Background: In FOURIER, the PCSK9 inhibitor evolocumab reduced LDL-C and risk of cardiovascular events and was safe and well-tolerated over 2.2 years median follow-up. However, large-scale, long-term data are lacking. Methods: The parent FOURIER trial randomized 27,564 patients with ASCVD and LDL-C ≥70mg/dl on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in two open-label extension studies (FOURIER-OLE) in the United States and Europe; primary analyses were pooled across studies. The primary endpoint was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. Results: 6,635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in 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% 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 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, MI, stroke, hospitalization for unstable angina or coronary revascularization (HR 0.85 [95% CI 0.75-0.96]; P=0.008), a 20% lower risk of cardiovascular death, MI or stroke of (HR 0.80 [0.68-0.93]; P=0.003), and a 23% lower risk of cardiovascular death (HR 0.77 [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 over >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.

BackgroundLimited information exists on the role of B‐cell‐dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B‐cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP).Methods and Results CMP protocol involved the use of l‐NAME and NaCl in the drinking water and angiotensin‐II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild‐type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T‐ and B‐cell deficient); CD22− CMP (B‐cell depleted); and Nude CMP (T‐cell deficient), with their respective controls. We performed B‐cell depletion and reconstitution protocols. The protective effect of B‐cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22− CMP group compared to WT CMP. Once SCID mice underwent B‐cell reconstitution with isolated CMP B‐cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B‐cells stimulate collagen production by cardiac fibroblasts.ConclusionsThe absence of B‐cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B‐cells play a contributory role in an angiotensin‐II‐induced HF model.

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Evidence of anti-cardiac antibodies and complement activation was found in a large number of patients with end-stage cardiomyopathy regardless of the aetiology. Adenosine triphosphate synthase appears to be a new prominent antigenic stimulus; but more interestingly, the simultaneous co-existence of activated complement components suggests that this humoral mechanism may participate in disease progression.

BACKGROUND: 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 P trend <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. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.