Lipid-lowering therapy in patients with coronary artery disease undergoing percutaneous coronary interventions in Italy: an expert opinion paper of Interventional Cardiology Working Group of Italian Society of Cardiology

Abstract

 

After percutaneous coronary interventions (PCIs), patients remain at high risk of developing recurrent cardiovascular events. Despite advances in interventional cardiology, the correct management of residual low-density lipoprotein cholesterol (LDL-C) risk continues to be crucial for improving long-term outcomes after PCI. However, several observational studies have demonstrated suboptimal LDL-C control, poor adherence to statin therapy, and underutilization of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors in real-world clinical practice despite a strong endorsement from international guidelines. Recent studies have shown that early intensive lipid-lowering therapy stabilizes atheromatous plaque and increases fibrous cap thickness in patients with acute coronary syndrome. This finding emphasizes the importance of achieving therapeutic targets by establishing an effective treatment as early as possible.

The aim of this expert opinion paper of the Interventional Cardiology Working Group of the Italian Society of Cardiology is to discuss the management of lipid-lowering therapy in patients undergoing PCIs according to Italian reimbursement policies and regulations, with a particular focus on the discharge phase.

Low-density lipoprotein cholesterol as a causal factor for atherosclerosis

Atherosclerosis is an evolutionary process that begins with intima invasion by cholesterol and continues with activation of inflammatory responses.¹ Epidemiologic, genetic, and interventional studies provide strong support for the central role of cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), as a causative agent of atherosclerosis.² Mendelian randomization studies may address this point.³ Several variants of various genes have been linked to variations in LDL-C levels.⁴ Thus, it is possible to determine whether a genotype that causes a phenotype with increased LDL-C levels is associated with a heightened risk of ischemic heart disease. Conversely, a gene whose phenotype implies a reduction in LDL-C should be associated with a decreased risk of ischemic heart disease.⁵ Mendelian randomization studies have consistently demonstrated that reduced LDL-C levels associated with these genetic variants are associated with a lower risk of ischemic heart disease.⁶

To confirm the causal relationship between LDL-C and atherosclerosis, it is relevant to highlight the evidence obtained in both primary and secondary prevention trials demonstrating that a more significant reduction in LDL-C levels, achieved with statins and other nonstatin treatments, is associated with a more significant decrease in the rates of cardiovascular (CV) events.⁷ Most of these trials were included in one of the cholesterol treatment trials (CTTs) meta-analyses, which enrolled 170 000 participants across 26 clinical trials. It showed that for each mmol/l (over 39 mg/dl) reduction in LDL-C levels, the relative risk of major CV events decreases by 22–23% with statin therapy over a median of 5 years.⁸ Later, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study, with ezetimibe, also confirmed that reduction of LDL-C was associated with a decrease in CV events.⁹ More recently, this hypothesis has been confirmed in trials conducted with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i), which, combined with statins or alone in patients with statin intolerance, achieved a 50–60% rapid and sustained reduction in LDL-C levels, resulting in decreased risk of cardiovascular events.^10,11

Rupture of the fibrous cap of the atheroma is recognized as the principal mechanism of acute myocardial infarction (AMI) in patients with coronary artery disease (CAD)¹² and thrombosis resulting from atheroma rupture is usually associated with lesions in the thin fibrous cap.^13,14 Recent studies have shown that intensive lipid-lowering therapy (LLT) stabilizes atheromatous plaque and increases fibrous cap thickness in patients with acute coronary syndrome (ACS).^15,16 This highlights the importance of achieving therapeutic targets by establishing an effective therapy as early as possible.¹⁷

This expert opinion paper aims to discuss the management of LLT in patients with CAD undergoing percutaneous coronary interventions (PCIs) in accordance with Italian reimbursement policies and regulations. We provide a special focus on the discharge phase, which plays a key role in early intensive LLT prescription, LDL-C target achievement, and long-term patient drug adherence.

Low-density lipoprotein cholesterol target in patients undergoing percutaneous coronary intervention

Patients undergoing percutaneous coronary revascularization have an increased risk for recurrent CV events. Despite advances in revascularization techniques and coronary stents, the overall assessment and correct management of residual LDL-C risk continue to be crucial for improving long-term outcomes after PCI. According to the National Cardiovascular Data Registry CathPCI registry, approximately one in six patients develops new major adverse events within 1 year after PCI.¹⁸

In patients with ACS, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias recommend lipid assessment at the time of admission, without the need for fasting.¹⁹ Based on well established evidence,^20,21 the guidelines also recommend early administration of high-intensity statins (HIS) in ACS patients, regardless of baseline LDL-C values. In patients already on low or moderate-intensity statin therapy at the time of ACS, intensity upgrading should be pursued. The European and American LDL-C goals for patients undergoing PCI, who are considered to be at very high risk of CV, are summarized in Table 1.^19,22 A progressive titration of therapy with HIS, again deployed at the forefront, preludes the addition of ezetimibe and subsequently PCSK9i if the goal is not achieved.

Table 1 - European and American recommendations for LDL-C therapeutic goals

Guidelines	Risk class	LDL-C goal	Recommendation	Ref.
2019 ESC/EAS guidelines for the management of dyslipidaemias	Very high risk Documented ASCVD Documented ASCVD includes previous ACS (MI or unstable angina), stable angina, coronary revascularization (PCI, CABG, and other arterial revascularization procedures)	<55 mg/dl and at least 50% reduction from baseline	I, A	19
2017 ACCE guidelines for management of dyslipidemia and prevention of cardiovascular disease	Extreme risk Progressive ASCVD including unstable angina in patients after achieving an LDL-C <70 mg/dl; established clinical cardiovascular disease in patients with DM. CKD 3/4, or HeFH	<55 mg/dl	Grade A, BEL 1	22
	Very high risk Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease	<70 mg/dl	Grade A, BEL 1	22

ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DM, diabetes mellitus; EAS, European Society of Atherosclerosis; ESC, European Society of Cardiology; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention.

In clinical practice, only a small proportion of patients achieve LDL-C targets despite ambitious and stringent goals and a variety of treatment options. The European EUROASPIRE-V survey revealed that statin use was 80% among approximately 8000 patients with a previous cardiovascular event.²³ Moreover, a closer examination of the data and analysis of the proportion of patients eventually achieving the therapeutic targets recommended by the guidelines reveals that the situation is even further from being considered ‘ideal’. In that survey, only 14% of the population achieved the absolute and relative LDL-C reduction targets. Even when the less stringent targets of the previous guidelines (in place at the time these data were collected) were applied, the proportion of subjects on target rose to only 35%.²³ The DA VINCI study examines the application of the 2016 ESC/EAS guidelines in daily clinical practice and, in a subsequent analysis, the implementation of the 2019 guidelines.²⁴ Overall, DA VINCI highlights that patient management is suboptimal as only 33% of patients achieved the new levels recommended by the 2019 ESC/EAS guidelines. The results also indicate that statin monotherapy remains predominant with residual use of combination therapies with ezetimibe (9%) and/or PCSK9i (1%), despite their recommendation in very high-risk patients.²⁴ Consequently, it is necessary to change how patients at high and very high risk are managed in daily clinical practice. This is especially relevant in secondary prevention because these patients have a higher residual risk of cardiovascular events.

First-line lipid-lowering therapy

Among patients undergoing PCI, statins play a primary role in lowering cholesterol levels.¹⁹ Numerous randomized and observational studies, including millions of individuals worldwide, have investigated and proved the efficacy and safety of these agents.¹⁹ Based on available evidence, current ESC guidelines recommend the early administration of HIS (atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg daily) in ACS patients, irrespective of their baseline levels of LDL-C (class I/A recommendation) unless there are specific contraindications.¹⁹ The value of intensive statin treatment has also been demonstrated in elective PCI. In a meta-analysis of randomized trials including individual data from 3341 patients undergoing PCI, either pretreatment (i.e. statin-naive patients) or loading (i.e. patients already on statin therapy) with HIS significantly reduced the risk of peri-procedural myocardial infarction and cardiovascular events at 30 days by more than 40% (7.0% vs. 11.9%; P < 0.0001, and 7.4% vs. 12.6%; P = 0.05, respectively).²⁵ Consequently, this strategy with routine pretreatment or loading is recommended by ESC guidelines in patients undergoing PCI irrespective of the indication (chronic or ACS) (Class IIa, level of evidence B). As an ancillary benefit, pretreatment with statins provides the additional benefit of contrast-induced acute kidney injury,²⁶ and such an approach is also recommended by ESC guidelines on myocardial revascularization (Class IIa, level of evidence A).²⁷

Muscle-related adverse effects are frequently reported, but are usually mild and dose-dependent. Severe adverse effects, such as rhabdomyolysis and hepatotoxicity, rarely occur.¹⁹ Therefore, careful clinical and laboratory monitoring is required to manage patients on chronic statin therapy.¹⁹ Ezetimibe reduces the absorption of dietary and biliary cholesterol through interaction with the Niemann-Pick C1-like protein 1 (NPC1L1) located in the small intestine, causing a reduction in the transit of intestinal cholesterol to the liver.²⁸ Consequently, the liver upregulates LDL-C receptors and increases LDL-C uptake in the cells, thus decreasing LDL-C plasma levels. When given as monotherapy, ezetimibe (10 mg/day) can reduce LDL-C by 15–22% compared with placebo.²⁸ Greater efficacy in terms of LDL-C reduction has been shown when ezetimibe is associated with statins, with a further 21–27% LDL-C reduction irrespective of baseline concentrations.²⁹ The IMPROVE-IT study was the first to demonstrate the incremental clinical benefit of adding ezetimibe to standard statin therapy in patients with ACS.⁹ The study randomized 18 144 subjects to simvastatin (40 mg daily) plus ezetimibe vs. simvastatin monotherapy. The results showed an incremental lowering of LDL-C and a modest but significant reduction in the primary composite end point in the simvastatin/ezetimibe group compared with simvastatin alone [hazard ratio (HR) 0.936; 95% confidence interval (CI): 0.89–0.99; P = 0.016]. Based on these data, ezetimibe is recommended with class I/B as a second-line therapy in association with statins in PCI patients who have not achieved the LDL-C goal despite maximally tolerated statin doses or reported statin intolerance.¹⁹

In the foregoing complex context, which is still evolving, in addition to the historical fixed combination of simvastatin and ezetimibe, new combinations have recently been made available. These formulations include statins with high intensity and efficacy, such as rosuvastatin, at dosages of 5, 10 or 20 mg and ezetimibe at a fixed dosage of 10 mg; or atorvastatin 10, 20, 40 or 80 mg and ezetimibe at a fixed dosage of 10 mg. The combination of ezetimibe with even a moderate-intensity statin allows better management of any intolerance and still achieves acceptable results. Indeed, the recent RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy Versus Statin/Ezetimibe Combination for High-risk Cardiovascular Diseases (RACING) trial showed that among patients with atherosclerotic CV disease, moderate-intensity statin with ezetimibe combination therapy was not inferior to HIS monotherapy for the 3-year composite outcomes. This resulted in a higher proportion of patients with LDL-C concentrations of less than 70 mg/dl and lower intolerance-related drug discontinuation.³⁰

The key role of diet, physical activity and proper lifestyle on controlling the lipid profile should not be overlooked. The relationship between high saturated fat intake and increased LDL-C concentrations is well known; in fact, saturated fatty acids are the dietary component with the greatest impact on LDL-C levels.¹⁹ Although lifestyle recommendations remain the mainstay of cardiovascular prevention, weight loss and regular exercise have a moderate effect on reducing circulating cholesterol levels.¹⁹

New therapeutic strategies

In recent decades, we have witnessed an impressive development of cholesterol-lowering drugs, among them, certainly PCSK9i. A serine protease secreted by the liver, PCSK9 binds the LDL receptor on the surface of hepatocytes and induces its degradation by addressing the receptor to lysosomes.³¹ By promoting LDL receptor degradation, PCSK9 plays a key role in regulating plasma LDL-C. Alirocumab and evolocumab are human anti-PCSK9 monoclonal antibodies (mAbs) approved for clinical practice. They were studied in two large trials: the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial for evolocumab and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY) OUTCOMES trials for alirocumab.^10,11 Both trials showed an unprecedented efficacy profile in LDL-C reductions with an average reduction of about 60%.^10,11 This reduction in LDL-C for both trials translated into a 15% reduction in cardiovascular events. These also showed an excellent safety profile.^10,11 Furthermore, the role of PCSK9i in ACS has been better defined by subsequent studies. The Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients with Acute Coronary Syndromes (EVOPACS) study showed that 4 weeks of in-hospital administration of evolocumab 420 mg (together with atorvastatin 40 mg) in patients with ACS reduced the LDL-C levels by 40.7% as compared with placebo (95% CI: −45.2 to −36.2; P < 0.001).³² Similarly, the Evolocumab in Acute Coronary Syndrome (EVACS) trial tested the administration of evolocumab 420 mg within 24 h of ACS, demonstrating its efficacy in reducing LDL-C levels after only 24 h compared with placebo, with a greater probability of achieving the target in the immediate post-ACS.³³

Focusing the setting of acute patients, the objective of the High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) was to test whether evolocumab, started within 7 days of the onset of ACS, in addition to statin therapy, could stabilize atherosclerotic plaques and, particularly, increase the thickness of the fibrous cap as assessed by optical coherence tomography (OCT) at a follow-up of 52 weeks.¹⁵ The study met its primary end point: evolocumab, together with statin therapy, increased fibrous cap thickness by 42.7 μm (microns) compared with an increase of 21.5 μm in the placebo group (75% vs. 39%; P = 0.01).¹⁵ The Vascular Effects of Alirocumab in Acute MI Patients (PACMAN-AMI) trial investigated the effect of alirocumab on atherosclerotic plaque. IVUS was used to assess atheroma volume, near-infrared spectroscopy (NIRS) to assess lipid core loading (the LCBI), and OCT to assess both fibrous cap thickness and macrophage infiltration.¹⁶ After 52 weeks, patients treated with alirocumab and HIS had a more significant reduction in mean change in the percentage volume of atheroma in noninfarct-related arteries (primary efficacy end point) than patients who received statins as monotherapy (−2.13% vs. −0.92%; P < 0.001).¹⁶ The addition of alirocumab was also associated with a significant reduction in the plaque lipid burden (mean change in maximum LCBI within 4 mm was −79.42 with alirocumab and −37.60 with placebo, P = 0.006), an increase in the minimum fibrous cap thickness (mean change 62.67 μm vs. 33.19 μm, P = 0.001), and a greater reduction in macrophage infiltration (P < 0.001).¹⁶

The HUYGENS and PACMAN-AMI studies conclusively demonstrate that lowering cholesterolemia to such low values modifies the atherosclerosis process by stabilizing coronary plaques through the fibrous cap.

Bempedoic acid is a novel, orally administered, nonstatin agent for LDL-C reduction that, like statins, targets the cholesterol biosynthesis pathway in the liver.³⁴ Although statins inhibit HMG-CoA reductase, bempedoic acid inhibits ATP-citrate lyase (ACL), two steps upstream of HMG-CoA reductase.³⁴ Unlike statins, bempedoic acid is administered as a prodrug and converted to the active form of coenzyme A by enzymes found only in the liver and not in muscle. The lack of active metabolites of bempedoic acid in skeletal muscle makes it a viable alternative for patients with statin-associated muscle symptoms.³⁴ Phase 3 studies, part of the Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen (CLEAR) study program, evaluated the efficacy of bempedoic acid.^35–38 The CLEAR Tranquility and the CLEAR Serenity studies investigated the efficacy and safety of bempedoic acid, showing a reduction of 28.5% and 21.4% in LDL-C compared with placebo at 12 weeks.^37,38 The CLEAR Tranquility trial enrolled patients who had a history of statin intolerance, were on no more than low-dose statin therapy (which could also include no statin), and required additional LDL-C lowering, with a fasting LDL-C ≥100 mg/dl (2.6 mmol/l) at screening.³⁹ The CLEAR Serenity trial enrolled patients receiving stable background lipid-modifying therapy who required additional lipid-lowering for primary or secondary prevention of cardiovascular events. At the screening visit, fasting LDL-C was required to be ≥130 mg/dl for primary prevention patients and ≥100 mg/dl for patients with heterozygous familial hypercholesterolemia.⁴⁰ In the CLEAR Wisdom study that enrolled adults at high cardiovascular risk because of ASCVD, heterozygous familial hypercholesterolemia, or both with LDL-C ≥70 mg/dl on maximally tolerated statin therapy, the addition of bempedoic acid resulted in a 13.9–17.4% reduction in LDL-C at 12 weeks.³⁵ Because of its lack of active metabolites in skeletal muscle, bempedoic acid combined with maximally tolerated statin therapy was not associated with an increased incidence of muscle disorders or serious adverse events compared with the placebo in the CLEAR study program. The effect of bempedoic acid on cardiovascular morbidity and mortality has yet to be determined. The CLEAR Outcomes trial (NCT02993406) is an ongoing phase 3 study designed to evaluate the effect of bempedoic acid on major cardiovascular end points in patients at high risk of cardiovascular disease and statin intolerance. The drug is currently available in most European countries; however, it is not yet available in Italy. It is still awaiting approval and reimbursement criteria from the Italian drug regulatory agency ‘Agenzia Italiana del Farmaco’ (AIFA).

Inclisiran is a long-acting siRNA that targets the mRNA of PCSK9.^41,42 The Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION) program investigated the efficacy and safety of inclisiran. In the ORION-1 study of 501 patients, inclisiran produced dose-dependent reductions in PCSK9 and LDL-C levels.⁴³ The most significant reduction in LDL-C was observed with two doses of 300 mg (the first dose on day 1 and a second dose on day 90), resulting in 48% of patients achieving LDL-C levels <1.2 mmol/l (50 mg/dl) at 6 months and 1 year. The outcome study is ongoing; in fact, the ORION-4 trial (NCT03705234) plans to randomize, to inclisiran or placebo, approximately 15 000 patients aged >55 years with cardiovascular disease. These will be followed for 5 years to test safety and efficacy in preventing major cardiovascular events. More than 1550 patient-years of safety data have been gathered in the ORION phase 3 program without significant reported adverse events.

In December 2020, inclisiran was approved in Europe for the treatment of adult patients with hypercholesterolemia or mixed dyslipidemia. This approval is based on results from the robust ORION clinical development program, where inclisiran provided effective and sustained LDL-C reductions of up to 52% in patients with elevated levels despite statin therapy at the highest tolerated dose. With two doses per year, after an initial dose and one at 3 months, inclisiran should support long-term adherence.³⁹ In December 2021, inclisiran received approval from the FDA.

Timeline and therapeutic algorithm

The recent introduction of new lipid-lowering drugs, along with the growing availability of an array of fixed-dose combinations, notwithstanding the upcoming drugs, has made the abovementioned regulatory restrictions rapidly outdated. Indeed, in Italy, the two anti-PCSK9 antibodies, evolocumab and alirocumab, have been reimbursed by the National Health Service (NHS) since 2017. However, the use of these drugs has been limited by regulatory barriers that restrict their use to specific categories of patients with certain characteristics. Inevitably, this has curbed the use of anti-PCSK9 mAbs, leaving a gap between what the guidelines recommend and what is possible in clinical practice. The current indications charged to the NHS in secondary prevention, common to both drugs, are for patients aged ≤80 years with LDL-C levels ≥70 mg/dl in at least three detections despite therapy for at least 6 months with HIS at the highest tolerated dose and ezetimibe or after a single LDL-C detection for recent (defined as in last 12 months) myocardial infarction or multiple cardiovascular events or with demonstrated intolerance to statins and/or ezetimibe. In this regard, patients with a recent event may benefit from a path defined as ‘fast-track’. The Italian regulatory agency AIFA has recently approved the joint proposal by the Società Italiana di Cardiologia (SIC) and the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) to lower the LDL-C threshold for reimbursement of PCSK9i therapy to 70 mg/dl. However, a major gap remains between the guidelines when compared with the ESC and all major international cardiac societies.¹⁹ In fact, LDL-C targets adopted in Nota 13 – the Italian regulation for using oral LLT curated by AIFA – do not reflect guidelines recommended for most risk categories. Furthermore, despite the latest Nota 13 updates presenting a significant step ahead in the general set-up, adopting the concept of differentiated threshold based on clinical risk classes, and allowing skipping of the risk calculation using the official score cards for patients with clinical evidence of atherosclerotic CV disease, the allowed first-line treatments are limited to monotherapy with statins (either low- or high-intensity, based on the clinical risk) with combination treatments reimbursed only after the failure of monotherapy. Although this approach is generally reasonable for primary prevention, it raises concern in a general framework characterized by low adherence and a suboptimal percentage of treated patients achieving the treatment target. In this context, it might be useful to start directly with dual LLT in higher-risk patients with LDL-C levels that are far from target values in anticipation that a single LLT would not be sufficient to reach the target. This would shorten the time needed to reach the target, but most importantly, would simplify patients’ management, allowing optimal use of healthcare resources and minimizing dropout risks.

Furthermore, ACS represents a particular setting; early initiation of HIS treatment is associated with improved outcomes,^40,44,45 and is recommended by current practice guidelines.¹⁹ Specifically, ESC guidelines recommend the early use of HIS (daily dose: atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg) in patients with ACS with initiation as soon as possible, irrespective of baseline LDL-C levels (Class I, level of evidence A). From a practical standpoint, statins should be administered once the diagnosis of ACS is established, ideally together with initial antithrombotic therapy. Despite this evidence, a recent European cross-sectional study showed that only two out of three ACS patients receive HIS and roughly 10% are treated with HIS plus ezetimibe. Even among patients who were already on LLT before the onset of the acute event, only 50% were upgraded to HIS, and fewer than a third were upgraded to HIS+ezetimibe.⁴⁶ Patients undergoing PCI in the context of chronic coronary syndrome are also classified as being at very high risk, and therefore, ESC guidelines recommend a 50% reduction in LDL-C with a goal of <1.4 mmol/l (< 55 mg/dl).

Discussing the gap between LDL-C guideline goals and current practice, Ray et al.¹⁷ – along with some of the guideline authors – recently emphasized the need to start with at least a combination of statins and ezetimibe in patients at very high risk, and statins + ezetimibe + PCSK9 targeted therapy in extreme-risk patients, rather than a guideline stepwise approach.

Consistently with a more intensive strategy, we believe it is appropriate to start with HIS + ezetimibe in all patients or upgrade therapy if previously on lower-intensity LLT at admission (unless there are contraindications or documented intolerance). Thereafter, measure LDL-C at baseline and calculate the gap between LDL-C at admission and the therapeutic target to be achieved (<55 or <40 mg/dl).

Based on the target gap and knowing the reduction efficacy as a percentage (Table 2), the most appropriate therapy can be implemented, assuming that a reduction of at least 50% is recommended by the guidelines. If the estimated gap is between 50% and 65%, an early therapy with HIS + ezetimibe should be started before discharge. If the estimated gap is ≥65%, statin + ezetimibe and PCSK9 targeted therapy (PCSK9i or inclisiran) should be started before discharge. The addition of bempedoic acid might also be helpful in achieving the target in both scenarios.

Table 2 - Main characteristics and efficacy of lipid-lowering agents

Drug	Dose	Administration	Expected reduction in LDL-C
Atorvastatin	40–80 mg/day	Oral	≥50%
Rosuvastatin	20–40 mg/day	Oral	≥50%
Ezetimibe	10 mg/day	Oral	18.5% as monotherapy 65% in addition to HIS
Alirocumab	75 mg Q2W 150 mg Q2W	Subcutaneous injection	50–60% as monotherapy 75% in combination with HIS 85% in combination with HIS and EZE
Evolocumab	140 mg Q2W 420 mg Q4W	Subcutaneous injection	50–60% as monotherapy 75% in combination with HIS 85% in combination with HIS and EZE
Bempedoic acid	180 mg/day	Oral	17.8% in combination with statins (moderate and high intensity) 24.5% in statin-intolerant patients (± eze) 38% in FDC with EZE (± statins)
Inclisiran	300 mg at baseline, after 3 months and then every 6 months	Subcutaneous injection	≥50%

EZE, ezetimibe; FDC, fixed dose combination; HIS, high-intensity statin; LDL-C, low-density lipoprotein cholesterol.

Although our recommendations are clinically driven, these have to address the current Italian reimbursement policies for PCSK9i and the pending Italian reimbursability approval for bempedoic acid and inclisiran, which will more precisely define their role in the treatment algorithm.

To better understand the different therapeutic options, different clinical scenarios must be envisioned for CAD patients undergoing PCI. Despite the fact that the therapeutic goals to be achieved are the same, we differentiated two main settings, acute and chronic, for PCSK9i reimbursability: patients undergoing PCI for ACS and patients undergoing PCI for stable CAD. In patients undergoing PCI for ACS, if the estimated gap is between 50% and 65%, an early therapy with HIS + ezetimibe should be started at discharge. In LLT-naive patients, this appears to be the only viable strategy. The addition of bempedoic acid might also be helpful in achieving the target. If the estimated gap is ≥65%, statin + ezetimibe and PCSK9 targeted therapy (PCSK9i or inclisiran) should be started at discharge. In Italian clinical practice, PCSK9 mAb prescription is feasible at discharge for patients with ACS even after a single LDL-C detection, if LDL-C is ≥70 mg/dl with ongoing HIS at the highest tolerated dose plus ezetimibe or with demonstrated intolerance to statins and/or ezetimibe. In patients undergoing PCI for stable CAD, if the estimated gap is between 50% and 65%, an early therapy with HIS + ezetimibe should be started at discharge. If the estimated gap is ≥65%, statin + ezetimibe and PCSK9 targeted therapy (PCSK9i or inclisiran) should be started at discharge. In this scenario, PCSK9 mAbs prescription is possible if LDL-C levels are ≥70 mg/dl in at least three detections despite therapy for at least 6 months with HIS at the highest tolerated dose plus ezetimibe or with demonstrated intolerance to statins and/or ezetimibe. If patients are not intolerant but have not received HIS + ezetimibe for at least 6 months, they may not benefit immediately from PCSK9i prescription. The proposed LLT management algorithm for PCI patients is illustrated in Fig. 1, and an implementation of the algorithm in the ACS patient is shown in Fig. 2.

Fig. 1: Proposed LLT algorithm for PCI patients at discharge. EZE, ezetimibe; FDC, fixed dose combination; FUP, follow-up; HIS, high-intensity statin; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering treatment; mAbs, monoclonal antibodies; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors.∗Bempedoic acid: Italian approval for reimbursement pending. PCSK9 mAbs prescription is possible if LDL-C levels are ≥70 mg/dl in at least three detections despite therapy for at least 6 months with HIS at the highest tolerated dose plus ezetimibe or with demonstrated intolerance to statins and/or ezetimibe. In ACS patients after a single LDL-C detection, if LDL-C is ≥70 mg/dl with ongoing HIS at the highest tolerated dose plus ezetimibe or with demonstrated intolerance to statins and/or ezetimibe.

Fig. 2: LLT algorithm for ACS patients at discharge. ACS, acute coronary syndrome; BA, bempedoic acid; HIS, high-intensity statin; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering treatment; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors.

Short- and long-term follow-up

Response to LLT can be assessed 4–6 weeks after treatment initiation. If the LDL-C target is achieved at 4–6 weeks, patients should maintain their LLT. If the LDL-C target is not achieved, ACS patients on HIS + ezetimibe therapy can start PCSK9i with one detection of LDL-C values ≥70 mg/dl; if they are patients with stable CAD, they need a therapy upgrade if possible (i.e. bempedoic acid) and they will be able to access PCSK9i after 6 months of stable therapy. Therefore, further follow-up at 6 months is recommended.

As a general rule, follow-up with blood tests should be performed at 6–12 months, although this period is arbitrary. As a minimum, LDL-C should be determined, and a complete lipid profile is recommended. Non-high density lipoprotein (HDL) cholesterol or Apolipoprotein B should also be analyzed and used as secondary therapeutic targets. Periodic monitoring of the lipid profile can positively impact on patients’ adherence to lifestyle changes and drug regimens. In addition to blood tests, other aspects, such as the patient's educational level, regular contact and follow-up evaluation could intervene in adherence. The follow-up timeline faces problems related to long hospital waiting lists. Longer waiting times, especially for outpatient specialist services, is one of the most important problems in healthcare, and the relevant authorities are gradually taking steps to try to contain them. Before considering any therapeutic change, it is necessary to assess adherence to treatment and emphasize its relevance in achieving the proposed goals. Predictors of lack of adherence to statins have been identified; these include low income, advanced age, multiple and complex drug regimens, economic costs, and forgetfulness due to the absence of symptoms or psychological comorbidities. In this regard, PCSK9i showed good performance in terms of adherence and also improved adherence to statins.^47,48 New pharmacological approaches, such as inclisiran, will certainly be useful in increasing therapeutic compliance.

Mendelian studies have demonstrated that only long-term exposure to lower LDL-C levels is associated with a much lower risk of CV events.⁴⁹ Therefore, after an acute ischemic event or in patients with chronic ischemic heart disease, rapidly achieving the target LDL-C for that specific patient and maintaining this value for a long time are recommended.¹⁹

Long-term follow-up of patients enrolled in trials included in the CTT collaboration meta-analysis has found that the benefits of statin therapy persist for many years beyond the randomized exposure to statins,^50–52 thus conferring a legacy benefit that can be observed up to two decades later.⁵³

Sustained use of PCSK9i and concomitant treatment with other LLT agents reduce the frequency of CV episodes with few adverse events (10). In this regard, therapies targeting PCSK9 have been shown to be more effective in long-term control.³⁹

Gaps and future perspectives

Over the past 10 years, extensive research into the molecular mechanisms of dyslipidemia and the biology of lipids and lipoproteins has enriched the therapeutic armamentarium with new pharmacological options. The spread of new therapeutic strategies and the broadening of the beneficiary population make it possible to reach the targets in most patients. However, there are still some gaps to be filled. For example, there is a proportion of patients who have LDL-C levels between 55 and 70 mg/dl despite maximal therapy with statins and ezetimibe: these patients, in Italy, cannot benefit from the prescription of PCSK9i therapy; and until bempedoic acid is marketed, there are no tools to optimize treatment. Furthermore, long-term maintenance of the treatment goal is as important as its immediate achievement. This is reflected in a long-term adherence issue that occurs with statin therapy, which is partly mitigated with PCSK9i therapy. Further benefits on this issue may come from the use of therapeutic strategies involving patient engagement with the lipid and/or cardiology clinical center such as for the administration of inclisiran. The gene silencing strategies described represent a real frontier in treating dyslipidemia. Initial clinical studies have documented its safety, tolerability, and efficacy. These new pharmacological technologies will probably allow us to overcome many obstacles and obtain optimal results, especially in patients at very high risk, such as patients undergoing myocardial revascularization for coronary atherosclerosis.

Acknowledgements

Funding: none.

Conflicts of interest

There are no conflicts of interest.