| |
Efficacy and Safety of Evolocumab in
Reducing Lipids and Cardiovascular Events
|
| |
| |
Download the PDF PCSK9 - Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Download the PDF Supplementary Appendix
Coronary Syndrome
Abstract
Background
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data.
Methods
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies (“parent trials”) of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined.
Results
As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).
Conclusions
During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880. opens in new tab and NCT01854918. opens in new tab.)
Reduction in low-density lipoprotein (LDL) cholesterol levels has proved to be highly effective in reducing rates of major cardiovascular events in numerous large outcome trials.1-3 For this reason, LDL cholesterol reduction has been incorporated into practice guidelines as a fundamental means of reducing cardiovascular morbidity and mortality.4-7
During the past 3 years, monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have emerged as a new class of drugs that very effectively lower LDL cholesterol levels.8 One of the members of this class is evolocumab, a fully human monoclonal antibody that typically achieves approximately a 60% reduction in LDL cholesterol levels when administered at the doses that were studied in phase 3 trials.9-13
On completing a trial of evolocumab (parent trial), patients could enroll into one of two longer-term extension trials, designated Open-Label Study of Long-Term Evaluation against LDL Cholesterol 1 (OSLER-1), for patients completing phase 2 trials, and OSLER-2, for those completing phase 3 trials. The OSLER-1 and OSLER-2 trials had as their primary goal the gathering of longer-term data on safety, side-effect profile, and LDL cholesterol reduction and also included a prespecified exploratory analysis on adjudicated cardiovascular outcomes. Here, we report on the combined results of the OSLER-1 and OSLER-2 trials.
Methods
Study Design and Oversight
The OSLER-1 trial was an open-label, randomized, controlled study conducted at 190 centers that participated in at least one of five phase 2 studies of evolocumab.14-19 Analogously, the OSLER-2 trial was an open-label, randomized, controlled study conducted at 305 centers that participated in at least one of seven phase 3 studies of evolocumab (Table 1).9-13,20,21
The protocols for the OSLER-1 and OSLER-2 trials were approved by the relevant ethics committee at each participating site and are available with the full text of this article at NEJM.org. Amgen sponsored and designed the two trials and was responsible for data collection and analysis. The first draft of the manuscript was written by the first and last authors. All the coauthors participated in subsequent revisions of the manuscript. The academic authors had full access to the data and vouch for their accuracy and completeness and for the analyses as presented and for the fidelity of this report to the trial protocols. The first and last authors made the decision to submit the manuscript for publication.
Patients
There was variation in the clinical characteristics of the patients enrolled in the 12 parent studies (Table 1). Patients who had completed one of the parent studies could enroll in one of the OSLER extension studies, provided that they did not have an adverse event that led to the discontinuation of a study drug during the parent trial, did not have an unstable medical condition (in the judgment of the investigator), and were not expected to need unblinded lipid measurements or adjustment of background lipid-regulating therapy during the first 12 weeks of participation in the OSLER trials. All patients provided written informed consent before enrollment in the extension study.
End Points
The primary end point in the two trials was the incidence of adverse events. Additional safety end points included serious adverse events, adverse events leading to the discontinuation of the study drug (for patients in the evolocumab group), abnormalities in creatine kinase levels and liver-function testing, and the development of binding and neutralizing antibodies against evolocumab, which were assayed as reported previously.22
The secondary end point was the percent change in the LDL cholesterol level. Other efficacy lipid measurements included non-high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, HDL cholesterol, apolipoproteins A1 and B, and lipoprotein(a). Lipids were measured at a central laboratory (Medpace Reference Laboratories, Cincinnati, and Leuven, Belgium) after a fast of at least 9 hours. The LDL cholesterol level was calculated with the use of the Friedewald formula.23
A prespecified exploratory outcome was the incidence of adjudicated cardiovascular events, which was ascertained over the course of the study. (Definitions are provided in the Methods section in the Supplementary Appendix, available at NEJM.org.) Cardiovascular events included death, coronary events (myocardial infarction, unstable angina requiring hospitalization, or coronary revascularization), cerebrovascular events (stroke or transient ischemic attack), and heart failure requiring hospitalization. Potential cardiovascular events were adjudicated by the central clinical-events committee at the Thrombolysis in Myocardial Infarction (TIMI) Study Group in Boston, whose members were unaware of treatment assignments. All cardiovascular events were combined in an exploratory composite analysis that was based on the events that were prespecified in the trial protocols. In addition, all cardiovascular end points except for heart failure were combined into a post hoc composite of major adverse cardiovascular events.
Lipid Changes
The median baseline LDL cholesterol, before randomization into a parent study, was 120 mg per deciliter. At the week 12 visit in the OSLER trials, evolocumab, as compared with standard therapy, reduced the LDL cholesterol level by 61% (95% confidence interval [CI], 59 to 63; P<0.001), for a mean absolute reduction of 73 mg per deciliter to a median of 48 mg per decileter. Data were similar in the OSLER-1 and OSLER-2 trials (Table S1 in the Supplementary Appendix). The reduction in LDL cholesterol levels with evolocumab was consistent over time (Figure 1). At 12 weeks, the LDL cholesterol level was reduced to 100 mg per deciliter or less in 90.2% of patients and to 70 mg per deciliter or less in 73.6% of patients in the evolocumab group, as compared with 26.0% and 3.8%, respectively, in the standard-therapy group.
In the evolocumab group, as compared with the standard-therapy group, changes in related atherogenic lipid measures were similar to those observed for LDL cholesterol, with reductions of 52.0% in non-HDL cholesterol, 47.3% in apolipoprotein B, 36.1% in total cholesterol, 12.6% in triglycerides, and 25.5% in lipoprotein(a) (P<0.001 for all comparisons) (Fig. S2 in the Supplementary Appendix). Evolocumab raised levels of HDL cholesterol and apolipoprotein A1 by 7.0% and 4.2%, respectively (P<0.001 for both comparisons).
Cardiovascular Events
Cardiovascular events were prospectively adjudicated in an exploratory analysis (Table S4 in the Supplementary Appendix). When these events were combined in a composite of all cardiovascular events, patients in the evolocumab group had a significantly lower rate of all cardiovascular events than did patients in the standard-therapy group (Kaplan-Meier estimates at 1 year, 0.95% and 2.18%, respectively; hazard ratio, 0.47; 95% CI, 0.28 to 0.78; P=0.003). The cumulative incidence curves diverged progressively over time (Figure 2). Similar results were obtained for the post hoc composite of major adverse cardiovascular events (Table S4 in the Supplementary Appendix).
Discussion
In the OSLER-1 and OSLER-2 trials, open-label treatment with evolocumab reduced LDL cholesterol levels by 61%, from a pretreatment median level of 120 mg per deciliter to a 12-week on-treatment median level of 48 mg per deciliter. This result was consistent with reports from previous short-term trials of evolocumab.9-17,19 In the OSLER trials, the reduction in LDL cholesterol levels was sustained through 48 weeks, a finding consistent with the results of a much smaller study of evolocumab.9 Effects on other lipid fractions were also similar to those seen in previous studies.
Some nonspecific adverse events (arthralgia, headache, limb pain, and fatigue) and neurocognitive adverse events were reported more frequently in the evolocumab group than in the standard-therapy group. These observations should be viewed in the context of the greater number of protocol-stipulated in-person visits for patients in the evolocumab group as well as the open-label nature of the trial, which could predispose patients who are receiving the study intervention to be more likely to note adverse events, particularly those associated with other therapies that reduce LDL cholesterol.24 Moreover, there did not appear to be any excess of these events in patients who had very low versus higher on-treatment levels of LDL cholesterol. Furthermore, PCSK9 loss-of-function variants have not been associated with impaired cognitive performance.25 Nonetheless, much larger trials, including a dedicated neurocognitive substudy (ClinicalTrials.gov number, NCT02207634),26 are ongoing to provide more definitive assessments of safety over longer-term follow-up.
An unanswered question is whether a reduction in the LDL cholesterol level with a PCSK9 inhibitor will lead to a reduction in cardiovascular events. Reduction in such events with statins has been well established during the past two decades in numerous large, randomized, controlled trials.1,2 In contrast, it has been difficult to show that adding other lipid-modifying drugs to statins results in a further decrease in cardiovascular events, which is probably due to the modest effects on LDL cholesterol or off-target adverse effects.27-30 This issue was a factor contributing to the most recent set of practice guidelines from the American College of Cardiology-American Heart Association, in which the role of nonstatin lipid-modifying drugs was diminished, as compared with previous guidelines.4 Recently, however, in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), an additional reduction in LDL cholesterol levels with the addition of ezetimibe, a cholesterol-absorption inhibitor, to a statin significantly reduced cardiovascular events, as compared with statin monotherapy.3 These data have refocused attention on the potential cardiovascular benefit of greater LDL cholesterol reduction through nonstatin mechanisms.
Evolocumab, unlike other nonstatin lipid-modifying drugs, reduces LDL cholesterol levels as much as, if not more than, high doses of statins. Also, PCSK9 inhibitors have the same ultimate mechanism for LDL reduction as statins - namely, by increasing LDL receptor activity on the hepatocyte surface,8 suggesting that PCSK9 inhibitors should similarly have a beneficial effect on cardiovascular outcomes. Additional support for the potential of PCSK9 inhibition in reducing cardiovascular events comes from the observation that loss-of-function genetic variants leading to reductions in PCSK9 activity have been associated with significantly lower lifetime rates of cardiovascular events.31 Thus, the reduction in cardiovascular events seen in the OSLER trials within the first year of evolocumab therapy, even though the analysis was both exploratory and based on a relatively small number of events, is consistent with the large reduction in LDL cholesterol levels, the mechanism of action, and the PCSK9 genetic data.
The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study (NCT01764633) is an ongoing trial that is intended to provide a definitive assessment of the cardiovascular benefit of evolocumab. The FOURIER study is a randomized, placebo-controlled trial involving 27,500 high-risk patients with cardiovascular disease who are receiving background statin therapy; the primary end point is a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization.32Similar trials of alirocumab and bococizumab to evaluate cardiovascular outcomes are in progress (NCT01663402, NCT01975376, and NCT01975389).33-35
Several study limitations are noteworthy. First, the open-label design of the trials could have had an influence on the reporting of events, both cardiovascular and safety. This issue would especially be a concern for coronary revascularization, the single most frequently reported cardiovascular event, since the decision to perform this procedure could have been influenced by knowledge of treatment assignment. Second, the numbers of cardiovascular and select adverse events were relatively small. Third, although rates of adverse events and study-drug discontinuation were low in the parent trials,9-17,19 patients were eligible to transition to the OSLER trials if they had not had an adverse event that led to the discontinuation of a study drug. Thus, data on safety and side-effect profiles in our study come from a cohort of patients who had all successfully received injections and many of whom had received evolocumab for at least 12 weeks. Fourth, the OSLER program included a mix of patients with varying degrees of cardiovascular risk and use and intensity of statin therapy. Thus, not all the study patients would necessarily have been the optimal target population for this novel treatment.
In conclusion, patients who had previously participated in 12 shorter-term parent trials of the PCSK9 inhibitor evolocumab underwent repeat randomization to receive either evolocumab or standard therapy in the OSLER program. Evolucumab reduced levels of LDL cholesterol by 61% by 12 weeks, with sustained reduction through the median 11-month follow-up. In a prespecified exploratory analysis, there was evidence of a reduction in the rate of cardiovascular events among patients receiving evolocumab.
|
|
| |
| |
|
|
|
