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Association Between Achieved LDL-C Levels and Long-Term Cardiovascular and Safety Outcomes
TAKE-HOME MESSAGE
- This prespecified analysis of the FOURIER-OLE study assessed the relationship between achieved LDL-C levels and the incidence of subsequent cardiovascular and safety outcomes among 6559 patients treated with evolocumab over 7 years of follow-up. The authors found that lower achieved LDL-C levels, down to <20 mg/dL, were associated with lower risks of the primary efficacy endpoint (composite of cardiovascular death, myocardial infarction, stroke, and hospital admission for unstable angina or coronary revascularization) and the secondary efficacy endpoint (composite of cardiovascular death, myocardial infarction, and stroke), with no significant safety concerns.
- These findings suggest that long-term achievement of lower LDL-C levels is safe and associated with a lower risk of adverse cardiovascular events and all-cause mortality in patients with atherosclerotic cardiovascular disease.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Low-density lipoprotein cholesterol (LDL-C) level is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown.
METHODS
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed up with for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels.
RESULTS
In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the trial's primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, or hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for both end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years.
CONCLUSIONS
In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns.
Additional Info
Disclosure statements are available on the authors' profiles:
Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE
Circulation 2023 Feb 13;[EPub Ahead of Print], P Gaba, ML O'Donoghue, JG Park, SD Wiviott, D Atar, JF Kuder, K Im, SA Murphy, GM De Ferrari, ZA Gaciong, K Toth, I Gouni-Berthold, J Lopez-Miranda, F Schiele, F Mach, JH Flores-Arredondo, JAG López, M Elliott-Davey, B Wang, ML Monsalvo, S Abbasi, RP Giugliano, MS SabatineFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
One of the downsides to the two landmark PCSK9 inhibitor randomized clinical trials was that their follow-up periods were too short. The follow-up of FOURIER was 2.2 years and ODYSSEY was 2.8 years. Concerns were expressed that these lengths of follow-up did not allow for a full evaluation of safety nor allow for proper interrogation of hard outcomes like all-cause and cardiovascular disease (CVD) death. After all, most patients take lipid-lowering drugs long term (often for the rest of their lives).
In the current report published in Circulation, FOURIER investigators report on an observational open-label extension of a subset of FOURIER trial participants (N = 6635 of the full trial cohort of 27,546). The follow-up period was approximately 7.2 years in total, 2.2 years of which in trial and a median of 5 years more in the open-label extension trial.
Two main messages emerge from the longer-term follow-up data. First, safety, even down to extremely low LDL-C levels (<20 mg/dL), appears to be preserved. Second, like the known reductions in nonfatal CVD outcomes during the original trial follow-up, there was a trend to lower coronary heart disease death and all-cause death (but none for CVD death) among those with the lowest achieved LDL-C levels during extended follow-up. This was important to note because there was a minor signal, which was not statistically significant, that death during the original PCSK9 inhibitor trials may have been higher in the active treatment arm (certainly for the FOURIER trial).
Obviously, these observational data are hypothesis-generating, but they do give some reassurance that achievement of very low LDL-C levels is safe and effective.