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Optimizing CV outcomes with evolocumab

Dr. Robert Giugliano
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, US
Prof. Ulrich Laufs
University of Saarland
Homburg, Germany
Prof. Gaetano De Ferrari
University of Pavia, Italy
Prof. Naveed Sattar
University of Glasgow, UK
11 Oct 2018

The FOURIER trial previously demonstrated that adding the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to background statin therapy lowered LDL-cholesterol (LDL-C) below target levels and significantly reduced the risks of cardiovascular (CV) events in patients with atherosclerotic cardiovascular disease (ASCVD). At the European Society of Cardiology (ESC) Congress 2018 in Munich, Germany, experts reiterated how evolocumab helps lower LDL-C levels and reduces CV events even in patients with various comorbidities.

LDL-C lowering and CV risk reduction

“Among the modifiable CV risk factors, lowering LDL-C levels has been established to have significant benefits in reducing patients’ CV risk,” said Dr Robert Giugliano of the Harvard Medical School in Boston, Massachusetts, US. [Am J Cardiol 1998;82(suppl 2):3-12; J Am Coll Cardiol 2004;43:2142-2146]

“However, survey results of EUROASPIRE V revealed that only 36 percent of patients on high-intensity lipid-lowering therapy achieved the target LDL-C level of <1.8 mmol/L,” he continued. [De Backer G, et al, EAS 2018] “This highlights the need for continued efforts to improve lipid management especially in very high-risk patients.”

In patients with stable ASCVD, the FOURIER trial demonstrated that treatment with evolocumab on top of background statin therapy significantly reduced LDL-C levels by 59 percent (ie, from 2.4 mmol/L at baseline to 0.78 mmol/L; p<0.001). Compared with placebo, evolocumab treatment significantly reduced the risk of the primary efficacy endpoint (ie, composite of CV death, MI, stroke, hospitalization for unstable angina [UA] or coronary revascularization; hazard ratio [HR], 0.85; 95 percent confidence interval [CI], 0.79 to 0.92; p<0.001) and key secondary efficacy endpoint (ie, composite of CV death, MI or stroke; HR, 0.80; 95 percent CI, 0.73 to 0.88; p<0.001], with no significant safety concerns. [N Engl J Med 2017;376:1713-1722]

“Secondary analysis of FOURIER showed that evolocumab reduced CV events regardless of whether patients’ baseline LDL-C levels were <1.8 or 1.8 mmol/L,” noted Giugliano. The risk of the primary endpoint was reduced by 20 percent in patients with baseline LDL-C <1.8 mmol/L (HR, 0.80; 95 percent CI, 0.60 to 1.07) and by 14 percent in those with baseline LDL-C 1.8 mmol/L (HR, 0.86; 95 percent CI, 0.79 to 0.92) (p interaction=0.65). The corresponding risk reduction for the secondary endpoint was 30 percent (HR, 0.70; 95 percent CI, 0.48 to 1.01) and 19 percent (HR, 0.81; 95 percent CI, 0.73 to 0.89) (p interaction=0.44), respectively. [JAMA Cardiol 2017;2:1385-1391]

“Importantly, achievement of lower LDL-C levels translated to greater reductions in CV events, with no associated safety issues,” he added. [Lancet 2017;390:1962-1971]

Evolocumab in patients with stroke history or PAD

“Patients with a history of stroke or peripheral arterial disease [PAD] have very high vascular risk,” said Professor Ulrich Laufs of Leipzig University, Germany. “In subgroup analyses of FOURIER, absolute CV risk reduction associated with evolocumab treatment was higher in these patients.”

“In the cohort of patients with a history of stroke, evolocumab treatment continued to significantly reduce the risk of the primary endpoint [HR, 0.85; 95 percent CI, 0.72 to 1.00; p=0.047],” he said. [Pedersen TR, et al, ESC 2017] “Similarly, evolocumab treatment significantly reduced key secondary endpoints in patients with [HR, 0.73; 95 percent CI, 0.59 to 0.91; p=0.0040] or without PAD [HR, 0.81; 95 percent CI, 0.73 to 0.90; p<0.0001].” (Figure 1) [Circulation 2018;137:338-350]

HK-AMG-105md IU2 Figure 1

Major adverse limb events (MALEs) were also reduced with evolocumab treatment in patients with (HR, 0.63; 95 percent CI, 0.39 to 1.03; p=0.063) or without PAD (HR, 0.37; 95 percent CI, 0.16 to 0.88; p=0.0197). Overall, lower achieved LDL-C levels were associated with a lower risk of MALE with a roughly linear relationship. [Circulation 2018;137:338-350]

Evolocumab in patients with diabetes

“Patients with type 2 diabetes have increased CV risk and shorter life expectancy,” said Professor Naveed Sattar of the University of Glasgow in Glasgow, Scotland. [JAMA 2015;314:52-60] “In a meta-analysis of randomized clinical trials comparing the efficacy of evolocumab, placebo and ezetimibe, evolocumab consistently lowered LDL-C in patients with or without type 2 diabetes, confirming that it provides consistent LDL-C reductions regardless of whether or not patients have diabetes.” [Lancet Diabetes Endocrinol 2016;4:403-410]

Evolocumab in patients with CAD

“Patients with more recent or multiple prior MIs and those with residual multivessel coronary artery disease [CAD; ie, ≥40 percent stenosis in ≥2 large vessels] are at significantly higher risk of CV events,” said Professor Gaetano De Ferrari of the University of Pavia in Pavia, Italy. “In another FOURIER subgroup analysis, the risk reductions in CV outcomes at 3 years associated with evolocumab treatment were greater in these high-risk subgroups, with correspondingly lower numbers needed to treat [NNTs].” [Circulation 2018, doi: 10.1161/CIRCULATIONAHA.118.034309]

Subgroup analysis results showed that evolocumab treatment was associated with relative risk reductions (RRRs) in CV events (ie, composite of CV death, MI, or stroke) of 24 percent in patients with qualifying MI <2 years ago (HR, 0.76; 95 percent CI, 0.64 to 0.89; p<0.01; NNT, 35), 13 percent in patients with MI 2 years ago (HR, 0.87; 95 percent CI, 0.76 to 0.99; p=0.04; NNT, 101), 30 percent in patients with multivessel CAD (HR, 0.70; 95 percent CI, 0.58 to 0.84; p<0.001; NNT, 29), and 11 percent in those without multivessel CAD (HR, 0.89; 95 percent CI, 0.79 to 1.00; p=0.055; NNT, 78).

“Greater reductions in CV events were also seen in patients with a higher number of high-risk MI features than those without,” added De Ferrari.

In patients with at least one high-risk MI feature (ie, <2 years from qualifying MI, 2 prior MIs, or residual multivessel CAD), treatment with evolocumab resulted in a 22 percent RRR in CV events [ie, from 11.0 percent to 8.6 percent; absolute risk reduction (ARR), 2.5 percent], compared with a 6 percent RRR in patients with no high-risk features (ie, from 7.8 percent to 7.3 percent; ARR, 0.5 percent). (Figure 2) [Circulation 2018, doi: 10.1161/CIRCULATIONAHA.118.034309]

HK-AMG-105md IU2 Figure 2

“The NNT in 3 years to prevent one CV death, MI or stroke is about 50 in the overall population in FOURIER,” he continued. “The corresponding NNT is 29–40 for patients with additional high-risk MI features. These patients will thus likely experience more substantial risk reductions with evolocumab treatment.” [De Ferrari G, personal calculations]

Summary

Based on subgroup analyses of FOURIER, the LDL-C lowering and CV benefits associated with evolocumab therapy remain consistent across various patient subgroups regardless of their baseline characteristics.

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