1. This multi-year, open-label extension of phase 2 trials examining the LDL-lowering efficacy of evolocumab (PCSK9-inhibitor) showed that evolocumab plus standard of care lipid lowering therapy had continued lipid lowering response after over four years of follow-up.
2. Significant adverse events, including new-onset diabetes, neurocognitive complications, or development of neutralizing antibodies, were very uncommon in the study population and not increased compared to those receiving standard of care therapy.
Evidence Rating Level: 2 (Good)
Study Rundown: Numerous trials have shown the efficacy of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9-inhibitor) at reducing low-density lipoprotein cholesterol (LDL-C) when statins were not sufficient. These trials, however, have only been studied over short periods, and none exceeded 24 months of follow-up. This study enrolled patients who had taken part in clinical trials for the PCSK9-inhibitor evolocumab to continue therapy in an open label trial to evaluate long term efficacy and safety.
This study demonstrated that evolocumab was associated with persistently low levels of LDL-C up to 4 years of follow-up both compared to standard-of-care (SOC) and prior baseline. Rates of significant adverse events did not differ between treatment and control arms, and development of new diabetes, neurocognitive deficits, or neutralizing antidrug antibodies were very low. The strengths of the study included large sample size, long follow up, and appropriate evaluation of possible adverse effects. Limitations of the study included the inherent bias of an open-label trial. Additionally, the trial enrolled patients who completed prior trials for evolocumab and thus excluded patients who had adverse events during the earlier trials. In addition, long term cardiovascular endpoints were not evaluated, which is the main outcome of concern.
In-Depth [prospective cohort]: This study (Open-Label Study of Long-term Evaluation Against LDL-C, OSLER-1) was comprised of a cohort selected from phase 2 trials evaluating evolocumab therapy in patients with high risk of cardiovascular disease not receiving adequate lipid management with statin therapy. Patients were excluded if they developed a serious adverse event (SAE) during prior therapy with evolocumab and if they required unblinded adjustment of lipid therapy during the first 12 weeks of the study. The current study included a 52-week control period that compared evolocumab therapy to standard-of-care (SOC) in a 2:1 ratio. Following completion of the 52-week period, the SOC group then transitioned to evolocumab therapy. Follow up lipid evaluation at 1,2,3, and 4 years was available for 92%, 85%, 80%, and 61% of patients respectively.
After 52-weeks of therapy, evolocumab plus SOC was associated with reduction in LDL-C by 61%, compared to 2% with SOC alone (P<0.001). Compared to patient baseline LDL-C levels, there was 59%, 59%, and 57% reduction in LDL-C at 2, 3, and 4 years respectively. SAE occurred in 6.9% of the evolocumab plus SOC arm compared to 6.8% in the SOC alone arm. New onset diabetes (2.8% vs 4.0%), neurocognitive events (0.4% vs. 0.0%), and muscle related events (4.7% vs. 8.5%) did not significantly increase for the evolocumab therapy arm compared with the SOC arm. Non-neutralizing antidrug antibodies developed transiently in 4 patients and then resolved. No neutralizing antidrug antibodies developed during the study.
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