Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease
Abstract
Background:
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking.
Methods:
The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected.
Results:
A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75–0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68–0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60–0.99]; P=0.04).
Conclusions:
Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02867813 and NCT03080935.
Clinical Perspective
What Is New?
•
In this open-label extension study of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab in 6635 patients with atherosclerotic cardiovascular disease who completed a randomized trial of evolocumab versus placebo, the incidence of adverse events of interest did not increase over time.
•
During the open-label extension follow-up period, patients who were originally randomized to evolocumab had a 15% to 20% lower risk of major adverse cardiovascular events and a 23% lower risk of cardiovascular death than those originally randomized to placebo.
What Are the Clinical Implications?
•
Long-term low-density lipoprotein cholesterol lowering with evolocumab is safe and well tolerated for over >8 years.
•
Long-term treatment with evolocumab leads to a greater reduction in cardiovascular events compared with delayed treatment initiation.
•
These findings underscore the legacy effect that occurs from aggressive lowering of low-density lipoprotein cholesterol that continues to be observed through very long-term follow-up.
Editorial, see p 1120
Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are now established as an effective method to lower low-density lipoprotein cholesterol (LDL-C) and to reduce the risk of major adverse cardiovascular events.1,2 In particular, evolocumab is a fully human monoclonal antibody directed toward the PCSK9 protein that reduces LDL-C by ≈60% at the end of the dosing interval and 65% to 68% averaged over the dosing interval.3 In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), treatment with evolocumab for a median of 2.2 years reduced the risk of the primary composite outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization by 15% and the key secondary composite outcome of cardiovascular death, myocardial infarction, or stroke by 20% in patients with established atherosclerotic cardiovascular disease on statin therapy.4 It is notable that there was greater apparent benefit with more prolonged exposure to drug.4,5 During the trial follow-up period, the drug appeared to be safe and well tolerated.4 In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), the monoclonal PCSK9 antibody alirocumab reduced the risk of major adverse cardiovascular events by 15% and nominally reduced mortality in patients after an acute coronary syndrome over a median of 2.8 years with greater apparent benefit for those patients treated for >3 years.6,7
In statin trials, the median follow-up duration for many of the original cardiovascular outcomes trials was 4 to 5 years.8 Ezetimibe was studied in addition to background statin in the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) with a median follow-up of 6 years.9 Because large-scale, very long-term data were limited for PCSK9 inhibition, the FOURIER-OLE (FOURIER Open-Label Extension) was designed to capture prolonged data on long-term safety, tolerability, lipids levels, and risk of major adverse cardiovascular events with continued evolocumab exposure after completion of the parent FOURIER trial.
Methods
Study Design and Oversight
The parent FOURIER trial was a randomized, double-blind, placebo-controlled, multinational clinical trial.4 At study conclusion, patients at sites throughout the United States and Europe were considered for participation in the open-label long-term extension program (FOURIER-OLE; Figure S1).
Participation in FOURIER-OLE was initially in 197 FOURIER sites in the United States and Eastern Europe, including Russia, Ukraine, Poland, Hungary, Czechia, and Slovakia (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02867813), with an enrollment start date in September 2016. Enrollment was subsequently expanded in March 2017 in a companion protocol to include 86 FOURIER sites in Western Europe, including Germany, Belgium, Denmark, Sweden, Italy, Portugal, and France (URL: http://www.clinicaltrials.gov. Unique identifier: NCT03080935). Both protocols had similar entry criteria and schedules of assessments. The studies were designed by Amgen in collaboration with the TIMI (Thrombolysis in Myocardial Infarction) Study Group, an academic research organization at Brigham and Women's Hospital and Harvard Medical School (Boston, MA). The protocol and amendments were approved by the relevant ethics committees at all participating sites. The sponsor was responsible for data collection. The raw database was provided to the TIMI Study Group, which conducted data analyses independently of the sponsor. The first author drafted the current manuscript; all authors reviewed and approved the manuscript.
Trial Population
The parent FOURIER trial enrolled patients with a history of established atherosclerotic cardiovascular disease and a fasting LDL-C level of ≥70 mg/dL or non–high-density lipoprotein cholesterol level of ≥100 mg/dL while on an optimized statin regimen.4,10 Patients were eligible for participation in FOURIER-OLE if they completed the parent FOURIER trial on study drug (evolocumab or placebo) at a site participating in FOURIER-OLE. Patients who experienced a nonfatal event during the parent study remained eligible for participation in FOURIER-OLE. Patients were excluded from participation in FOURIER-OLE if they were participating in another study with an investigational drug or device or if they were not expected to be able to complete follow-up for the duration of the extension program (Supplemental Material). Written informed consent was obtained from all patients.
Study Drug Administration
Eligible patients were treated with open-label subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) during the extension period regardless of whether they were originally randomized to evolocumab or placebo. Patients who discontinued study drug during the extension period were asked to remain in active follow-up for the duration of the study.
End Points and Study Procedures
The primary end point was the subject incidence of treatment-emergent adverse events. The secondary end points were the percent change in LDL-C from FOURIER baseline and achievement of an LDL-C <40 mg/dL at each scheduled visit. We also prespecified examining the proportion who achieved LDL-C below other relevant thresholds, including <70, <55, and <20 mg/dL. Major adverse cardiovascular events were prespecified exploratory end points. The primary cardiovascular composite outcome was cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization; the key secondary cardiovascular composite outcome was cardiovascular death, myocardial infarction, or stroke.
Study visits during FOURIER-OLE occurred at week 12 and then every 24 weeks throughout follow-up and included clinical and laboratory assessments: fasting lipids, apolipoprotein A1, apolipoprotein B, and lipoprotein(a). During FOURIER and for at least 12 weeks after the subject’s last study drug administration from the parent FOURIER trial, investigators were advised not to measure lipid levels in order to avoid inadvertent unblinding. Patients were also advised to remain on consistent background lipid-lowering therapy whenever appropriate throughout all of follow-up. Safety was assessed through the collection of data on adverse events. A central clinical events committee led by the TIMI Study Group, with members blinded to original study group assignments and lipid levels, reviewed and categorized cause of death and cardiovascular events of interest (cardiac ischemic events, cerebrovascular events, coronary revascularization, and heart failure hospitalizations). End point definitions are provided in the Supplemental Material.
Statistical Analysis
Safety evaluations for treatment-emergent adverse events included all patients enrolled in FOURIER-OLE who received at least 1 dose of study drug and for whom post-dose data were available during the extension program. Patients were censored for safety analyses 30 days after permanent drug discontinuation or at end-of-study (whichever was sooner). Analyses for major adverse cardiovascular events were conducted on an intention-to-treat basis. For cardiovascular event analyses that were restricted to the FOURIER-OLE follow-up period, patients were considered eligible for a first event regardless of whether they had experienced a nonfatal event during the parent study.
Lipids and changes in lipids during FOURIER-OLE from the baseline assessment in the parent FOURIER study are reported as summary statistics and least-squares mean percent change with the use of a mixed model for repeated measures. Because the distributions for triglycerides and lipoprotein(a) were skewed, descriptive changes were reported as the median percent change without the use of a mixed repeated-measures model. Annualized subject incidence rates for adverse events of interest were calculated during the parent FOURIER trial by randomized treatment arm and during the combined parent and FOURIER-OLE studies for patients originally allocated to evolocumab (because this group had the longest evolocumab exposure times). For cardiovascular outcomes, the hazard ratio (HR) and 95% CI were calculated from stratified Cox models with the prespecified stratification factors at randomization and FOURIER-OLE study protocol as covariates. If the proportional hazards assumption was violated, modified Poisson regression was conducted as a sensitivity analysis. Yearly landmark analyses were performed for the primary and key secondary composite end points.
We encourage parties interested in collaboration and data sharing to contact the corresponding author directly for further discussions.
Results
A total of 6635 patients were enrolled in FOURIER-OLE, of whom 2201 (33.2%) were from the United States and 4434 (66.8%) were from Europe. Of the 6635 patients, 3355 (50.6%) were originally randomized in the parent trial to treatment with evolocumab and 3280 (49.4%) were randomized to placebo (Figure S2). The baseline characteristics of the FOURIER-OLE study population at the start of FOURIER were well balanced across groups by original treatment assignment (Table 1) and similar to the complete parent FOURIER population other than study region and race (Table S1). For patients who entered FOURIER-OLE, the mean±SD age of the patients at randomization was 62.4±8.6 years, and 23.3% were women. Overall, 83.8% had a history of myocardial infarction, 16.0% had a history of ischemic stroke, and 14.3% had symptomatic peripheral arterial disease.
| Baseline characteristics at the time of randomization in the parent FOURIER trial | Randomized treatment in FOURIER parent trial | |
|---|---|---|
| Placebo (n=3280) | Evolocumab (n=3355) | |
| Age, mean (SD), y | 62.4 (8.6) | 62.4 (8.6) |
| Male sex, n (%) | 2504 (76.3) | 2582 (77.0) |
| White race, n (%) | 3135 (95.6) | 3195 (95.2) |
| Region, n (%) | ||
| Europe | 2173 (66.3) | 2261 (67.4) |
| United States | 1107 (33.8) | 1094 (32.6) |
| Type of atherosclerosis | ||
| Myocardial infarction, n (%) | 2752 (83.9) | 2807 (83.7) |
| Median time from most recent myocardial infarction (IQR), y | 3.8 (1.1–8.3) | 3.8 (1.1–8.2) |
| Nonhemorrhagic stroke, n (%) | 517 (15.8) | 547 (16.3) |
| Median time from most recent stroke (IQR), y | 4.0 (1.4–8.3) | 3.8 (1.4–8.3) |
| Peripheral artery disease, n (%) | 460 (14.0) | 488 (14.5) |
| Cardiovascular risk factors | ||
| Hypertension, n/N (%) | 2772/3279 (84.5) | 2767/3355 (82.5) |
| Diabetes, n (%) | 1144 (34.9) | 1121 (33.4) |
| Current cigarette use, n/N (%) | 888/3279 (27.1) | 884/3355 (26.3) |
| Medications at time of enrollment in FOURIER, n (%) | ||
| Statin | ||
| High intensity | 2505 (76.4) | 2584 (77.0) |
| Moderate intensity | 769 (23.4) | 758 (22.6) |
| Low intensity, unknown intensity, or no data | 6 (0.2) | 13 (0.4) |
| Ezetimibe | 182 (5.5) | 200 (6.0) |
| Other cardiovascular medications, n/N (%) | ||
| Aspirin, P2Y12 inhibitor, or both | 3059/3279 (93.3) | 3149/3355 (93.9) |
| β-Blocker | 2664/3279 (81.2) | 2729/3355 (81.3) |
| ACE inhibitor or ARB, aldosterone antagonist, or both | 2606/3279 (79.5) | 2667/3355 (79.5) |
| Median lipid measures at randomization (IQR) | ||
| LDL-C, mg/dL | 91 (80–109) | 92 (80–108) |
| High-density lipoprotein cholesterol, mg/dL | 45 (38–53) | 45 (38–54) |
| Total cholesterol, mg/dL | 167 (151–188) | 167 (151–188) |
| Triglycerides, mg/dL | 132 (98–183) | 131 (98–177) |
| Apolipoprotein B, mg/dL | 83 (72–97) | 83 (72–96) |
| Lipoprotein(a), nmol/L | 37 (12–172) | 39 (13–177) |
All comparisons between randomized treatment arms were P>0.05 except for hypertension, which was P=0.02. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; FOURIER-OLE, FOURIER Open-Label Extension; IQR, interquartile range; and LDL-C, low-density lipoprotein cholesterol.
The median duration of follow-up in FOURIER-OLE was 5.0 years with an interquartile range (IQR) of 4.6 to 5.1 years and maximum follow-up time of 5.5 years. For patients randomized to evolocumab at the start of the parent FOURIER trial, median and maximum follow-up times in the study (parent FOURIER plus FOURIER-OLE) were 7.1 and 8.7 years, respectively. During FOURIER-OLE, premature study drug discontinuation occurred in 15% of patients (3.4% annualized incidence rate versus 6.3% annualized incident rate in the parent FOURIER trial) and in only 0.1% for an adverse event ascribed to evolocumab. Premature study drug discontinuation occurred in 14.0% of patients who were randomized to evolocumab in the parent study and 15.8% of patients originally randomized to placebo. Withdrawal of consent occurred in 2.1% and loss to follow-up without known vital status occurred in 0.2%, regardless of original treatment assignment in the main FOURIER trial (Figure S2).
Lipid Data
The baseline median LDL-C of the FOURIER-OLE population at randomization in the parent FOURIER trial was 91 mg/dL (IQR, 80–108 mg/dL). At the end of FOURIER, the values were 29 mg/dL (IQR, 18–47 mg/dL) for patients on evolocumab and 89 mg/dL (IQR, 74–111 mg/dL) for patients on placebo. At 12 weeks after the start of FOURIER-OLE, the median LDL-C was 30 mg/dL (IQR, 19–48 mg/dL) for the study population in aggregate and was similar for patients regardless of original treatment assignment. At that time, the achieved LDL-C was <70 mg/dL in 87.3%, <55 mg/dL in 80.3%, <40 mg/dL in 63.2%, and <20 mg/dL in 26.6% of patients and consistent when stratified by original treatment assignment. At 12 weeks, the least squares mean percentage reduction in LDL-C from baseline with evolocumab was 58.4% (95% CI, 57.6%–59.2%) in FOURIER-OLE. For patients randomized at the start of FOURIER to evolocumab, the reduction in LDL-C was consistent over long-term follow-up on evolocumab (median, 7.1 years; Figure 1). Evolocumab had similar sustained effects on related atherogenic measures, including a 50.2% (95% CI, 49.4%–50.9%) reduction in non–high-density lipoprotein cholesterol and a 44.4% (95% CI, 43.7%–45.2%) reduction in apolipoprotein B at week 12 compared with baseline (P<0.001 for each; Table S2).
Safety Events
During the parent study, the annualized incidence rates of all adverse events of interest were similar by randomized treatment arm for the FOURIER-OLE population, except for a nominally higher incidence of injection site reactions for patients treated with evolocumab versus those treated with placebo (0.81% versus 0.65%). There was no observed trend toward an increase in the incidence of any of the adverse events of interest over time (Table 2). Similarly, when annualized through the end of long-term follow-up, the overall annualized incidence rates for safety events of interest for patients randomized to evolocumab did not exceed the annualized incidence rate for patients treated with placebo (Table 2).
| Event type | Placebo (during parent FOURIER only; n=3277), n (%) | Evolocumab (during parent FOURIER only; n=3353), n (%) | Year of evolocumab exposure (parent FOURIER+FOURIER-OLE; n=3353), n (%) | Randomized to evolocumab (all follow-up; n=3353) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (n=3353) | 2 (n=3353) | 3 (n=3346) | 4 (n=3261) | 5 (n=3139) | 6 (n=3018) | 7 (n=2863) | 8 (n=1768) | ||||
| Serious adverse event | 813 (12.5) | 845 (12.8) | 454 (14.6) | 428 (13.7) | 413 (13.4) | 395 (13.1) | 374 (12.9) | 340 (12.2) | 260 (11.1) | 87 (9.9) | 1618 (10.2) |
| Injection site reaction | 49 (0.65) | 62 (0.81) | 47 (1.4) | 15 (0.45) | 13 (0.39) | 11 (0.34) | 3 (0.10) | 5 (0.17) | 3 (0.12) | 2 (0.22) | 92 |
| Potential drug-related allergic reaction | 83 (1.1) | 83 (1.1) | 48 (1.4) | 32 (0.96) | 16 (0.49) | 12 (0.37) | 10 (0.33) | 13 (0.44) | 6 (0.24) | 2 (0.22) | 128 (0.58) |
| Muscle-related event | 140 (1.9) | 157 (2.1) | 117 (3.6) | 50 (1.5) | 43 (1.3) | 24 (0.75) | 24 (0.78) | 17 (0.58) | 10 (0.41) | 1 (0.11) | 247 (1.2) |
| Rhabdomyolysis/myopathy event | 4 (0.05) | 3 (0.04) | 1 (0.03) | 2 (0.06) | 2 (0.06) | 0 | 1 (0.03) | 2 (0.07) | 1 (0.04) | 0 | 8 (0.04) |
| New-onset diabetes* | 107/2033 (2.32) | 90/2155 (1.84) | 32/2155 (1.49) | 40/2123 (1.90) | 27/2068 (1.34) | 22/1963 (1.15) | 12/1871 (0.66) | 15/1796 (0.86) | 14/1707 (0.96) | 4/1023 (0.78) | 166/2155 (1.21) |
| Cataract formation | 64 (0.85) | 55 (0.72) | 25 (0.75) | 26 (0.78) | 26 (0.79) | 26 (0.81) | 27 (0.88) | 26 (0.89) | 14 (0.57) | 5 (0.55) | 163 (0.74) |
| Hemorrhagic stroke | 4 (0.05) | 0 | 0 | 0 | 2 (0.06) | 2 (0.06) | 1 (0.03) | 3 (0.10) | 3 (0.12) | 0 | 10 (0.04) |
| Neurocognitive events | 42 (0.56) | 48 (0.63) | 25 (0.75) | 18 (0.54) | 28 (0.85) | 16 (0.50) | 30 (0.98) | 16 (0.54) | 11 (0.45) | 3 (0.33) | 132 (0.59) |
Data for parent FOURIER trial are restricted to patients who entered FOURIER-OLE. FOURIER indicates Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; and FOURIER-OLE, FOURIER Open-Label Extension.
*
Patients with diabetes at baseline in FOURIER and FOURIER-OLE were not at subsequent risk for developing new-onset diabetes mellitus.
Cardiovascular Events
During the FOURIER-OLE study period alone, patients originally randomized to evolocumab had a lower incidence of the FOURIER primary outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization compared with patients originally randomized to placebo (HR, 0.85 [95% CI, 0.75–0.96]; P=0.008) despite both treatment arms receiving evolocumab during this time (Figure 2). Likewise, the HR for the composite of the key secondary outcome of cardiovascular death, myocardial infarction, or stroke was 0.80 (95% CI, 0.68–0.93; P=0.003) and for cardiovascular death was 0.77 (95% CI, 0.60–0.99; P=0.04) during this period. Additional outcomes are given in Table 3.
| End points | Placebo (n=3280) | Evolocumab (n=3355) | ||||
|---|---|---|---|---|---|---|
| Patients with event, n | Incidence rate, % | Patients with event, n | Incidence rate, % | HR (95% CI) | P value | |
| Primary end point FOURIER: cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization | 551 | 3.96 | 490 | 3.36 | 0.85 (0.75–0.96) | 0.008 |
| Key secondary end point FOURIER: cardiovascular death, myocardial infarction, or stroke | 374 | 2.58 | 309 | 2.05 | 0.80 (0.68–0.93) | 0.003 |
| Coronary heart disease death or myocardial infarction | 267 | 1.82 | 199 | 1.30 | 0.72 (0.60–0.86) | 0.0004 |
| Cardiovascular death | 138 | 0.90 | 107 | 0.68 | 0.77 (0.60–0.99) | 0.04 |
| Coronary heart disease death | 97 | 0.63 | 64 | 0.40 | 0.65 (0.48–0.90) | 0.008 |
| Myocardial infarction | 194 | 1.32 | 151 | 0.99 | 0.75 (0.60–0.93) | 0.007 |
| Stroke | 94 | 0.63 | 102 | 0.66 | 1.05 (0.80–1.39) | 0.72 |
| Coronary revascularization | 313 | 2.20 | 280 | 1.88 | 0.85 (0.73–1.00) | 0.052 |
| Urgent revascularization | 166 | 1.13 | 132 | 0.87 | 0.77 (0.61–0.96) | 0.02 |
| Elective revascularization | 178 | 1.22 | 174 | 1.15 | 0.93 (0.76–1.15) | 0.52 |
| All-cause mortality | 344 | 2.23 | 338 | 2.14 | 0.97 (0.83–1.13) | 0.68 |
Incidence rate is per 100 person-years (annualized rate or events/100 person-years). All patients were treated with evolocumab during the extension program. The proportional hazards assumptions were violated for the primary outcome, key secondary outcome, and composite of coronary heart disease death or myocardial infarction. However, modified Poisson regression yielded identical relative risks (95% CI) compared with Cox models for the primary outcome and the composite of coronary heart disease death or myocardial infarction. For the key secondary outcome, modified Poisson regression yielded a relative risk of 0.79 (95% CI, 0.68–0.92; P=0.003). FOURIER indicates Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; FOURIER-OLE, FOURIER Open-Label Extension; and HR, hazard ratio.
Landmark analyses (Figure 3) demonstrated that the clinical benefit of earlier initiation of evolocumab was more apparent in the first 3 years of FOURIER-OLE (primary end point HR, 0.74 [95% CI, 0.64–0.86]; key secondary end point HR, 0.69 [95% CI, 0.57–0.83]) than after 3 years after the transition of all patients to open-label evolocumab (HR, 1.17 [95% CI, 0.93–1.46] and 1.06 [95% CI, 0.81–1.37]; respectively; Pinteraction<0.001 and 0.0088, respectively). Cardiovascular outcome data for the parent and extension studies combined are shown in Table S3 and Figures S3 and S4.
Discussion
In the longest follow-up available to date with a PCSK9 inhibitor, the current findings demonstrate that evolocumab is both safe and well tolerated long-term, with the majority of patients achieving LDL-C levels <40 mg/dL. There was also a lower rate of major adverse cardiovascular events, including cardiovascular death, in patients originally randomized to evolocumab. These findings highlight that achieving very low LDL-C concentrations over the long term through blockade of the PCSK9 protein is both safe and efficacious in patients with stable atherosclerotic cardiovascular disease. Furthermore, earlier initiation of treatment was more beneficial and there was a legacy effect of having lower LDL-C as evidenced by subsequent continued accrual of cardiovascular benefit over several years despite patients treated with placebo during FOURIER being transitioned to open-label evolocumab at the start of FOURIER-OLE and the LDL-C levels thereafter being the same in the 2 original treatment arms.
To date, the availability of studies to examine the long-term safety and efficacy of PCSK9 inhibitors has been limited. The phase 3 FOURIER trial demonstrated that lowering of LDL-C to a median LDL-C of 30 mg/dL on a background of statin therapy reduced the risk of major adverse cardiovascular events by 15% to 20%.4 A reduction in cardiovascular death was not observed over a median of 2.2 years, although there was a nonstatistically significant lower risk of death attributable to acute myocardial infarction (HR, 0.84 [95% CI, 0.49–1.42]).4 It is notable that the clinical benefit of evolocumab toward a reduction in major adverse cardiovascular events was more apparent after the first 12 months of treatment in the parent FOURIER study. This observation is consistent with the lag in clinical benefit also observed with LDL-C lowering with statins.11 Similarly, evolocumab appeared to be safe and well tolerated in OSLER-1 (Open Label Study of Long Term Evaluation Against LDL-C Trial), an open-label study of evolocumab in patients with hypercholesterolemia that followed up patients for up to 5 years. However, the number of patients followed up through 5 years was modest (n=651).12
In the phase 3 ODYSSEY OUTCOMES trial,6 alirocumab significantly reduced the risk of major adverse cardiovascular events by 15% over a median of 2.8 years in patients after an acute coronary syndrome on maximally tolerated statin therapy. There was a nominally lower rate of mortality with greater apparent benefit for those patients treated for >3 years.7
In the FOURIER-OLE study, long-term treatment with evolocumab was studied in 6635 subjects with a median follow-up of 5 years and maximum exposure times of >8 years when parent and extension studies were combined. The majority of subjects achieved very low LDL-C levels, with 63% achieving an LDL-C of <40 mg/dL at 12 weeks. Some early epidemiological studies raised concerns that very low LDL-C may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects.13 However, the current study did not suggest that the frequency of adverse events of interest increased over time through long-term follow-up for patients on evolocumab and did not exceed the observed rates in the placebo arm during the parent study. These findings are consistent with prior observations on the safety of long-term low levels of LDL-C achieved with statins and ezetimibe14,15 but now extend to LDL-C levels <40 mg/dL and through PCSK9 inhibition.
It is also notable that compared with patients originally randomized to placebo, those randomized to evolocumab in the parent trial continued to accrue cardiovascular benefit for several years during the extension period, although all patients were transitioned to open-label evolocumab at the start of the extension. Specifically, FOURIER-OLE patients originally randomized to evolocumab were less likely to have major adverse cardiovascular events or to die of cardiovascular causes, particularly coronary causes, compared with FOURIER-OLE patients originally randomized to placebo. These findings are consistent with 2 observed phenomena related to the same underlying biological principle. The first phenomenon is the legacy effect of intensive LDL-C lowering that has been documented in trials of statins,16–20 including the emergence of a benefit on cardiovascular mortality only after a relatively shorter-duration trial was completed.20 In these trials, after the randomized placebo comparisons, the use of statins was similar in the 2 arms, varying from a minority to being offered to all. Thus, although the term legacy effect is often used to describe the persistence of clinical benefit that continues beyond cessation of the intervention, the term in the setting of LDL-C lowering may be used to describe a clinical benefit that persists or emerges between 2 treatment arms that previously had different LDL-C levels but were subsequently similar during an extension phase.
The second phenomenon is a lag before the full onset of clinical benefit of LDL-C lowering, as has been documented across all the major LDL-C–lowering drug classes.4,6,9,11 Both of these observed phenomena are related to the principle that the clinical benefit of LDL-C lowering, mediated through modifying atherosclerotic plaque volume and composition,21–25 is neither immediate in onset nor immediate in offset. Thus, the continued divergence in the risk of major adverse cardiovascular events in the first several years in FOURIER-OLE between patients originally allocated to evolocumab and those allocated to placebo in the parent FOURIER trial reflects both the legacy effect from the wide separation in LDL-C between those 2 arms during FOURIER and the lag in the onset of clinical benefit from the patients receiving placebo transitioned to evolocumab in the extension. These data support the notion that earlier initiation of treatment strategies to lower LDL-C is of clinical benefit and underscore the importance of having cardiovascular outcomes trials of lipid-modifying therapy have adequate follow-up, typically on the order of 5 years, to fully define the clinical benefit of such therapy in patients with stable atherosclerotic cardiovascular disease, particularly any cardiovascular mortality benefit.16,17,26 The current study did not show an effect on noncardiovascular or all-cause mortality
Limitations of the current analysis merit consideration. All patients in the extension program were treated with open-label evolocumab, resulting in no concurrent placebo arm during this period. Although not all patients participated in FOURIER-OLE, baseline characteristics were broadly comparable between the originally randomized treatment arms, thereby allowing reasonably unconfounded exploratory comparisons between groups. Nonetheless, one cannot exclude that unmeasured confounders may have existed between patients originally randomized to evolocumab and those originally randomized to placebo. Patients who participated in the extension program were overall similar to those who participated in the parent trial other than differences in race and global region. Because patients needed to have survived the parent study to be enrolled in FOURIER-OLE, the extension population would be expected to be at somewhat lower risk than all those entering the parent FOURIER trial. However, because all-cause mortality was similar between treatment arms in the parent study, one would not expect differential effects of survival bias between treatments. Commensurate with clinical practice, not all patients in the parent or extension studies were on a high-intensity statin or ezetimibe, but effect modification was not observed in FOURIER on the basis of background therapy.4 Cardiovascular outcomes were prespecified for the current analysis but considered exploratory; no adjustments were made for multiplicity, thereby increasing the risk for type 1 error. After FOURIER completely closed out, sites were provided with their patients’ treatment assignment. Because all patients were on open-label therapy at this time, one would not expect this to influence safety reporting, but the possibility of bias cannot be excluded. All cardiovascular outcomes were reviewed centrally by a clinical events committee made up of members who remained blinded to treatment assignment.
Conclusions
The present findings show that long-term use of evolocumab with a median follow-up of >7 years appears both safe and well tolerated. Furthermore, several years of earlier intensive LDL-C lowering with evolocumab was associated with continued accrual of cardiovascular benefit over the next several years, arguing for early initiation and continued LDL-C reduction to maximize clinical benefit.
Article Information
Supplemental Material
Appendixes A–C
Tables S1–S3
Figures S1–A4
Footnote
Nonstandard Abbreviations and Acronyms
- FOURIER
- Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk
- FOURIER-OLE
- Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk Open-Label Extension
- HR
- hazard ratio
- IQR
- interquartile range
- LDL-C
- low-density lipoprotein cholesterol
- ODYSSEY OUTCOMES
- Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab
- PCSK9
- proprotein convertase subtilisin-kexin type 9
- TIMI
- Thrombolysis in Myocardial Infarction
Supplemental Material
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© 2022 American Heart Association, Inc.
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History
Received: 8 July 2022
Accepted: 1 August 2022
Published online: 29 August 2022
Published in print: 11 October 2022
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Disclosures
Disclosures Dr O’Donoghue has received grant funding through Brigham and Women’s Hospital from Amgen, Novartis, AstraZeneca, Janssen, Intarcia, and GlaxoSmithKline and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr Giugliano reports personal fees from Medical Education Resources, Amarin, AstraZeneca, Boeringer-Ingelheim, Bristol Myers Squibb, CVS Caremark, Artivion, Janssen, Medscape, CSL Behring, Pfizer, Servier, Esperion, Gilead, Eli Lilly, Samsung, SAJA Pharmaceuticals, Dr Reddy’s Laboratories, Centrix, Hengrui, Inari, Novartis, PhaseBio, St. Luke’s Hospital System, Menarini, Shanghai Medical Group, VoxMedia, Bayer, LabCorp, Paratek, and Caladrius; grants and personal fees from Amgen, Daiichi Sankyo, Merck, and Sanofi Aventis; grants from Anthos and Ionis, outside the submitted work; and an institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital for research in which he is not directly involved from Abbott, Aralez, AstraZeneca, Bayer, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Roche, Takeda, and Zora Biosciences. Dr Atar reports speaker’s honoraria and consultancy fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Merck, Novartis, and Sanofi-Regeneron, as well as research funding to his institution from Bristol Myers Squibb, Pfizer, Medtronic, and Roche Diagnostics. Ms Kuder, Dr Im, and Ms Murphy are members of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., The Medicines Company, and Zora Biosciences. Drs Abbasi, Lopez, Monsalvo, Elliott-Davey, Flores-Arredondo, and Wang are employees of Amgen. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis, The Medicines Company, MedImmune, Merck, Novartis, and Pfizer, as well as consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.
Sources of Funding
The study was funded by Amgen.
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