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 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter). 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 mg per deciliter (2.6 mmol per liter) to 70 mg per deciliter (1.8 mmol per liter).13,14 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 mg per deciliter (1.8 mmol per liter) to 54 mg per deciliter (1.4 mmol per liter) and significantly reduced major cardiovascular events.15 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 mg per deciliter (3.3 mmol per liter) to 43 mg per deciliter (1.1 mmol per liter) (with the achieved level similar to that achieved with ezetimibe in patients in the lowest quartile for admission LDL cholesterol levels in IMPROVE-IT16), 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 mg per deciliter (1.9 mmol per liter) to 22 mg per deciliter (0.57 mmol per liter). 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) trial17 and show that continued cardiovascular benefit can be accrued even when LDL cholesterol levels are reduced to 20 to 25 mg per deciliter (0.52 to 0.65 mmol per liter), a range that is well below current targets.18-20

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.15,21-24 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.

In an observation consistent with previous trials of more intensive LDL cholesterol–lowering therapy as compared with moderate-intensity statin therapy,15,25 we found no effect of additional lowering of LDL cholesterol levels on cardiovascular mortality. The rate of use of evidence-based cardiovascular pharmacotherapies that lower cardiovascular mortality was very high in FOURIER, in which the rates of cardiovascular mortality were one third of the rates in the Scandinavian Simvastatin Survival Study (4S).26 Similar to the findings in the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) and IMPROVE-IT, in our trial we found no effect on hospitalization for unstable angina. The advent of increasingly sensitive cardiac troponin assays probably makes cardiac ischemia increasingly questionable as the true cause of a hospitalization for chest-pain symptoms without biochemical evidence of myocyte injury.27 Finally, the rate of urgent coronary revascularization appeared to be more modifiable than that of elective revascularization.

Given these caveats, the magnitude of benefit of evolocumab in reducing the risk of major coronary events, stroke, and urgent coronary revascularization is largely consistent with the benefit seen with statins on a per–millimole-per-liter basis of LDL cholesterol lowering (Fig. S6 in the Supplementary Appendix). These observations are in accord with meta-analyses of data from clinical trials of different lipid-lowering interventions, which show consistent clinical benefits per unit reduction in LDL cholesterol.28 Likewise, these observations are supported by data from a recent mendelian randomization study in which variants in PCSK9 and variants in HMGCR were associated with nearly identical lower risks of cardiovascular events per unit reduction in LDL cholesterol.29

Achievement of these very low LDL cholesterol levels with evolocumab did not lead to any significant differences between the two study groups in the overall rates of adverse events or in rates of study-regimen discontinuation. 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.14,15 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.30,31 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),32 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-C Trial (OSLER-1).33

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.28 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 per deciliter (0.78 mmol per liter) 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.