CASE REVIEW

A case of patient with recurrent cardiovascular events stabilized by evolocumab in Hong Kong

29 Jun 2020
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Dr. Tsui, Ping-Tim

Specialist in Cardiology
Honorary Secretary,
Hong Kong Society of Transcatheter ENdo-cardiovascular Therapeutics (HKSTENT)

Patients who have recently experienced a myocardial infarction (MI), with multiple prior MIs or residual multivessel coronary artery disease (CAD) are at higher risk for recurrent MACEs. In these high-risk groups, a substantial relative and absolute risk reduction for further MACEs has been observed with evolocumab in the FOURIER trial.1 Dr. Tsui, Ping-Tim, Specialist in Cardiology, Honorary Secretary of HKSTENT, shared a case of patient with history of recurrent MACEs and multivessel CAD who was stabilized by evolocumab.

Introduction

Atherosclerotic plaque is the main cause of multivessel CAD and recurrent atherothrombotic events resulting from frequent plaque rupture or ulceration. Atherosclerotic plaques, which are prone to rupture, having a large lipid-rich core, a thin fibrous cap, and a large inflammatory content mainly comprise of macrophages.2 A correlation between atherosclerotic plaque characteristics and CV risk factors has been observed, with diabetes mellitus patients presenting not only with a larger plaque burden, but also with larger necrotic cores.3 Exclusion or reduction of lipid‐rich plaque underneath fibrous cap of vessels has also been predicted to lower risk for future MACEs.4 Medications that promote plaque stability and regression may help reduce the recurrent episodes of atherothrombotic events.

Despite achieving very low LDL-C levels, high-intensity statin therapy alone cannot prevent all recurrent MACEs due to persistent coronary atheroma volume.5 Furthermore, the major determinant of coronary plaque vulnerability is the thickness of fibrous cap in affected vessels – the thinner the fibrous cap, the higher the risk of MI and stroke. Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, has been shown to reduce the PAV and increase the fibrous cap thickness.6,7 These changes have been associated with better clinical outcomes by reducing MACEs in high-risk patients.1

In this case review, Dr. Tsui presented a patient who experienced recurrent CV events despite high-dose statin therapy and was stabilized with evolocumab treatment. Dr. Tsui commented, “In addition to reducing LDL-C levels, evolocumab might have improved blood circulation to heart muscles and stabilized atherosclerotic plaque, enhancing the positive clinical outcome.”

Case report

The patient is a 57-year-old non-smoking man with familial hypercholesterolemia who first presented with acute heart attack at the age of 36. At initial presentation, the patient was overweight with central obesity, had high total cholesterol level of 12mmol/L and LDL-C level of 10mmol/L. His fasting blood sugar was normal and triglyceride level mildly elevated. He was then diagnosed with inferior ST-elevation MI and underwent percutaneous coronary intervention (PCI) to the occluded right coronary artery.

The patient has since received PCI five more times for symptomatic and significant CAD. At the age of 38, in-stent restenosis in the right coronary artery was detected and treated with brachytherapy. Drug-eluting stent (DES) was inserted in the new stenosis of left anterior descending artery. Subsequent angiography imaging displayed triple vessels disease with a complete distal occlusion of the right coronary artery, progression of left anterior descending artery disease and diffuse left circumflex artery stenosis. Balloon angioplasty to the left circumflex artery was performed at the age of 44, followed by PCI with DES to the proximal right coronary artery, and mid-right coronary artery and left anterior descending artery, at age 49 and 53, respectively. “Why does he keep having episodes?” questioned Dr. Tsui, who said, “Because his LDL-C was not well-controlled, and the underlying atherosclerotic plaque burden remained.”

The patient has also been treated with acetylsalicylic acid 80mg daily, pantoprazole sodium 40mg daily, and bisoprolol 2.5mg daily. Despite aggressive anti-lipid therapy with potent high-dose statins and ezetimibe 10mg daily, the lowest LDL-C level achieved was 4.7mmol/L. At the age of 56, the patient-initiated treatment with evolocumab 140mg once every two weeks, which subsequently reduced LDL-C levels to 1.1mmol/L, an approximate 60% reduction. This was the first time this patient’s LDL-C levels could be controlled. Evolocumab was well tolerated and the patient experienced no side effects. He is currently on a combination of evolocumab and statins and has not encountered any symptomatic CV events during the past year.

Discussion

According to 2019 European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) guidelines, the patient presented in this case review was at very high risk for MACEs. He was categorized as such due to his previous MI, history of coronary revascularization, and the significant plaque evident on his coronary angiography (multivessel coronary disease with two major epicardial arteries having >50% stenosis).8 Dr. Tsui commented on the risk classification, “In order to classify a patient according to CV risk, the patient should be considered as a whole,” and noted, “I would consider the patient’s compliance also as a very good risk indicator.”

A LDL-C reduction of ≥50% from baseline and a LDL-C goal of <1.4mmol/L are recommended for the secondary prevention of MACEs in very-high-risk patients.8 Patients with atherosclerotic cardiovascular disease (ASCVD) who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while receiving maximally tolerated statin therapy should consider a LDL-C goal of <1.0mmol/L.8 “According to my experience, high-dose statin alone will not reduce LDL-C to such low levels,” stated Dr. Tsui, who continued, “Especially in patients who have residual risk, it is important to lower LDL-C levels as much as possible to prevent further events; therefore additional therapy with evolocumab could facilitate lower LDL-C levels.”

In the FOURIER trial, analysis of patients with at least 1 high-risk feature observed a 19% reduction in CV death, MI or stroke with evolocumab in the first year, and 27% beyond the first year.1 Evolocumab consistently lowered LDL-C by 59-61% regardless of time from most recent MI, number of prior MIs or presence of residual multivessel CAD.1 With regard to the timing of prior MI, evolocumab reduced CV death, MI or stroke by 20% in those with a more recent MI versus 5% in those without; likewise, with regard to number of prior MIs, evolocumab reduced the primary endpoint by 18% in those with multiple prior MIs versus 8% in those with only 1 prior MI (Figure 1).1

OP#21-website images_CR2_fig1

As previously mentioned, low LDL-C levels alone cannot completely prevent secondary MACEs, and further mechanisms are needed to reduce the burden of atherosclerosis. In the GLAGOV trial, the addition of evolocumab in patients treated with moderate or high intensity statin therapy reduced coronary atherosclerosis.6 Regression of atherosclerotic plaque was observed during 18 months of therapy in patients treated with the combination of evolocumab and statins.6 Compared with the baseline, patients in the evolocumab group showed significant reductions in both PAV and total atheroma volume.6 These findings provide evidence that evolocumab has confirmed clinical benefit regarding reduced CAD progression in statin-treated patients.

Similarly, evolocumab plus statin led to higher rates of increased fibrous cap thickness and decreased macrophage accumulation compared with statin treatment alone.7 The reduction in release of matrix metalloproteinases, combined with decreased accumulation of macrophages, thus induced fibrous cap thickening with evolocumab plus statin regimen.7 Figure 2 demonstrates the increasing fibrous cap thickness and decreasing lipid arc in the evolocumab plus statin group in 12 weeks.7

OP#21-website images_CR2_fig2

“By reducing percent atheroma volume and increasing the fibrous cap thickness, we have stabilized the atherosclerotic plaque and improved blood circulation through the vessels for the patient, which is explained well by the results of the FOURIER trial,” highlighted Dr. Tsui.

Conclusion

Recurrent atherothrombotic events result from frequent plaque rupture or ulceration. Evolocumab has been shown to regress the atherosclerotic plaques by reducing both PAV and total atheroma volume. Moreover, evolocumab can enhance the thickness of fibrous cap of the affected vessels. These effects were evident through the positive clinical outcomes observed from the FOURIER trial. The patient presented in this case was also seen to benefit from evolocumab, having been stabilized after many years of uncontrolled LDL-C levels despite statin therapy. By regression of atherosclerotic plaque and increasing fibrous cap thickness, evolocumab enhances blood circulation, resulting in durable clinical outcomes in patients with ASCVD.

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