Once-monthly PCSK9 inhibitor in a patient with FH at very high CV risk

Presentation and history
A 62-year-old lady first presented on 15 September 2023 with severe chest pain typical of acute coronary syndrome (ACS), pointing to an immi­nent heart attack. She had been expe­riencing chest pain and shortness of breath on exertion over the past year, which had worsened in the 3 months prior to presentation, especially when she played tennis. She eventually had to quit all sports activities. The patient did not smoke or drink and had good past health, apart from some renal cysts. She had no history of atheroscle­rotic cardiovascular disease (ASCVD), but her younger sister suffered acute myocardial infarction (MI) at the age of 51 years, suggesting familial hypercho­lesterolaemia (FH).

On presentation, the patient’s blood pressure was 110/75 mm Hg, body mass index was 23 kg/m², and physical examination was unremark­able. Two weeks before presenta­tion, the patient detected proteinuria on a home urine dipstick test, which prompted her to consult her nephrol­ogist, who referred her to our clinic as she had cardiorenal symptoms and was found to have very high LDL-cholesterol (LDL-C) level of 6.73 mmol/L. (Table 1) Other laboratory tests showed HbA_1c level of 5.5 per­cent and normal renal function. Tro­ponin I and N-terminal pro B-type na­triuretic peptide (NT-proBNP) levels were also normal.

Echocardiography on 15 Septem­ber 2023 revealed normal left ventri­cle size and function, ejection fraction (EF) of 71.2 percent, no diastolic dys­function and no valvular abnormal­ity. CT coronary angiography on 25 September 2023 found right coro­nary artery (RCA)–dominant, normal origins, mid-left anterior descending artery (LAD) severe stenosis (70–99 percent) by non-calcified plaque (Ca score, 0). Results were consistent with unstable angina.

Coronary angiography on 29 Sep­tember 2023 revealed occlusion of 30 percent of the distal left main (LM) coronary artery, 50 percent of the ostial-LAD, 20 percent of the proximal left circumflex artery, and 70–90 per­cent of the proximal- to mid-LAD by fibrofatty plaque with rich lipid core, and normal perfusion of RCA. Ad hoc intravascular ultrasound (IVUS)–guided LM/LAD percutaneous coro­nary intervention (PCI) and stenting (with a drug-eluting stent) was per­formed.

Treatment and response
The patient commenced ro­suvastatin 10 mg QD on 30 Au­gust 2023 when her dyslipi­daemia was first discovered. Aspirin 100 mg QD and clopidogrel 75 mg QD were added post-PCI. Subcutaneous alirocumab 300 mg Q4W was added on 4 October 2023 for intensive LDL-C lowering, as well as plaque stabilization and volume reduction.

Follow-up blood tests on 17 Jan­uary 2024 showed that LDL-C level had dropped to 1.0 mmol/L (target level for patients with FH at very high CV risk: <1.4 mmol/L plus LDL-C reduction of ≥50 percent from base­line). Tests to monitor statin-related adverse effects (AEs) reported normal liver function and creatine phosphoki­nase (CPK) level. The patient was satisfied with the prescribed therapy and did not report any AEs.

A test on 3 July 2024 showed that the LDL-C level had risen to 1.4 mmol/L, leading to the addition of ezetimibe 10 mg QD to the treatment regimen. Liver function and CPK lev­el remained normal. When the patient was last seen on 16 December 2024, her LDL-C level had dropped to 0.6 mmol/L. (Table 1)

The patient has remained chest pain–free since PCI and compliant with her therapy. She also partici­pated in a community rehabilitation programme, which helped her adopt healthy lifestyle habits, and has re­sumed her normal level of activity, including playing sports.

Discussion
Patients with FH and ASCVD and very high LDL-C level often have high-risk CV conditions. Reduction of LDL-C by 1 mmol/L has been shown to reduce major vascular events (MI, stroke, coronary revascularization or death from coronary artery disease) by about 22 percent and thus inten­sive lowering of LDL-C to target lev­els is of paramount importance.^1-4

LDL-C goal attainment in patients with very high CV risk
However, approximately 70–80 percent of patients with very high CV risk are unable to attain LDL-C goals (≥50 percent reduction from baseline and <1.4 mmol/L) rec­ommended by the 2019 Europe­an Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines even with maximum tol­erated dose of statin and ezetimibe. For such patients, the 2019 ESC/ EAS guidelines recommend aggres­sive lipid-lowering therapy (LLT) with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, such as alirocumab.^1-4

Alirocumab is a PCSK9 mono­clonal antibody with established long-term safety and clinical effica­cy in intensive LDL-C reduction (to <1.0 mmol/L), as well as in minimiz­ing atherosclerotic plaque volume, improving plaque morphology and vulnerability, and stabilizing plaque features, which consequently reduc­es major adverse CV events (MACE) and morbidity.^5-12

The phase III ODYSSEY-OUTCOMES trial, conducted in 18,924 patients with an ACS event (MI or unstable angina) within 12 months prior to randomization who had an LDL-C level ≥1.8 mmol/L, demonstrated significant LDL-C re­duction with alirocumab 75 mg Q2W vs placebo at 4 months (average, 62.7 percent), which was sustained through 48 months (average, 54.7 percent). Furthermore, among the patients treated with alirocumab, 94.6 percent of patients achieved the 2019 ESC guideline LDL-C goal of <1.4 mmol/L at ≥1 post-baseline measurement with alirocumab vs 17.3 percent with placebo.^6,13

A statistically significant 15 per­cent relative risk reduction (RRR) in MACE (composite of death from coro­nary heart disease, ischaemic stroke, nonfatal MI or unstable angina requiring hospitalization) was observed with alirocumab vs placebo over a median follow-up of 2.8 years in the same trial. Benefits of similar magni­tude were observed in patients eligi­ble for 3 to 5 years of follow-up, with no excess AEs except for mild-to-moderate local injection-site reac­tions.^6,7

Alirocumab 300 mg Q4W, which offers a more convenient dosing regimen that helps foster better compliance, was shown to be a vi­able treatment option in moderate-to-very-high CV risk patients with hy­percholesterolaemia on MTD of sta­tin or no statin (both with or without other LLTs). The phase III ODYSSEY CHOICE I trial demonstrated signifi­cant reductions in LDL-C and signifi­cant improvements in key secondary efficacy lipid parameters from base­line with alirocumab 300 mg Q4W at week 24. Improvements in second­ary efficacy lipid parameters associ­ated with alirocumab were generally maintained at week 48.⁵ (Table 2)

Early initiation of PCSK9 inhibitors
Early initiation of PCSK9 inhibi­tors regardless of prior statin use in patients with ACS (such as our pa­tient) or stable CAD leads to substan­tial and prompt LDL-C level reduc­tion, reducing the risk of subsequent events.^14-16

The composition of athero­sclerotic plaques influences risk of progression and acute coronary events. The double-blind, placebo-controlled, PACMAN-AMI tri­al (n=300; mean age, 58.5 years; women, 18.7 percent; mean LDL-C level, 3.94 mmol/L) assessed if the initiation of biweekly subcutaneous alirocumab 150 mg <24 hours after urgent PCI of the culprit lesion in ad­dition to high-intensity statin therapy (rosuvastatin 20 mg) would result in coronary plaque regression in non–infarct-related arteries after 52 weeks.¹¹

At 52 weeks, mean change in atheroma volume (primary endpoint) was -2.13 percent with alirocumab vs -0.92 percent with placebo (differ­ence, -1.21 percent; p<0.001). The mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with pla­cebo (difference, -41.24; p=0.006), and the mean change in minimal fi­brous cap thickness was 62.67 μm vs 33.19 μm (difference, 29.65 μm; 95 percent confidence interval, 1.75– 47.55; p=0.001), respectively. Tak­en together, these findings indicate that alirocumab initiated early in the setting of acute MI produced incre­mental benefits on coronary plaque evolution, composition, and pheno­type compared with intensive statin therapy alone.¹¹

Conclusion
LDL-C control is crucial to pre­venting CV events in very high-risk patients such as those with FH and ASCVD. In alignment with clinical data, the present case demonstrates that early addition of alirocumab, immediately after successful PCI and stenting, to other LLTs resulted in rapid (>80 percent after the first dose) and significant LDL-C reduc­tion and treatment goal achievement.

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