Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment

Literature - Stiekema LCA, Stroes ESG, Verweij SL et al. - Eur Heart J. 2018 Dec 18. doi: 10.1093/eurheartj/ehy862

Introduction and methods

Lipoprotein(a) [Lp(a)], composed of an apolipoprotein(a) tail covalently bound to an LDL-c core, is a potential, independent and causal risk factor for CVD. The Lp(a)-mediated risk is partly driven by pro-inflammatory oxidized phospholipids (OxPL), which are present on the apo(a) tail [1,2]. In patients with elevated Lp(a) levels, Lp(a)-associated OxPL act as crucial intermediates in arterial wall inflammation [3].

To date, no potent Lp(a)-lowering therapies are available, thus it is recommended to target other modifiable CVD risk factors to lower CVD risk in individuals with high Lp(a)[4]. Monoclonal antibodies directed at PCSK9 not only lower LDL-c levels, but also modestly reduce Lp(a). In patients without elevated Lp(a) levels, the PCSK9 inhibitor evolocumab was shown to lower Lp(a) by about 20-30% [5]. A posthoc analysis of FOURIER data showed that patients with elevated baseline Lp(a) showed greater absolute CVD risk reduction after evolocumab treatment [6], although they had a smaller percent reduction in Lp(a) levels than seen in those with normal Lp(a) levels at baseline [7]. Thus, low Lp(a) levels were not achieved with PCSK9 inhibition.

The multicenter phase 3b, double-blind ANITSCHKOW study evaluated whether potent LDL-c lowering combined with modest Lp(a) lowering with evolocumab attenuates arterial inflammation as a surrogate for CVD risk in patients with elevated Lp(a). Eligible patients had a fasting LDL-C of

≥2.6mmol/L (100mg/dL), an Lp(a) level of ≥125 nmol/L (50mg/dL). Patients also had arterial wall inflammation as assessed by a most diseased segment target-to-background ratio (MDS TBR) of >_1.6 in an index vessel measured with 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT). 129 Patients were randomized to monthly subcutaneous injections of either evolocumab 420 mg or placebo, for 16 weeks. Mean (SD) LDL-c level at baseline was 3.7 (1.0) mmol/L [144.0 (39.7) mg/dL] and median (IQR) Lp(a) level was 200.0 (155.5, 301.5) nmol/L [80.0 (62.5-121.0) mg/dL) in the total study population.

Main results

• Treatment with evolocumab significantly reduced LDL-c at week 16 by 60.7% (95%CI: -65.8 to -55.5, P<0.0001) as compared with placebo. In the evolocumab-treated group, mean LDL-c at week 16 was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL).
• After treatment with evolocumab, a mean percent change in Lp(a) from baseline of -13.9% (95%CI: -19.3 to 08.5%, P<0.0001) was seen, as compared with placebo.
• Median absolute changes in Lp(a) were -28.0 (IQR: -56.5 to 9.0) nmol/L [-11.2 IQR: -22.6 to 3.6) mg/dL] for evolocumab vs. 1.5 (-19.o to 18.0) nmol/L [0.6 (7.6 to 7.2) mg/dL] for placebo. The median Lp(a) level at week 16 in the evolocumab group was 188.0 (IQR: 140.0-268.0) nmol/L [75.2 (IQR: 56.0-107.2) mg/dL].
• Least square (LS) mean percentage change from baseline in MDS TBR of the index vessel was -8.3% (95%CI: -11.6 to -5.0%) in those treated with evolocumab, compared with -5.3% (95%CI: -8.6% to -2.0%) in the placebo group. No significant treatment difference was observed (-3.00, 95%CI: -7.40 to 1.39, P=0.18).
• In evolocumab-treated patients, the effect on MDS TBR of the index vessel did not depend on baseline statin use.
• No significant correlation was found between baseline Lp(a) and baseline MDS TBR (Pearson correlation coefficient R= -0.05, P=0.61), nor between baseline Lp(a) and baseline MDS TBR (R= -0.06, P=0.48).
• Absolute change in LDL-c or Lp(a) were not correlated to change in MDS TBR in patients receiving evolocumab (LDL-c: R=0.01, P=0.95; Lp(a): R=-0.16, P=0.21).

Conclusion

References

Find this article online at Eur Heart J View this video in which Prof. Erik Stroes summarizes the results of the Anitschkow study