About 28,000 patients with established cardiovascular disease while taking statin or zetia were randomized to receive a PCSK9 inhibitor or placebo.
Participants were followed for 2.2 years. Median LDL was lowered from 92 to 30 mg/dL. Cardiovascular events were reduced accordingly by 15-20% in individuals treated with PCSK9 inhibitor vs. those in the placebo group.
This original study adds more evidence to the notion “the lower the LDL the better the outcomes”. Adverse events were overall similar and no increased risk of diabetes or dementia was seen.
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N E J M
Randomized Trial
March 2017
BACKGROUND
Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers LDL-cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with ASCVD and LDL-cholesterol >70 mg/dL who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
RESULTS
At 48 weeks, the least-squares mean percentage reduction in LDL-cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 to 30 mg/dL (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (hazard ratio, 0.85; CI, 0.79-0.92; P<0.001) and the key secondary end point (hazard ratio, 0.80; CI, 0.73- 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL-cholesterol levels (median, 74 mg/dL]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).
CONCLUSIONS
In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL-cholesterol levels to a median of 30 mg/dL and reduced the risk of cardiovascular events. These findings show that patients with ASCVD benefit from lowering of LDL-cholesterol levels below current targets.
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LDL-cholesterol is a well-established and modifiable risk factor for cardiovascular disease. Monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower LDL-cholesterol levels. Evolocumab, a member of this class, is a fully human monoclonal antibody that reduces LDL-cholesterol levels by approximately 60%.
Genetic studies have shown that carriage of PCSK9 loss-of-function alleles is associated with lower LDL-cholesterol levels and a reduced risk of myocardial infarction. Moreover, exploratory data from longer-term follow-up in phase 2 and phase 3 trials of PCSK9 inhibitors showed significant reductions in cardiovascular outcomes. However, there were little more than 100 events in these studies combined. Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) was a dedicated cardiovascular outcomes trial that tested the clinical efficacy and safety of evolocumab when added to high-intensity or moderate-intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease.
When added to statin therapy, the PCSK9 inhibitor evolocumab lowered LDL-cholesterol levels by 59% from baseline levels as compared with placebo, from a median of 92 to 30 mg/dL.This effect was sustained without evidence of attenuation. In this dedicated cardiovascular outcomes trial, we found that the addition of evolocumab to statin therapy significantly reduced the risk of cardiovascular events, with 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 and a 20% reduction in the risk of the more clinically serious key secondary end point of cardiovascular death, myocardial infarction, or stroke. During a median of 26 months of follow-up, the only adverse events that were noted to be nominally significantly more common in association with evolocumab were injection-site reactions, but these were rare, and the rate of discontinuation of the study regimen was no higher with evolocumab than with placebo
The data from our trial provide insight into the benefit of decreasing LDL-cholesterol levels to median levels lower than those in previous trials. Previously, significant reductions in major cardiovascular events were found in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) and Treating to New Targets (TNT) trials, in which the more intensive statin regimen lowered LDL-cholesterol levels from approximately 100 to 70 mg/dL. More recently, the addition of ezetimibe to statin therapy in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) lowered LDL-cholesterol levels from 70 to 54 mg/dL and significantly reduced major cardiovascular events. In extending this concept further in FOURIER, we found consistent reductions in rates of cardiovascular events across the range of baseline LDL-cholesterol levels.
Specifically, there was a 17% reduction in the risk of the key secondary end point among patients in the top quartile for baseline LDL-cholesterol level, in whom evolocumab lowered the median LDL-cholesterol level from 126 to 43 mg/dL (with the achieved level similar to that achieved with ezetimibe in patients in the lowest quartile for admission LDL-cholesterol levels in IMPROVE-IT), and there was a 22% reduction in the risk of the key secondary end point among the patients in the lowest quartile for baseline LDL-cholesterol level, in whom evolocumab lowered the median LDL-cholesterol level from 73 to 22 mg/dL These observations align well with the effects of evolocumab on coronary atherosclerotic plaque volume in the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial and show that continued cardiovascular benefit can be accrued even when LDL-cholesterol levels are reduced to 20-25 mg/dL, a range that is well below current targets.
A delay between the onset of LDL-cholesterol lowering and the emergence of the full clinical benefit of the intervention in terms of clinical risk reduction has been well documented in trials of statins, ezetimibe, and other LDL-cholesterol-lowering therapies. Likewise, in FOURIER, the magnitude of the risk reduction with regard to the key secondary end point appeared to grow over time, from 16% during the first year to 25% beyond 12 months, which suggests that the translation of reductions in LDL-cholesterol levels into cardiovascular clinical benefit requires time. Overall, 74 patients would need to be treated over a period of 2 years to prevent a cardiovascular death, myocardial infarction, or stroke.
The rate of discontinuation of evolocumab injections because of adverse events that were ascribed to the drug was similar to the rate with placebo (0.76% vs. 0.67% per year) and compares favorably to the rates that have been found with atorvastatin at a dose of 80 mg daily (1.5% per year) and with ezetimibe (1.1% per year) in other trials. The risk of new-onset diabetes in our trial appeared to be similar in the two groups, although the 95% confidence intervals did not exclude the point estimates observed with statins. Potential concerns about an increased risk of neurocognitive adverse events were not borne out in this trial. In contrast to recent data for bococizumab (a humanized but not fully human monoclonal antibody against PCSK9), evolocumab-binding antibodies were rarely detected in our trial, no neutralizing antibodies developed, and the overall LDL-cholesterol-lowering effect continued without attenuation. Furthermore, similarly reassuring findings with evolocumab were observed over a period of 4 years in the Open Label Study of Long-Term Evaluation against LDL-cholesterol Trial (OSLER-1).
The major limitation of this trial was a relatively short duration of follow-up as compared with that in other lipid-lowering trials, in which follow-up periods have averaged approximately 5 years. Although the median follow-up period in FOURIER was originally planned to be approximately 4 years, an event rate that was approximately 50% higher than had been postulated led to a shorter required duration of follow-up to accrue the prespecified number of events. Most but not all of the patients in the trial received high-intensity statin therapy, and ezetimibe use was infrequent. However, the benefit of evolocumab was consistent regardless of the intensity of statin therapy or ezetimibe use
In conclusion, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL-cholesterol levels to a median of 30 mg/dL and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from the lowering of LDL-cholesterol levels below current targets.