Inclisiran for fast-track lipid-lowering treatment early after an acute coronary syndrome: a pilot study

Abstract

Background

Elevated low-density lipoprotein cholesterol (LDL-C) after acute coronary syndrome (ACS) significantly increases cardiovascular risk. Timely reduction of LDL-C is crucial, but it takes several weeks to achieve optimal LDL-C levels with standard therapy. Monoclonal antibodies that inhibit PCSK9 have been demonstrated in some small randomised trials to rapidly abate LDL-C levels when used early after hospital admission for ACS. Inclisiran, a PCSK9-inhibiting siRNA, has recently been introduced into clinical practice; however, no information is available about its effectiveness and safety as a fast-track lipid-lowering agent in this clinical context.

Methods

We conducted a prospective, real-world study evaluating a fast-track lipid-lowering approach starting inclisiran on top of standard therapy in 16 consecutive ACS patients admitted to our cardiac intensive care unit with a high baseline LDL-C level (147.2 ± 35.7 mg/dL). Patients started inclisiran as add-on therapy as soon as baseline LDL-C levels were available. We assessed LDL-C levels and the mean change of LDL-C at baseline, discharge, 15-day and 30-day follow-up.

Results

Inclisiran, added to standard therapy, reduced LDL-C levels to 30.3 ± 13.0 mg/dL at 30-day follow-up. The guideline-recommended LDL-C levels (≤55 mg/dL, ≥50 % reduction) were achieved in 73.3 % of patients at 15 days and in 100 % of patients at 30 days, with no adverse effects.

Conclusion

This pilot study shows promise for inclisiran as a novel therapeutic option to improve cardiovascular outcomes in patients with ACS by contributing to achieving an early and sustained reduction in LDL-C levels.

Graphical abstract

Graphical abstract illustrating the study design, patient enrolment process, and primary study findings.

Highlights

• •Elevated LDL after acute coronary syndrome (ACS) raises cardiovascular risk.
• •PCSK9 inhibitors on top of standard anti-lipid treatment contribute to lowering LDL rapidly to guidelines-recommended levels.
• •Inclisiran, taken within one month of ACS hospitalisation, was safe.
• •This study suggests that inclisiran should be further studied as a valuable addition to early ACS management.

1. Introduction

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of adverse cardiovascular outcomes in the early period after an acute coronary syndrome (ACS) [1]. Achieving recommended LDL-C levels for secondary prevention in patients with recent ACS is therefore of paramount clinical importance, even though patients rarely accomplish this outcome in the real world. In addition, even under the most favourable conditions, standard lipid-lowering therapy with high-dose, highly effective statins plus ezetimibe typically takes four weeks to achieve the maximum reduction in LDL-C [2,3]. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been an attractive option for improving the effectiveness and speed of LDL-C lowering since the earliest phase of ACS [4,5]. In particular, two small randomised trials evaluated evolocumab, a human monoclonal antibody that blocks PCSK9, for the early treatment of patients with ACS [6,7]. In the EVACS (Evolocumab in Acute Coronary Syndrome) trial, patients with non-ST-elevation myocardial infarction (NSTEMI) and elevated troponin levels were randomised to receive a single subcutaneous (sc) dose of evolocumab 420 mg or a matching placebo within 24 h of hospital admission [6]. All patients received intensive statin therapy unless contraindicated. LDL-C levels measured at baseline, throughout hospitalisation, and at 30 days decreased from baseline in the evolocumab group on day 1 and were significantly lower than those in the placebo group on day 3. In addition, LDL-C levels remained significantly lower in the evolocumab group throughout hospitalisation and at the 30-day follow-up. As a result, the proportion of patients discharged with LDL-C levels at or below the American and European guideline targets [2,3] was significantly higher in the treatment group than in the placebo group at admission [6]. In EVOPACS (Evolocumab for Early Reduction of LDL-Cholesterol Levels in Patients With Acute Coronary Syndromes), patients with ACS were randomised to receive 420 mg of sc evolocumab or a matching placebo, administered in hospital or four weeks after discharge [7]. Evolocumab added to high-dose atorvastatin therapy was associated with significantly greater LDL-C lowering than placebo, with guideline-recommended LDL-C levels achieved at week eight in 95.7 % of patients in the evolocumab group versus 37.6 % in the placebo group. The incidence of adverse events and centrally adjudicated cardiovascular events was similar in the two groups [7].

An alternative approach to reducing LDL-C levels is to inhibit hepatic PCSK9 production using small interfering RNA (siRNA) [8]. Inclisiran is a first-in-class siRNA therapy that targets PCSK9 mRNA in the liver, reducing the production of PCSK9 protein [9]. The reduced blood concentration of PCSK9 results in increased recycling and increased availability of LDL receptors on the cell surface of hepatocytes, thereby decreasing plasma LDL-C levels [10]. Inclisiran is safe and effective in lowering LDL-C in patients with familial heterozygous hypercholesterolaemia, patients at high cardiovascular risk and patients with atherosclerotic cardiovascular disease (ASCVD) [11,12]. The VICTORION-INITIATE trial, which evaluated an "inclisiran first" implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite maximally tolerated statins) in patients with ASCVD, showed that inclisiran led to greater LDL-C lowering compared with usual care without new safety concerns [13]. In real-world practice, inclisiran has demonstrated promising effectiveness in reducing LDL-C, supporting the results of the clinical trials [14,15]. A recent retrospective study found greater LDL-C reductions in patients receiving inclisiran in combination with statin and ezetimibe therapy [16]. This finding is consistent with earlier, smaller studies [17,18]. In addition, the population-wide impact of inclisiran on LDL-C levels in individuals with ASCVD was estimated, along with its potential to reduce cardiovascular events in similar high-risk populations. The results suggest that inclisiran could significantly reduce the prevalence of hypercholesterolaemia and potentially prevent nearly 200,000 cardiovascular events in eligible adults in the United States [19]. In addition, compared to monoclonal antibodies that inhibit PCSK9, inclisiran has a more convenient dosing protocol (a single subcutaneous injection every six months), which may enhance patient compliance [10].

Italian regulators recently approved this drug as an LDL-C-lowering agent for high-risk patients in primary and secondary prevention. However, no information is available on the potential use of this drug early after hospital admission for ACS. Therefore, our study aimed to evaluate the safety and effectiveness profile of treatment with inclisiran early after hospital admission for ACS in addition to recommended standard lipid-lowering therapies.

2. Methods

2.1. Study design

We conducted an investigator-initiated, single-centre, prospective, non-interventional registry (Inclisiran for eaRly reduction of LDL-cholesterol levels in patients with acute coronary synDromEs, IRIDE -1 registry) as part of the post-marketing surveillance programme for innovative drugs/devices activated in our institution ("Registro Prospettico VCO").

We evaluated consecutive patients admitted to our cardiac intensive care unit with a diagnosis of ACS by current European Society of Cardiology (ESC) guidelines [20] and satisfying the registry inclusion criteria (Table 1) were enrolled in the trial. Exclusion criteria included pregnancy, breastfeeding and chronic liver disease, and all patients had stable haemodynamic parameters (Table 1). In our institution, patients with ACS typically receive standard lipid-lowering therapy consisting of atorvastatin 40 mg once daily (OD) and ezetimibe 10 mg OD, unless contraindicated, as well as other pharmacological and interventional treatments according to current ACS guidelines [20]. Patients with a baseline LDL-C level of ≥140 mg/dL who are not on lipid-lowering therapy or ≥110 mg/dL in patients already on lipid-lowering treatment are unlikely to achieve the guideline-recommended LDL-C level [21]. In these patients, as soon as baseline LDL-C levels were available after hospital admission (ranging from 1 to 4 days), we administered rapid PCSK9 inhibition with a single injection of 284 mg of inclisiran. Patients had their serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), LDL-C, non-HDL-cholesterol (non-HDL-C) and triglycerides measured at admission, discharge, 15-day and 30-day follow-up.

Table 1.

Inclusion criteria of the study.

Inclusion criteria

Age >18 and ≤ 80years

Naive to PCSK9 inhibitor therapy

No contraindications to PCSK9 inhibitor therapy

LDL-C ≥ 110 mg/dL at admission in patients taking lipid-lowering therapy (statins, ezetimibe, bempedoic acid)

LDL-C ≥ 140 mg/dL at admission, off lipid-lowering medications

Stable haemodynamic parameters (no intra-aortic balloon pump support, no indications of emergency coronary artery bypass graft surgery, no symptoms/signs of overt congestive heart failure)

No pregnancy/breastfeeding

No chronic liver disease

Signed written consent to the study

The study's primary endpoint was the achievement of a significant reduction in LDL-C (defined by p-value <0.05) at the 30-day follow-up compared to the LDL-C level at baseline. Secondary endpoints were the reduction of LDL-C and other lipid metabolism parameters (total cholesterol, HDL-C, triglycerides, non-HDL-C) at discharge and 15- and 30-day follow-up, and the percentage of patients achieving recommended LDL-C targets according to the 2019 ESC/European Atherosclerosis Society (EAS) clinical guidelines for the prevention of cardiovascular disease (reduction of LDL-C ≤55 mg/dL and ≥50 % of baseline value) at discharge and 15- and 30-day follow-up [2].

2.2. Statistical analyses

The present study is a cohort study designed to gather data on the potential benefits of early add-on therapy with the novel PCSK9 inhibitor, inclisiran, in patients with ACS. The final endpoint analysis began when all the enrolled patients who had received at least the first dose of inclisiran had completed or withdrawn from the study visits. Data were analysed using the intention-to-treat principle, and patients with missing data from the primary endpoint were excluded. The Kolmogorov-Smirnov test was used to assess the normal distribution of continuous data, which is reported as mean ± SD. Comparisons were performed using two-way ANOVA and post-hoc pairwise comparisons with the Newman-Keuls test for repeated measures. Data with skewed distributions were reported as median/interquartile range (IQR) and compared using the non-parametric Wilcoxon signed-rank test with Bonferroni's correction for multiple comparisons. Descriptive statistics were used to summarise the occurrence of adverse events (AEs) for analyses of safety outcomes. A significance level of p < 0.05 was used for all statistical analyses in this study. Statistics were calculated using the statistical package NCSS 11 (NCSS, LLC: Kaysville, Utah, USA, ncss.com/software/pass).

2.3. Ethical issues

This study was approved by the local Ethics Committee with authorisation # CE006/2023 and conducted in accordance with the 1975 Declaration of Helsinki.

3. Results

This report included the first consecutive 16 patients (93.8 % male, mean age 57.4 ± 8.9 years) who received inclisiran early after hospitalisation for ACS in our Institution from 1st November to 31st December 2024 (26.6 % of the overall 60 patients admitted to our Institution for ACS in the same period). All patients were followed up for 1 month, except one who refused the follow-up visit. Most patients were admitted to the hospital for STEMI (75.0 %), while the same percentage (12.5 %) were admitted for NSTEMI or unstable angina. Of these patients, 18.8 % had a previous coronary artery disease (CAD), and 37.5 % were active smokers. Most patients had high LDL-C levels (56.25 %), of whom only three were on treatment, while six were not. The most prevalent other cardiovascular risk factors were systemic arterial hypertension (87.5 %), obesity (25 %), and diabetes mellitus type 2 (25 %). Two patients (12.5 %) suffered from chronic kidney disease (CKD) with an estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m² BSA. All patients had normal thyroid-stimulating hormone (TSH) levels. None of the patients reported statin intolerance or major adverse cardiovascular events (MACE). After hospital admission, most patients received combination lipid-lowering therapy with atorvastatin 40 mg OD plus ezetimibe 10 mg OD. Only one patient received rosuvastatin 20 mg OD plus ezetimibe 10 mg OD. Percutaneous Coronary Intervention (PCI) was performed following coronary angiography in most patients (87.5 %). The percentage of Left Ventricular Ejection Fraction (LVEF) at discharge was 43.3 ± 10.9. The clinical and demographic characteristics of these patients are detailed in Table 2.

Table 2.

Clinical features of the patient population of the IRIDE study.

	Mean ± SD Count (percentage)		Mean ± SD Count (percentage)
Age (years)	57.4 ± 8.9	Body mass index (kg/m2)	27.1 ± 5.6
Male sex	15 (93.8 %)	Total cholesterol (mg/dL)	216.6 ± 39.4
Systemic Arterial Hypertension	14 (87.5 %)	HDL cholesterol (mg/dL)	46.8 ± 11.5
Hypercholesterolemia:		LDL cholesterol (mg/dL)	147.2 ± 35.7
Not treated	6 (37.5 %)	Triglycerides (mg/dL)	123.1 ± 32.2
Treated	3 (18.8 %)	C-reactive protein (mg/dL)	3.23 (1.55–7.91)
Active smoker	6 (37.5 %)	Estimated glomerular filtration rate (eGFR, mL/min/1.73m2)	73.5 ± 14.4
Type 2 Diabetes	4 (25.0 %)	Abnormal thyroid-stimulating hormone	0 (0.0 %)
Coronary artery disease family history	2 (12.5 %)	Urates (mg/dL)	5.7 ± 1.3
Peripheral vascular disease	1 (6.3 %)	Glycated haemoglobin (%)	5.3 ± 1.1
Previous coronary artery disease	3 (18.8 %)	Statin intolerance	0 (0.0 %)
Chronic kidney disease, eGFR<60 ml/min/1.73m2)	2 (12.5 %)	Major adverse cardiovascular events (MACE)	0 (0.0 %)
Obesity (BMI >30 kg/m2 BSA)	4 (25 %)	Patients evaluated at discharge	16 (100.0 %)
Acute coronary syndrome:		Patients evaluated at 15-day FUP	15 (93.8 %)
STEMI	12 (75.0 %)	Patients evaluated at 30-day FUP	15 (93.8 %)
NSTEMI	2 (12.5 %)	Left ventricular ejection fraction (%) at discharge	43.3 ± 10.9
Unstable angina	2 (12.5 %)	Atorvastatin 40 mg/Ezetimibe 10 mg	15 (93.8 %)
Percutaneous coronary intervention	14 (87.5 %)	Rosuvastatin 20 mg/Ezetimibe 10 mg	1 (6.3 %)
Time between admission and inclisiran administration (days)	2 (1–4)

The mean baseline total cholesterol in the study population was 216.6 ± 39.4 mg/dL, and the mean baseline LDL cholesterol was 147.2 ± 35.7 mg/dL (Table 2, Table 3).

Table 3.

Trend of various blood lipid parameters from admission to 30-day follow-up.

	mean ± SD			p values vs admission
Total cholesterol (mg/dL)
admission	216.6	±	39.4	n/a
discharge	150.1	±	27.9	<0.0001
15 days	111.3	±	26.4	<0.0001
30 days	89.5	±	15.9	<0.0001
HDL cholesterol (mg/dL)
admission	46.8	±	11.5	n/a
discharge	42.2	±	11.1	0.0001
15 days	42.8	±	10.0	0.0001
30 days	42.1	±	6.2	0.001
Triglycerides (mg/dL)
admission	123.1	±	32.2	n/a
discharge	114.4	±	27.2	0.156
15 days	106.6	±	29.0	0.089
30 days	103.3	±	24.9	0.045
LDL cholesterol (mg/dL)
admission	147.2	±	35.7	n/a
discharge	84.8	±	23.9	<0.0001
15 days	47.7	±	25.1	<0.0001
30 days	30.3	±	13.0	<0.0001
Non-HDL cholesterol (mg/dL)
admission	169.8	±	39.0	n/a
discharge	107.9	±	28.1	<0.0001
15 days	68.5	±	26.8	<0.0001
30 days	47.4	±	16.1	<0.0001

n/a: not applicable.

As shown in Fig. 1, total cholesterol, LDL-C, and non-HDL-C levels were significantly lower at discharge compared to baseline levels at admission, with more significant reductions observed at 15- and 30-day follow-up. Table 2 provides a detailed description of the mean values of blood lipid parameters, expressed in mg/dL, at admission, discharge, 15- and 30-day follow-up, along with the statistical significance of each parameter compared to the mean value at admission. From admission to discharge and during the follow-up period, LDL-C decreased progressively and homogeneously in all patients (Fig. 2). The minimum LDL-C and total cholesterol levels were achieved at one-month follow-up with 30.3 ± 13.0 mg/dL and 89.5 ± 15.9 mg/dL, respectively (Table 3).

Fig. 1.

Lipid parameter trends in the study's patient population at admission, discharge, 15-day and 30-day follow-up. Data are presented as mean value ± SD. # Statistically significant compared to admission (p < 0.05); $ Statistically significant compared to 30-day follow-up (p < 0.05); * Statistically significant compared to 15-day follow-up (p < 0.001); § Statistically significant compared to admission (p < 0.001). Chol: total cholesterol; TRGL: triglycerides.

Fig. 2.

LDL-C levels in the study's patient population from admission to 30-day follow-up. Data are presented as mean ± SD of the group and individual values.

At discharge, only 13.3 % of patients (2 patients) treated with inclisiran as add-on therapy achieved LDL-C levels recommended by guidelines (≤55 mg/dL and ≥50 % reduction from baseline). This percentage increased to 73.3 % of patients (11 patients) at the 15-day follow-up, and the entire study population (16 patients) achieved this goal at the 1-month follow-up (Fig. 3). No clinical or laboratory adverse events were observed in the study population (Table 2).

Fig. 3.

Percentage of patients achieving guidelines-recommended LDL-C goals at discharge, at 15-day and 30-day follow-up.

4. Discussion

The present pilot study represents the first prospective evaluation of adding inclisiran on top of routine high-dose statin and ezetimibe treatment in patients with ACS with high LDL-C levels at admission, as a strategy of fast-track lipid-lowering treatment. The results reported demonstrate that this therapeutic approach rapidly and significantly attained guidelines-recommended lipid goals. The magnitude of LDL-C reduction observed in our study is consistent with that reported in previous studies (ORION-9, -10 and −11) evaluating inclisiran in other clinical settings, such as atherosclerotic cardiovascular disease and familial hypercholesterolemia [11,12]. Notably, nearly three-quarters of patients achieved guideline-recommended LDL-C targets within 15 days of treatment with inclisiran, and all patients achieved this target by 30 days. These results underscore the potential of inclisiran for swift and effective LDL-C management in the critical period following ACS when timely lipid lowering is paramount.

While most of the current evidence on fast-track PCSK9 inhibition in ACS derives from clinical trials with monoclonal antibodies [4], some real-world data exist on the early initiation of other PCSK9 inhibitors, such as alirocumab and evolocumab, in ACS patients [7,22,23]. Real-world studies have shown that early administration of evolocumab and alirocumab in the acute setting can achieve rapid LDL-C reductions similar to those observed in randomised controlled trials, with good tolerability profiles [22,23]. However, these studies have generally involved smaller patient cohorts and shorter follow-up periods, which limits the generalizability of the findings [23,24]. The inclusion of inclisiran in this fast-track approach represents a novel strategy that has not been previously explored in real-world practice [24,25], making our study particularly relevant for understanding the feasibility and preliminary effectiveness of this approach in routine clinical care.

The discovery of PCSK9 as a critical regulator of LDL-C levels has opened a significant opportunity for treating patients at high risk for ASCVD. Since then, multiple approaches targeting PCSK9 have been developed. Monoclonal antibodies against PCSK9, for instance, have demonstrated the ability to reduce LDL cholesterol levels by over 50 %, although they require administration every 2–4 weeks [11,26]. Inclisiran, administered twice a year, has also shown a stable reduction of ∼50 % in LDL-C levels across various clinical conditions, resulting in a reduction of plasma PCSK9 levels by about 80 % [8]. Early administration of PCSK9 inhibitors has been shown to safely, rapidly and effectively reduce several lipid levels in patients with ACS. This reduction was associated with a significant decrease in MACEs, including revascularisation, recurrent ACS and hospital readmission [27,28].

Inclisiran's rapid onset of action presents a particularly promising advantage in the setting of ACS. Traditional lipid-lowering therapies, even when optimised, often take several weeks to reach their peak effect, leaving patients at increased risk of recurrent cardiovascular events in the early post-ACS period, a time when the risk of complications is particularly high. By significantly reducing LDL-C levels within days, inclisiran effectively contributed to filling this critical therapeutic gap, offering the potential to improve outcomes and better protect patients during this vulnerable period [29]. In addition, the twice-yearly dosing regimen of inclisiran is another potential advantage compared to monoclonal antibodies against PCSK9, which require more frequent injection schedules, as it may improve patient adherence [10].

In terms of safety, a comprehensive analysis of data from seven clinical trials underscores inclisiran's favourable tolerability profile across a diverse patient population over long-term treatment, with no significant safety concerns identified [30]. In our study, inclisiran also demonstrated a favourable safety profile, and no adverse events were reported.

Our study has several limitations. The lack of a control group is the most critical limitation, precluding definitive conclusions about the causal relationship between inclisiran administration and LDL-C reduction. Additionally, the lack of randomisation further limits the strength of our conclusions. As a pilot study, the small sample size and single-centre design warrant caution when generalising the results. The lack of a control group precludes definitive conclusions about the causal relationship between inclisiran administration and LDL-C reduction. In addition, the relatively short follow-up period limits our ability to assess the long-term effects of inclisiran on the clinical outcomes of patients with ACS.

Despite these limitations, our study provides promising preliminary evidence for the use of inclisiran in the early management of ACS. The rapid and profound LDL-C lowering achieved with inclisiran, its favourable safety profile, and its convenient dosing schedule suggest it may be a valuable addition to the therapeutic arsenal for ACS. More extensive randomised controlled trials are needed to confirm these findings and to assess the impact of inclisiran on hard clinical endpoints in this high-risk patient population.

Ethic declaration

All procedures were in accordance with national and international ethical standards and the 1964 Helsinki Declaration standards. The trial was not for profit. Apart from the time that the investigators volunteered for the project, they provided no resources other than the usual care of the enrolled patients. There were no additional costs to the hospital due to the trial.

Summary box

What is already known about this topic

Elevated LDL cholesterol (LDL-C) after an acute coronary syndrome (ACS) raises cardiovascular risk. PCSK9 inhibitors, added to standard therapies, accelerate LDL-C reduction to achieve target levels.

What this study adds

This pilot study evaluates the effectiveness and safety of adding Inclisiran to standard lipid-lowering therapy as a fast-track strategy in patients hospitalised for ACS, showing a fast and impressive LDL-C reduction with a favourable safety profile and a convenient dosing schedule.

How might this study affect research, practice or policy

This preliminary data suggest that a fast-track therapeutic approach, including in-hospital administration of inclisiran, is feasible, safe, and valuable to ACS management. Larger trials are needed to confirm these findings and assess their impact on clinical outcomes in high-risk patients.

Author contributions

All authors helped develop the concept for this manuscript, provided a critical review of the manuscript drafts with suggestions for substantial revisions of the intellectual content, and reviewed and agreed on the final version for submission. All named authors agree to take responsibility and be accountable for the article's contentsand share responsibility for resolving any questions raised about the accuracy or integrity of the published work.

Funding

No funding or sponsorship was received for this study.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.