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FOURIER: Reducing LDL to very low levels with evolocumab confers reduced risk for CV events
WASHINGTON — Reduction of LDL to a median of 30 mg/dL with the PCSK9 inhibitor evolocumab in patients with atherosclerotic CVD was associated with lowered risk for CV events, according to data presented at the American College of Cardiology Scientific Session and published in The New England Journal of Medicine.
Previous research had shown evolocumab (Repatha, Amgen), a fully human monoclonal antibody, dramatically lowers LDL, but its effect on clinical outcomes was unknown. The drug is currently approved by the FDA for lowering of LDL in patients with atherosclerotic CVD or familial hypercholesterolemia.
Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women’s Hospital, and colleagues randomly assigned 27,564 patients with atherosclerotic CVD and LDL 70 mg/dL to subcutaneous injections of evolocumab 140 mg every 2 weeks or 420 mg monthly or matching placebo.
Most patients were also assigned statin therapy, and some were also assigned ezetimibe (Zetia, Merck), Sabatine said during a press conference.
The primary outcome was a composite of CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization. The key secondary outcome was a composite of CV death, MI or stroke. Median follow-up was 2.2 years.
Compared with placebo, evolocumab at 48 weeks was associated with a least-squares mean percentage reduction in LDL of 59% from a median of 92 mg/dL at baseline to a median of 30 mg/dL, and 87% of those in the evolocumab group had LDL reduced to 70 mg/dL, whereas 67% had it reduced to 40 mg/dL and 42% had it reduced to 25 mg/dL (P < .001 vs. placebo for all), Sabatine and colleagues found.
“One-quarter of the patients had an achieved LDL level of less than 20 [mg/dL],” Sabatine said at the press conference. “This LDL reduction was rock steady over the duration of the trial.”
The primary endpoint occurred in 9.8% of those assigned evolocumab vs. 11.3% of those assigned placebo (HR = 0.85; 95% CI, 0.79-0.92), according to the researchers.
Sabatine and colleagues also found that the key secondary endpoint was lower in the evolocumab group vs. the placebo group (5.9% vs. 7.4%; HR = 0.8; 95% CI, 0.73-0.88).
Magnitude of risk reduction for the primary endpoint associated with evolocumab increased over time, from 12% (95% CI, 3-20) in the first year to 19% (95% CI, 11-25) beyond the first year, according to the researchers. Evolocumab reduced the key secondary endpoint by 16% in the first year (HR = 0.84; 95% CI, 0.74-0.96) and 25% beyond the first year (HR = 0.75; 95% CI, 0.66-0.85), and fatal or nonfatal MI or stroke by 19% in the first year and 33% beyond the first year, Sabatine said.
“The curves separate sometime during the first year and the continue to separate over time,” Sabatine said. “An important point ... is that it takes time for LDL lowering to translate into healthier arteries.”
There was no significant difference between the groups in CV death (HR = 1.05; 95% CI, 0.88-1.25), so the other individual endpoints must be considered exploratory, Sabatine and colleagues wrote in NEJM. Compared with placebo, evolocumab was linked to reduced risk for MI (HR = 0.73; 95% CI, 0.68-0.82), stroke (HR = 0.79; 95% CI, 0.66-0.95) and coronary revascularization (HR = 0.78; 95% CI, 0.71-0.86), but not for hospitalization for unstable angina (HR = 0.99; 95% CI, 0.82-1.18), CV death or hospitalization for worsening HF (HR = 0.98; 95% CI, 0.86-1.13) or all-cause mortality (HR = 1.04; 95% CI, 0.91-1.19).
Results were consistent regardless of age, sex, type of atherosclerotic vascular disease and quartiles of baseline LDL, according to the researchers.
“Even lower LDL ... appears to be even better,” Sabatine said during the press conference. “There is a very nice linear relationship now down to unprecedented levels of LDL, as low as 22 mg/dL.”
Adverse events, serious adverse events, adverse events leading to study drug discontinuation, muscle-related events, onset of cataracts, neurocognitive adverse events and hemorrhagic stroke did not differ between the groups, but injection-site reactions were more common with evolocumab (2.1% vs. 1.6%), according to Sabatine and colleagues.
There was no difference between the groups in new-onset diabetes (HR = 1.05; 95% CI, 0.94-1.17).
Among those assigned evolocumab, new binding antibodies developed in 0.3% of patients, but neutralizing antibodies did not develop in any patient.
Valentin Fuster, MD, PhD, physician-in-chief at The Mount Sinai Hospital, director of Mount Sinai Heart Institute, editor-in-chief of the Journal of the American College of Cardiology and past president of the American Heart Association and the World Heart Federation, said in a discussant presentation that the results are encouraging, but some caution is required.
“When you look at the absolute improvement in mortality [and other outcomes], it was just 2%,” he said. “The curves did diverge, so I assume that this 2% would be 4% in 2 or 3 more years. I feel very positive about that. The caution is cost-effectiveness. We live in a society where we have to be very, very careful about [a drug that is] very expensive. We cannot say that everyone will take PCSK9 inhibitors and it will be no problem. We have to be sure to identify the right people in which this type of approach should be meaningful.” – by Erik Swain
References:
Sabatine MS, et al. Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
Disclosure : The study was funded by Amgen. Sabatine reports receiving grants from Abbott Laboratories, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Janssen Research Development, Novartis, Poxel, Roche Diagnostics and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, MedImmune and Merck; and personal fees from Alnylam, Cubist, CVS Caremark, Esperion, Ionis, MyoKardia, The Medicines Company and Zeus Scientific.
Perspective
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No one could be certain before the trial was done whether or not lowering LDL to unprecedented low levels would produce an incremental benefit. In many areas of medicine, including BP, as you go to further extremes, you get a J-shaped curve or other diminishment of effect. What you see in this study, which is remarkable, is the lower you go, the more benefit you see. There is no apparent diminution of benefit to very low LDL. The lowest quartile was down to 22 mg/dL and still saw incremental benefit.
The size of the benefit was about what I had predicted and anticipated. There was no effect on death. I didn’t expect there to be, because it was too short a trial for that. There was 27% reduction in MI and a 21% reduction in stroke, which are very meaningful to patients.
These data put a lot of pressure on the payers and the guideline writers. We are now faced with the challenge of figuring out exactly who we’re going to treat. I will be comfortable with pushing hard to get the higher-risk patients I see to get their LDL lower, particularly if they’ve had one or more events and are already on a high-dose statin. I will at least present to the patient the option of additional LDL-lowering therapy.
This high-quality, well-run study lines up well with GLAGOV; they were designed in parallel to study the same population. GLAGOV predicted well what would happen in FOURIER; sometimes that has happened in the past, as with REVERSAL and PROVE-IT. There were very few patients that were lost to follow-up and FOURIER does not have a lot of warts that will make us concerned if it’s robust.
Expecting a greater magnitude of benefit was unrealistic; those expectations were likely based on meta-analyses published in The New England Journal of Medicine. I warned at the time that those were unrealistic, without the robust methodology of a large randomized controlled trial. However, these results are consistent with the Cholesterol Treatment Trialists’ Collaboration meta-analysis. When you lower LDL by 1 mmol/L, no matter where you start, you get about the same benefit. To put it another way, statins vs. placebo is about a 25% treatment effect. Now, PCSK9 inhibitors on top of statins is another 20%. The important endpoint is death/stroke/MI, and that is where we see a very clear signal.
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These results should help move practice. We now have outcome data that we have very much needed. We can also identify a group that benefits: higher-risk patients with known disease. We also now know that patients who had optimal statin therapy but did not reach an adequate LDL level look like they would benefit more and would be candidates. If you take the FOURIER data and extrapolate it for another 2 years, you get a number needed to treat of around 25 to prevent one CV event. We will see if this is confirmed in ODYSSEY OUTCOMES, which will have 4-year data.
I’m certain the groups that write the guideline recommendations will review them to see how they could fit in to recommendations for physicians.
Perspective
Back to TopIn a study of only 2.2 years, there was a significant reduction in a composite CV event. I prefer to consider the death/MI/stroke endpoint, which showed a 20% reduction associated with evolocumab, with the Kaplan-Meier curves diverging progressively, starting to separate at 6 months. Extrapolated out to 5 years, this is similar to statin data from the Cholesterol Treatment Trialists’ Collaboration. That speaks well for these results.
Some have focused on the absolute risk reduction of 2%. In the TNT trial, a 5-year study comparing atorvastatin 80 mg to atorvastatin 10 mg, the absolute risk reduction was the same. People have to recognize that the background levels of care are significant. It comes down to what will be done to prevent, or allow for, another event. In the 4S study, one of the original cholesterol-treatment studies, the mortality rate was 25%, compared with 4% to 5% for this study. This reflects the impact of contemporary therapy with ACE inhibitors, angiotensin receptor blockers, beta-blockers, other appropriate antihypertensives, and most importantly, background statins and antiplatelet activity. Sixty percent of this population were on a statin for at least 1 year and 40% were on it for more than 2 years. In that amount of time, there can be a considerable impact of cholesterol lowering, particularly intense cholesterol lowering, on the behavior of the plaque. In spite of contemporary background therapies including statins in the majority of patients, there was a significant reduction at 2 years that, based upon the slope of the Kaplan-Meier curves, we would expect to continue to do well going out further. The study should not be interpreted completely in the light of the older trials because it was a 2-year study, not a 5-year one and the older trials did not have this level of background care.
In that setting, I am thrilled with these results, especially in terms of benefit of getting down to the same levels of LDL as when we were born. We now know this therapy is safe and effective.
Some people were expecting a greater relative risk reduction. They will need to get over that expectation. To interpret this study, people need to understand cardiology, particularly lipids, and have a historical perspective. Some education will be necessary. This not a scenario where Babe Ruth points to the right-field bleachers and hits the first pitch there. Those kinds of studies will never exist again.
The study also shows that despite lipid lowering, there are still events, meaning that other things are important to treat, like blood sugar, BP and smoking. You can’t get away with only treating cholesterol.