supply in the United States, or approximately $1200 per month (6).
The estimated cost of treating 74 patients (the number needed to treat (NNT)) for two years with evolocumab is $2.123.800. That would be the cost of preventing one event (cardiovascular death, myocardial infarction or stroke) over a period of two years.
Does anybody doubt that the juice ain’t worth the squeeze?
I am sure we can all agree that the FOURIER trial is a great scientific achievement and I am truly proud to have been among the many investigators in the trial.
The study organizers, all the investigators, and research nurses deserve congratulations. But, most importantly, our gratitude goes to the 27.564 patients who should be praised for all their effort and their willingness to participate.
Certainly, FOURIER will teach us a lot about how to use PCSK9 inhibitors in patients with cardiovascular disease. However, despite the intense lowering of LDL cholesterol, the clinical efficacy of these drugs appears modest in this high-risk population.
Of course, the availability of PCSK9 inhibitors adds strength to our arsenal of cardiovascular therapies. But, despite what many have claimed, they are not miracle drugs, and cardiovascular events will continue to occur despite them.
Furthermore, although the absence of adverse effects is striking in the FOURIER trial, it has to be kept in mind that side effects such as diabetes and cognitive dysfunction may take a time to develop.
Evidence-based medicine is the backbone of modern healthcare. However, we have to to treat it for what it is and avoid hype and unsupported claims and predictions.