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 immiÂnent heart attack. She had been expeÂriencing 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 atheroscleÂrotic cardiovascular disease (ASCVD), but her younger sister suffered acute myocardial infarction (MI) at the age of 51 years, suggesting familial hyperchoÂlesterolaemia (FH).
On presentation, the patient’s blood pressure was 110/75 mm Hg, body mass index was 23 kg/m2, and physical examination was unremarkÂable. Two weeks before presentaÂtion, the patient detected proteinuria on a home urine dipstick test, which prompted her to consult her nephrolÂogist, 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 HbA1c level of 5.5 perÂcent and normal renal function. TroÂponin I and N-terminal pro B-type naÂtriuretic peptide (NT-proBNP) levels were also normal.
Echocardiography on 15 SeptemÂber 2023 revealed normal left ventriÂcle size and function, ejection fraction (EF) of 71.2 percent, no diastolic dysÂfunction and no valvular abnormalÂity. CT coronary angiography on 25 September 2023 found right coroÂnary 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 SepÂtember 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 perÂcent 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 coroÂnary intervention (PCI) and stenting (with a drug-eluting stent) was perÂformed.
Treatment and response
The patient commenced roÂsuvastatin 10 mg QD on 30 AuÂgust 2023 when her dyslipiÂdaemia 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 JanÂuary 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 baseÂline). Tests to monitor statin-related adverse effects (AEs) reported normal liver function and creatine phosphokiÂnase (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 levÂel 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 particiÂpated in a community rehabilitation programme, which helped her adopt healthy lifestyle habits, and has reÂsumed 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 intenÂsive lowering of LDL-C to target levÂels 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) recÂommended by the 2019 EuropeÂan Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines even with maximum tolÂerated dose of statin and ezetimibe. For such patients, the 2019 ESC/ EAS guidelines recommend aggresÂsive lipid-lowering therapy (LLT) with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, such as alirocumab.1-4
Alirocumab is a PCSK9 monoÂclonal antibody with established long-term safety and clinical efficaÂcy in intensive LDL-C reduction (to <1.0 mmol/L), as well as in minimizÂing atherosclerotic plaque volume, improving plaque morphology and vulnerability, and stabilizing plaque features, which consequently reducÂes 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 reÂduction 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 perÂcent relative risk reduction (RRR) in MACE (composite of death from coroÂnary 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 magniÂtude were observed in patients eligiÂble for 3 to 5 years of follow-up, with no excess AEs except for mild-to-moderate local injection-site reacÂtions.6,7
Alirocumab 300 mg Q4W, which offers a more convenient dosing regimen that helps foster better compliance, was shown to be a viÂable treatment option in moderate-to-very-high CV risk patients with hyÂpercholesterolaemia on MTD of staÂtin or no statin (both with or without other LLTs). The phase III ODYSSEY CHOICE I trial demonstrated signifiÂcant reductions in LDL-C and signifiÂcant improvements in key secondary efficacy lipid parameters from baseÂline with alirocumab 300 mg Q4W at week 24. Improvements in secondÂary efficacy lipid parameters associÂated with alirocumab were generally maintained at week 48.5 (Table 2)
Early initiation of PCSK9 inhibitors
Early initiation of PCSK9 inhibiÂtors regardless of prior statin use in patients with ACS (such as our paÂtient) or stable CAD leads to substanÂtial and prompt LDL-C level reducÂtion, reducing the risk of subsequent events.14-16
The composition of atheroÂsclerotic plaques influences risk of progression and acute coronary events. The double-blind, placebo-controlled, PACMAN-AMI triÂal (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 adÂdition 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 (differÂence, -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 plaÂcebo (difference, -41.24; p=0.006), and the mean change in minimal fiÂbrous 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. TakÂen together, these findings indicate that alirocumab initiated early in the setting of acute MI produced increÂmental benefits on coronary plaque evolution, composition, and phenoÂtype compared with intensive statin therapy alone.11
Conclusion
LDL-C control is crucial to preÂventing 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 reducÂtion and treatment goal achievement.
