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As it turns out, the PCSK9 inhibitor saga ends not with a bang but a whimper. The results of the highly anticipated FOURIER trial show that the drugs work, though not as powerfully as many had hoped and expected. The question now will be whether the modest efficacy of the drugs is worth their immodest cost, at least for the vast majority of patients who are not at extremely high risk for cardiovascular disease.
FOURIER is the first cardiovascular outcomes trial with one of the new cholesterol-lowering PCSK9 inhibitors, in this case Amgen's evolocumab (Repatha). A second trial, Odyssey Outcomes, is about a year behind FOURIER and is testing alirocumab (Praluent), the PCSK9 inhibitor from Sanofi and Regeneron, in 18,600 patients.
Both drugs have generated enormous controversy due to their high cost and, until now, uncertain efficacy. In the absence of clinical data, wide adoption of the drug has been resisted by many clinicians and, even more crucially, insurance companies and benefits managers.
Now the FOURIER trial will allow much more precise calculations of the drugs' benefits. In the trial, which was presented at the American College of Cardiology meeting in Washington, D.C., and published simultaneously in the New England Journal of Medicine, 27,564 patients with CV disease and LDL levels above 70 mg/dL already receiving statins were randomized to evolocumab or placebo. At 48 weeks, LDL fell by 59%, from 92 mg/dL at baseline to 30 mg/dL.
The primary end point, which was the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, was reduced by a relative 15%, from a rate of 11.3% in the placebo group to 9.8% with evolocumab (1,563 versus 1,344 patients, HR 0.85, 95% CI 0.79-0.92, P<0.001).
The key secondary endpoint, the more rigorous composite of CV death, MI, or stroke, was reduced by 20%, from 7.4% (1,013 patients) to 5.9% (816 patients, HR 0.80, 95% CI 0.73-0.88, P<0.001). The investigators reported that the findings were consistent across subgroups, including those with very low LDL levels at baseline. There were no significant differences in adverse events, including new onset of diabetes and neurocognitive events, although there were more injection site reactions in the active treatment group.
The investigators also reported an improvement over time. The risk reduction in the primary endpoint increased from 12% in the first year to 19% afterwards and for the secondary endpoint from 16% to 25%.
There was no significant difference in cardiovascular death or all-cause mortality. The difference in the primary endpoint was achieved through absolute reductions of 1.5% in coronary revascularization (reduced from 7% to 5.5%), 1.2% in MI (from 4.6% to 3.4%), and 0.4% in stroke (from 1.9% to 1.5%).
The authors calculated that 74 patients would need to be treated for 2 years to prevent a CV death, MI, or stroke.
What Does It Mean?
Experts with whom I spoke agreed that the trial successfully demonstrated clinical benefit with the drug, but they were less certain about the general importance of this benefit. And they were concerned by the modest size of the risk reduction and the lack of any signal of a mortality benefit. But all agreed that that trial represents a remarkable and positive example of the rapid translation of genetic research to clinical therapeutics.
Sek Kathiresan (Broad Institute) said that his take-home message was that "treating with a PCSK9 inhibitor to get LDL to ultra-low levels will prevent a recurrent heart attack or stroke. But," he asked, "at what cost?"
James Stein (University of Wisconsin) said that he sees the result as "an extra base hit in the late innings of a tight baseball game." The results validate the LDL hypothesis, and the reduction in MI and strokes in particular represents welcome news to his patients, but, he acknowledged, "the bigger question is going to be the economics of it because these drugs are so darn expensive."
Sanjay Kaul (Cedars-Sinai) questioned whether FOURIER represents an important "therapeutic advance." He said that the high number needed to treat "doesn't quite cut it for me," especially in the absence of even a signal of benefit for CV death or all-cause mortality. He said it will be "interesting to see how the payers view the value of the CV outcome benefit." Kaul also said it would be important to to learn whether the strokes and MIs in the trial were large and clinically significant.
Kaul and Kathiresan both wrestled with the observation that the trial results do not accord with the Cholesterol Treatment Trialists (CTT) meta-analysis, which would have predicted a 30% to 35% decrease in events based on the LDL reduction in the trial. "What we see actually is approximately half the predicted reduction in events," said Kaul. "Does this refute or confirm the LDL hypothesis?"
Kathiresan said that "many hypotheses will be put forward" to explain this discordance, "but I suspect we are seeing a plateauing of the benefit of LDL lowering as we get to lower and lower LDL levels." Another possible explanation for the more modest benefit in FOURIER is that statins may produce additional effects unrelated to their LDL-lowering effect. Kaul also speculated that the beneficial effect might have been larger with longer follow-up, "but that is a risk one takes with time-to-event trials." This also might suggest that the longer follow-up with the Odyssey Outcomes trial may produce a more robust result.
Stein offered a more practical view. "Whether it's above or below the CTT line isn't all that interesting to me, because almost all landmark studies are above or below the line: There's variability and, since these are the lowest lipid levels that have been achieved, I'm not surprised that it's not a perfect predictive relationship." Stein took a step back: "The big picture is that lower is better and that anyway you can lower LDL safely will reduce events. As we seem to learn each decade, even lower than we previously thought is better."
"We now have another potent weapon in our arsenal to lower lipids," said Stein. The trial confirmed that PCSK9 inhibitors are "very effective and, in the intermediate term, very safe."
One warning: Although the 2-year experience in FOURIER "suggests no major side effects," said Kathiresan, "I would still watch for type 2 diabetes, cataracts, and neurocognitive effects as the drugs get more widely used and for longer periods of time."
Kathiresan said that "in patients with established atherosclerotic CVD, treating to get LDL levels to less than 50 is a good goal if it can be done without adverse effects. We now have three options to get to this level: statin, ezetimibe [Zetia], and PCSK9 inhibitors. I will probably have patients take them in that order." But in the end it will come down to economics and not science. "There will be a vigorous debate about cost-effectiveness of PCSK9 [inhibitors] and this will be important for patients," he concluded.
Ethan Weiss (University of California San Francisco) agreed that "the key discussion will be around the economics of it. Does the reduction of one to two MIs per 100 [patients] per year and without a mortality effect justify the cost, especially with ezetimibe being basically free? How payers deal with this will be the key, and I predict they will make it hard. Again, how do you identify who should get this drug? Do you wait to treat people who fail max statin? Do you have to try Zetia first? Is there a way to identify prospectively those who will benefit and justify the cost? If so, how? I do not envy the guidelines writers..."