The addition of PCSK9 inhibitor evolocumab to optimised statin therapy improves features of plaque stability after acute coronary syndrome (ACS), according to a study presented by Australian cardiologist Professor Stephen Nicholls in a late-breaking session at the European Society of Cardiology (ESC) Congress 2021.¹

This new data adds to the growing evidence of the impact on atherosclerosis and clinical outcomes of intensive lipid lowering with evolocumab plus maximally tolerated statins.

It’s been previously shown that evolocumab added to optimal statin therapy leads to a reduction in plaque burden in patients with coronary artery disease (CAD), the extent of which is proportional to the reduction in LDL-C levels.²

With respect to clinical outcomes, the FOURIER study³ found that evolocumab plus statin therapy leads to a reduction in the risk of cardiovascular events, with the benefit seen across all patient subgroups, including in patients with low baseline LDL-C levels (median, 1.9 mmol/L).

Professor Nicholls says that this latest data may help further understand the underlying mechanisms for the reduction in cardiovascular risk that results from lowering LDL-C. He also says that the data is a further reminder of the benefits of early and intensive lipid lowering in high-risk patients.

Intensive lipid lowering has previously been shown to promote plaque regression

Clinical trials have shown that intensive lipid lowering with statins slows disease progression and promotes plaque regression, with the impact proportional to the extent of LDL-C lowering.^4-6

Since evolocumab significantly reduces LDL-C levels beyond what can be achieved with statin therapy,³ the GLAGOV trial² looked at whether adding evolocumab to statin therapy had any further impact on coronary atherosclerosis in patients with angiographic coronary disease. It found that evolocumab resulted in a greater decrease in percent atheroma volume and more plaque regression compared to placebo.²

Participants with angiographic coronary disease were randomised to receive monthly evolocumab (420 mg; n = 484) or placebo (n = 484) for 76 weeks, in addition to statins. The addition of evolocumab resulted in lower mean, time-weighted LDL-C levels (93.0 versus 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to 53.4]; P<0.001) and percent atheroma volume (PAV) decreased 0.95% (compared to an increase in PAV with placebo of 0.05%; difference, -1.0% [95% CI, -1.8% to -0.64%]; P<0.001). In addition, evolocumab induced plaque regression in a greater percentage of patients compared to placebo (64.3% versus 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < 0.001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < 0.001 for total atheroma volume [TAV]).²

HUYGENS investigated the impact on plaque features of intensive lipid lowering

The HUYGENS trial¹ used optical coherence tomography (OCT) to assess the impact on plaque phenotype of adding evolocumab to statin therapy (versus statin therapy alone) for patients who had experienced an ACS. Specifically, the trial assessed whether there were any benefits related to high-risk features of coronary artery plaques.

The study authors describe the significance of plaque phenotype on cardiovascular risk: “The presence of a lipid rich plaque, as evidenced by a thin fibrous cap, but also with wide lipid arc and presence of macrophages on OCT, has been reported to be associated with a greater rate of cardiovascular events on long term follow-up…Clinical trials using serial OCT imaging have demonstrated that statin therapy has a favourable effect on plaque, as evidenced by an increase in FCT [fibrous cap thickness] and a reduction in the size of lipid pool.”

HUYGENS design and results¹

In this multicenter 52-week study,¹ patients with NSTEMI, angiographic CAD on maximally tolerated statin therapy were randomised to receive evolocumab (420 mg) or placebo SC monthly, commencing within a week of the ACS event.

Using OCT analysis on regions of plaque containing FCT ≤120 µm and lipid arc >90 degrees, the primary endpoint was change in minimum FCT anywhere in the analysed segment. Secondary endpoints were percent change in minimum FCT, change in average minimum FCT and change in maximum lipid arc.

A total of 161 patients (81 placebo; 80 evolocumab) from 27 centres were enrolled in the study. At baseline, almost 80% of the study population were on high-intensity statins (82.7% in placebo group and 78.8% in evolocumab group).¹

Over 70% of patients at baseline (71.6% placebo group; 77.5% evolocumab group) were found to have regions of plaque with a minimum FCT <65µm, which the investigators point out is a feature associated with a high risk of plaque rupture. Additionally, lipid rich plaques (defined as three consecutive images containing FCT ≤120µm and lipid arc >90 degrees) were seen in 91% of the placebo group and 90% of the evolocumab group.¹

The addition of evolocumab to maximally tolerated statin therapy increased the fibrous cap thinkness by 42.7 µm compared to an increase of 21.5 µm with optimised statin therapy alone (75% increase versus 39%; p=0.01). The addition of evolocumab also improved all of the study’s secondary endpoints, including decreasing the maximum lipid arc by -57.5 degrees, compared to -31.4 degrees for high-intensity statin therapy alone (p=0.01).¹

The addition of evolocumab to high-intensity statin therapy also reduced LDL-C by 80% (140 mg/dL to 28 mg/dL) versus 39% for high-intensity statin therapy alone (142 mg/dL to 87 mg/dL). The most common treatment-emergent adverse events (>3%) were angina pectoris, myalgia, hypertension, diarrhoea, fatigue and cough.¹

The investigators conclude that after 12 months of more intensive lipid lowering with the addition of  evolocumab to maximally tolerated statins, there were greater increases in the minimum FCT and decreases in the maximum lipid arc, both throughout the vessel and within lipid rich plaques. They add, “At 12 months after a NSTEMI only 12.5% of patients treated with evolocumab in addition to maximally tolerated statins demonstrated evidence of any region with a minimum FCT <65 µm…The degree of benefit was directly proportional to the intensity of lipid lowering observed.”¹

 Intensive lipid lowering continues to be the take-home message

Professor Nicholls points out that statin intensification occurred in both groups of patients at baseline, resulting in improvements in plaque characteristics across the study population, albeit with significantly greater improvements in the group who received evolocumab.

“In a lot of ways, the take home message of this study is about intensive lipid lowering,” explained Prof Nicholls. “We really think the best opportunity to intervene [after ACS] is as early as possible…Even if you put the PCSK9 inhibitor impact to the side, these results explain why it’s important to treat these patients early and keep their lipids low, and their vessels do look better as a result,” he added.

When considering LDL-C goals, Prof Nicholls suggested, “How low should you go? As low as you possibly can…but that’s got to be balanced with tolerance considerations. We do know that even in patients where we have not achieved our LDL-C goal but we have lowered their lipid levels substantially, we have also altered their risk of future events substantially.”

The PBS criteria for initiating a PCSK9 inhibitor in non-familial hypercholesterolaemia necessitate at least a prior 12-week treatment period of maximum-tolerated statin plus ezetimibe. Unless these criteria are met, therapy with evolocumab cannot be started in hospital following an event. Prof Nicholls suggests that this necessitates a proactive approach:  “In clinical practice, we can allow inertia to creep in. We know that it takes time to modify any of the risk factors, so we need to be proactive about it. We need to commit to measuring the cholesterol six to eight weeks after hospitalisation.” He explains his approach to initiating intensive therapy during the hospital stay:  “In situations where I know I may need to initiate a PCSK9 inhibitor, I know I will have to treat the patient for twelve weeks with a statin and ezetimibe first. If their LDL-C is at 7 at the time, I know the statin plus ezetemibe combination is unlikely to reduce the LDL-C to goal, so I may as well start both of these as early as possible. We’re generally getting better at doing this,” he said.

Professor Nicholls is keen to see more early aggressive lipid lowering after cardiac events. “Are we sending people home on the right combinations of therapy that actually are going to keep them out of hospital? The time you are at the greatest risk as having another event in 6-12 months,” he explained.

References

1. Nicholls S et al. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: primary results of the HUYGENS Study. Oral presentation, European Society of Cardiology Congress, August 27-30, 2021.
2. Nicholls S et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA 2016; 316:2373–2384.
3. Sabatine MS et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1712–1722.
4. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-80.
5. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of
   very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65.
6. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87.
7. Nicholls S et al. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovasc Diagn Ther 2021;11(1):120–129.