Rationale and Design of the EPISODE Trial: A Randomized Controlled Trial on the Effect of PCSK9 Inhibitors in Calcific Aortic Valve Stenosis

Abstract

Background

Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emerging evidence has identified significant associations between CAVS and key biomarkers, including Lp(a) (lipoprotein [a]), low‐density lipoprotein cholesterol, and PCSK9 (proprotein convertase subtilisin/kexin type 9). However, robust evidence from randomized controlled trials is still lacking to substantiate these associations.

Methods

The EPISODE (Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis) trial is a prospective, evaluator‐blinded, randomized controlled trial designed to assess the therapeutic efficacy of PCSK9 inhibitors in patients with CAVS. A total of 160 patients with mild‐to‐moderate or asymptomatic severe CAVS will be randomly assigned to receive either statin monotherapy or a combination of statins and PCSK9 inhibitors. Participants will undergo follow‐up assessments at 3‐month intervals for 24 months, including transthoracic ultrasonic cardiogram, computed tomography, and quality‐of‐life evaluations using the EuroQol‐5 Dimension‐3 Level questionnaire. The primary end point is the annualized change in peak aortic jet velocity, whereas secondary end points encompass changes in aortic valve area, calcification score, incidence of heart valve surgery, and quality of life. Safety end points include all‐cause mortality and cardiovascular events.

Conclusions

The trial aims to evaluate the efficacy of PCSK9 inhibitors in modulating disease progression, reducing adverse cardiovascular events, and improving clinical outcomes in patients with CAVS. The anticipated findings are expected to provide critical insights for developing novel therapeutic strategies for early intervention in CAVS.

Registration

URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04968509.

Nonstandard Abbreviations and Acronyms

AS

aortic stenosis

CAVS

calcific aortic valve stenosis

Lp(a)

lipoprotein (a)

PCSK9

proprotein convertase subtilisin/kexin type 9

Clinical Perspective.

What Is New?

• This is the first randomized controlled trial evaluating the efficacy of PCSK9 inhibitors in delaying disease progression and improving clinical outcomes in patients with calcific aortic valve stenosis.

What Are the Clinical Implications?

• CAVS is anticipated to emerge as a major public health challenge in the future. However, effective pharmacological interventions to slow its progression remain limited. The anticipated findings of this study may provide novel therapeutic strategies for CAVS and potentially improve patient prognosis.

• If the results are positive, PCSK9 inhibitors could offer a new therapeutic option for patients with calcific aortic valve stenosis. Clinicians can use the study design as a reference to understand potential applications of PCSK9 inhibitors in this setting and to inform future treatment decisions.

In developed countries, calcific aortic valve stenosis (CAVS) ranks as the second most prevalent cardiovascular condition, following coronary artery disease and hypertension. The overall prevalence of CAVS is approximately 0.4%; however, it increases significantly with age, reaching 2% to 7% among individuals aged ≥65 years. ¹ A recent epidemiological survey revealed that the average prevalence of aortic stenosis (AS) in China is approximately 0.7%, with a notable increase to 3.4% among individuals aged >75 years. ² Considering China's large population and the ongoing demographic shift toward an aging society, CAVS is projected to become a major public health challenge in the near future.

The primary pathological feature of CAVS is mechanical obstruction, which currently limits the availability of effective pharmacological treatments for patients with severe CAVS. Surgical aortic valve replacement has played a pivotal role in reducing mortality rates among patients with CAVS. However, a significant proportion of older patients are ineligible for surgical treatment due to poor physical condition and high surgical risk. Although transcatheter aortic valve replacement offers a less‐invasive alternative, its high cost significantly restricts accessibility, making it unaffordable for most patients. In the absence of surgical intervention, the annual mortality rate for severe CAVS can reach up to 25%, with an average survival duration of only 2 to 3 years. ³ Therefore, early intervention and prevention of disease progression during the mild and moderate stages of AS are crucial for improving clinical outcomes and quality of life in patients with CAVS. Unfortunately, no pharmacological therapies have been proven effective in slowing CAVS progression.

Recent studies have showed that CAVS should not be viewed solely as a degenerative disease of older people. Instead, it is now recognized as a complex disease process driven by multiple pathophysiological mechanisms, including endothelial damage, inflammatory infiltration, lipid deposition, oxidative stress, fibrosis, and calcification, closely resembling the pathophysiological changes seen in atherosclerosis. ⁴ , ⁵ Despite the significant similarities between CAVS and atherosclerosis, evidence from 3 large‐scale prospective randomized controlled trials Scottish Aortic Stenosis and Lipid Lowering (SALTIRE), Simvastatin and Ezetimibe in Aortic Stenosis (SEAS), and Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) has demonstrated that statins, although highly effective in managing atherosclerosis, do not significantly impact the progression of CAVS. ⁶ , ⁷ , ⁸ As a result, the most recent guidelines from the American College of Cardiology/American Heart Association for valve disease management do not recommend statin therapy for CAVS. ⁹

Accumulating evidence has underscored the pivotal role of Lp(a) (lipoprotein[a]) in the pathophysiology of CAVS. ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Genome‐wide association studies in patients with CAVS have identified a single nucleotide polymorphism (rs10455872) within intron 25 of the Lp(a) gene (LPA), which is significantly associated with aortic valve calcification and stenosis. ¹⁴ Moreover, multiple studies have demonstrated a strong correlation between plasma Lp(a) levels and both the severity of aortic valve calcification and the progression of stenosis. ¹⁵ , ¹⁶ , ¹⁷ A post hoc analysis of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial further confirmed that elevated plasma Lp(a) levels were strongly associated with the incidence and progression of AS over a 2‐year period. For each standard deviation increase in Lp(a), the risk of CAVS progression requiring valve replacement increased by 122% (hazard ratio [HR], 2.22; P=0.001), whereas no significant association was observed for low‐density lipoprotein cholesterol (LDL‐C) (HR, 1.39; P=0.12). ¹⁸ Although statins effectively reduce plasma LDL‐C levels, they exhibit minimal impact on Lp(a) levels, likely explaining the lack of significant therapeutic efficacy of statins in CAVS.

In recent years, substantial evidence has emerged suggesting that PCSK9 (proprotein convertase subtilisin/kexin type 9) represents a promising therapeutic target for CAVS. ¹³ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ PCSK9, a serine protease encoded by the PCSK9 gene, interacts with low‐density lipoprotein receptors on hepatocytes, promoting their degradation. This process reduces the liver's ability to uptake and metabolize cholesterol, leading to elevated blood LDL‐C levels. PCSK9 inhibitors specifically target PCSK9, mitigating low‐density lipoprotein receptor degradation and thereby reducing plasma LDL‐C levels. Additionally, PCSK9 inhibitors reduce plasma Lp(a) levels by 20% to 30%. ²⁴ Thus, PCSK9 inhibitors may potentially inhibit the onset and progression of CAVS by lowering plasma Lp(a) levels. Moreover, PCSK9 has been independently associated with CAVS. Animal studies have shown that PCSK9 knockout mice exhibit significantly reduced aortic valve calcification, with levels only one‐fifth of those in wild‐type mice. ¹⁹ Clinical studies have similarly demonstrated that elevated plasma PCSK9 levels are strongly associated with the incidence and progression of CAVS. A recent observational study revealed that each 10 ng/mL increase in plasma PCSK9 was associated with a 1.4% (odds ratio, 1.014 [95% CI, 1.005–1.024]) higher risk of rapid CAVS progression (defined as an annual increase in peak aortic valve velocity of ≥0.45 m/s). ²⁰ Furthermore, mutations in the PCSK9 gene are significantly associated with the risk of CAVS. ¹³ , ²¹ These findings underscore the critical role of PCSK9 in the pathogenesis and progression of CAVS. ²² , ²³

This study represents the first clinical trial to investigate the therapeutic efficacy of PCSK9 inhibitors in CAVS, offering the potential to provide novel insights and strategies for the prevention and management of this condition.

METHODS

Study Design

The EPISODE (Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis) trial (URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04968509) is a single‐center, prospective, evaluator‐blinded, randomized controlled trial. The Figure provides an overview of the EPISODE trial design. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Figure 1. EPISODE trial design overview.

The R in the circle means randomization. CAVS indicates calcific aortic valve stenosis; CT, computed tomography; EPISODE, Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis; IWRS, interactive web response system; PCSK9, proprotein convertase subtilisin/kexin type 9; and UCG, ultrasonic cardiogram.

Ethics approval for this study was obtained from the ethics committee of Beijing Anzhen Hospital, Capital Medical University on October 16, 2023 (approval number: KS2023063). All participants will be provided with information about the study and will give their written informed consent before participation. This study was conducted in compliance with the Declaration of Helsinki and all applicable ethical guidelines.

Between January 2024 and December 2025, a total of 160 patients aged ≥18 years will be consecutively enrolled. Eligible participants must have mild‐to‐moderate CAVS or asymptomatic severe aortic valve stenosis confirmed by transthoracic ultrasonic cardiogram, along with either 1 major or 3 minor cardiovascular risk factors. Additionally, participants must have maintained a stable dose of statin therapy (rosuvastatin or atorvastatin) for at least 4 weeks, with LDL‐C levels ≥80 mg/dL or between 60 and 80 mg/dL. All patients provided written informed consent before any trial‐related activities. The complete inclusion and exclusion criteria are detailed in Tables 1 and 2.

Table 1.

Inclusion Criteria of the Trial

Inclusion criteria

Patients aged ≥18 y diagnosed with mild* or moderate † AS, or asymptomatic severe AS. ‡ Patients with an LDL‐C level of ≥80 mg/dL or between 60 and 80 mg/dL, along with 1 major § or 3 minor || cardiovascular risk factors, following a minimum of 4 wk on a stable dose of statin therapy (atorvastatin or rosuvastatin). Patients who provide written informed consent to participate in the study.

AS indicates aortic stenosis; and LDL‐C, low‐density lipoprotein cholesterol.

^*Mild AS means ultrasonic cardiogram measures peak aortic jet velocity between ≥2 and <3 m/s or mean transvalvular gradients <20 mm Hg.

^† Moderate AS means ultrasonic cardiogram measures peak aortic jet velocity between ≥3 m/s and <4 m/s or mean transvalvular gradients between ≥20 and <40 mm Hg.

^‡ Asymptomatic severe AS means ultrasonic cardiogram measures peak aortic jet velocity ≥4 m/s or mean transvalvular gradients ≥40 mm Hg, without any symptoms or signs related to AS and negative exercise treadmill test.

^§ Major risk factors include atherosclerotic cardiovascular disease, myocardial infarction, or hospitalization due to unstable angina within the past 2 y, or a diagnosis of type 2 diabetes.

^|| Minor risk factors include current cigarette smoking, hypertension, low levels of high‐density lipoprotein cholesterol, family history of premature coronary heart disease, high‐sensitivity C‐reactive protein level of 2 mg/L or higher (to convert high‐sensitivity C‐reactive protein values to nmol/L, multiply by 9.524), or men aged ≥50 y and women aged ≥55 y.

Table 2.

Exclusion Criteria of the Trial

Exclusion criteria

History of prior treatment with PCSK9 inhibitors. Patients requiring long‐term PCSK9 inhibitors therapy. Patients unable to maintain statin and/or PCSK9 inhibitor therapy for 24 mo. Known hypersensitivity to PCSK9 inhibitors and/or statins. Fasting triglyceride levels >400 mg/dL (4.5 mmol/L) at screening. Hypothyroidism. Active or chronic liver disease. Severe renal dysfunction (eGFR <30 mL/min per 1.73 m2). History of intracranial hemorrhage. History of alcohol or substance abuse. Known active infection or significant hematological, metabolic, or endocrine dysfunction. Treatment with systemic steroids or cyclosporine within the past 3 mo. Active malignancy. Any life‐threatening condition associated with a life expectancy of <12 mo. Severe mitral stenosis (valve area <1 cm2). Severe mitral or aortic regurgitation. Planned heart valve surgery. Left ventricular ejection fraction <30% or severe heart failure (NYHA class III–IV). Presence of a permanent pacemaker or implantable cardioverter‐defibrillator. Cardiac arrhythmias refractory to medical therapy. Current pregnancy, lactation, or plans to conceive during the study period.

eGFR indicates estimated glomerular filtration rate; NYHA, New York Heart Association; and PCSK9, proprotein convertase subtilisin/kexin type 9.

Eligible patients will be randomly allocated. The experimental group will receive PCSK9 inhibitors (140 mg evolocumab, 75 mg alirocumab, or 150 mg torcetrapib administered subcutaneously every 2 weeks) in combination with standard statin‐based lipid‐lowering therapy (atorvastatin 20–40 mg with or without ezetimibe 10 mg once daily, or rosuvastatin 10–20 mg with or without ezetimibe 10 mg once daily). The control group will receive standard statin‐based lipid‐lowering therapy alone. Central randomization will be performed using an interactive web response system, with stratification based on sex, age, and peak aortic valve flow velocity.

Follow‐up will be scheduled at baseline (0 months), 3, 6, 9, 12, 15, 18, 21, and 24 months. Ultrasonic cardiogram, computed tomography, and blood sampling will be conducted at baseline, 24 months, or before study withdrawal. Telephone follow‐up will be conducted at 3, 6, 9, 12, 15, 18, and 21 months postenrollment to collect quality‐of‐life questionnaire data and clinical end point information. The complete follow‐up plan is detailed in Table 3.

Table 3.

Follow‐Up Plan

Study stage	Baseline visit	First visit	Second visit	Third visit	Fourth visit	Fifth visit	Sixth visit	Seventh visit	Eighth visit
Study d	Preenrollment (0)	3 mo	6 mo	9 mo	12 mo	15 mo	18 mo	21 mo	24 mo
Time window (d)		±7	±14	±14	±14	±14	±14	±14	±14
Review of inclusion/exclusion criteria	X
Signing of informed consent	X
Clinical diagnosis at enrollment	X
Randomization	X
Contact information of subjects	X
Demographic data*	X
Current and past medical history†	X
Physical examination‡	X
Laboratory tests§ , || , ¶	X								X
ECG results#	X
UCG**	X								X
CT scan††	X								X
Quality of life questionnaire‡‡	X	X	X	X	X	X	X	X	X
Cardiac valve surgery§§		X	X	X	X	X	X	X	X
Medication history before randomization (>1 mo)	X
Other medication history before randomization	X
Medication history after randomization		X	X	X	X	X	X	X	X
Other medication history after randomization		X	X	X	X	X	X	X	X
Visit status each time	X	X	X	X	X	X	X	X	X
Safety events||||		X	X	X	X	X	X	X	X
Adverse events table		X	X	X	X	X	X	X	X
Serious adverse events table		X	X	X	X	X	X	X	X
Study completion status									X

CT indicates computed tomography; and UCG, ultrasonic cardiogram.

^*Demographic information: age, sex, height, weight, smoking history, alcohol consumption history, family history of early coronary artery disease.

^† Current and past medical history: The primary conditions include coronary artery disease, previous myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass grafting, heart failure, cerebrovascular diseases (ischemic stroke, transient ischemic attack, hemorrhagic stroke), hypertension, diabetes, hypercholesteremia, renal failure (estimated glomerular filtration rate <60 mL/min per 1.73 m², based on the Chronic Kidney Disease Epidemiology Collaboration formula), peripheral artery disease.

^‡ Physical examination: blood pressure and heart rate, measured within 7 d before enrollment. Blood pressure and heart rate should be measured after 5 to 10 min of rest.

^§ Complete blood count: white blood cells, red blood cells, neutrophils, hemoglobin, platelets, and hematocrit (measured within 7 d before enrollment).

^|| Blood biochemistry: alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, glycated hemoglobin, total cholesterol, triglycerides, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, lipoprotein (a), high‐sensitivity C‐reactive protein (measured within 7 d before enrollment).

^¶ Brain natriuretic peptide: measured within 7 d before enrollment.

^# ECG: results obtained within 7 d before enrollment.

^**UCG: peak aortic valve flow velocity, mean aortic valve pressure gradient, and valve area. (At least 3 consecutive heartbeats with a stable heart rate should be selected for imaging. For atrial fibrillation, images from at least 5 consecutive heartbeats should be used. In the apical 5‐chamber view, continuous Doppler imaging should be used to obtain the peak aortic valve flow velocity. The simplified Bernoulli equation should be used to calculate the instantaneous pressure gradient across the aortic valve, and the continuity equation should be used to calculate the normalized aortic valve area. All participating ultrasonographers will undergo standardized training, and fixed imaging planes will be used. Images will be reviewed by 2 experienced, blinded ultrasonographers from the core laboratory).

^†† CT scan: aortic valve calcification score. Aortic valve calcification is defined as calcific lesions located on the aortic valve leaflets, aortic annulus, or the aortic sinus walls near the aortic valve or annulus. These lesions are identified when the CT value of >3 consecutive pixels exceeds 130 Hounsfield units. Aortic valve calcifications were evaluated by the Agatston method, with 2 consecutive measurements obtained and averaged. The calcification score for each lesion was calculated by multiplying the volume of calcification multiplied by the maximum grayscale value. The sum of calcification scores for all lesions was recorded as the total calcification score. Three experienced radiologists blinded to clinical data and group allocation, measured the aortic valve calcification scores independently.

^‡‡ Quality of life questionnaire: EuroQol‐5 Dimension‐3 Level. This includes a multidimensional health description system and a visual analog scale. The former consists of 5 dimensions: mobility, self‐care, usual activities, pain/discomfort, and anxiety/depression. The patient's responses are converted into a health utility index based on the preferences of the Chinese population. This value provides an objective reflection of quality of life. The latter is a 0 to 100 scale, where 0 represents the worst possible health state and 100 represents the best possible health state or an individual's ideal health condition. Patients self‐rate their health status on this scale, providing a more subjective reflection of their health perception.

^§§ Cardiac valve surgery: transcatheter mitral/tricuspid/aortic valve replacement or repair, or surgical mitral/tricuspid/aortic valve replacement or repair.

^|||| Safety events: all‐cause death or cardiovascular events. Relevant information should be recorded at all times, and appropriate laboratory and imaging examinations should be completed.

The primary end point is the average annualized change in peak aortic valve blood flow velocity over the 24‐month follow‐up period (meters per second per year). This end point is calculated using the following formula (unit: meters per second per year):

$$\begin{array}{c}\text{Annual average change in peak aortic valve flow velocity}=\hfill \\ \frac{\text{peak aortic valve flow velocity}\mathrm{at}24\text{months or before exit}-\text{baseline peak aortic valve flow velocity}}{\text{total time of follow}-\mathrm{up}\left(\text{days}\right)/365}\hfill \end{array}$$

The secondary end points include the average annualized change in aortic valve opening area (square centimeters per year) $\left(\frac{\text{aortic valve area}\mathrm{at}24\text{months or before exit}-\mathrm{b}\text{aseline aortic valve area}}{\text{total time of follow}-\mathrm{up}\left(\text{days}\right)/365}\right)$, the average annualized change in aortic valve calcification score $\left(\frac{\text{aortic valve calcium score}\mathrm{at}24\text{months or before exit}-\text{baseline aortic valve calcium score}}{\text{total time of follow}-\mathrm{up}\left(\text{days}\right)/365}\right)$, the need for valve surgery (includes both transcatheter aortic valve replacement and surgical aortic valve replacement), and changes in quality‐of‐life (assessed using the EuroQol‐5 Dimension‐3 Level scale, with responses converted into health utility index values based on Chinese population preferences).

Safety end points include all‐cause mortality (classified as cardiovascular mortality, noncardiovascular mortality, and mortality of unknown cause) and cardiovascular events. The complete list of trial end points is detailed in Table 4.

Table 4.

End Points of the Trial

Primary end point (time frame: up to 24 mo) Average annualized change in peak aortic valve blood flow velocity (m/s per y).

Secondary end points (time frame: up to 24 mo) Average annual change in aortic valve opening area (cm2/y). Average annual change in aortic valve calcification score. Receive valve surgery (including TAVR and SAVR). Changes in quality‐of‐life scores (assessed using the EuroQol‐5 Dimension‐3 Level scale).

Safety end point All‐cause death or cardiovascular events.

SAVR indicates surgical aortic valve replacement; and TAVR, transcatheter aortic valve replacement.

This study established an independent clinical endpoint committee to ensure rigorous end point adjudication. The clinical endpoint committee consisted of 3 members with substantial expertise in the relevant clinical research areas. All members were independent from the investigative team and had no direct involvement in the trial's implementation. They were prohibited from holding any financial or professional interests that could compromise their impartiality or decision‐making. Before participating, all members were required to sign a confidentiality agreement, committing to protect the confidentiality of all deliberations and proceedings in line with established protocols.

Statistical Analysis

Sample Size Calculation

Sample size calculation was based on the primary end point. The SALTIRE ⁶ (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression) randomized trial was designed and conducted to investigate changes in aortic flow velocity on Doppler echocardiography before and after statin therapy and enrolled 155 patients with CAVS. In this study, patients treated with atorvastatin 80 mg daily exhibited a mean annual change in peak aortic velocity (the primary end point) of 0.199±0.210 m/s, compared with 0.203±0.208 m/s in the placebo group. Of note, the RAAVE ²⁵ (Rosuvastatin Affecting Aortic Valve Endothelium) study, including 121 patients with asymptomatic AS, showed that the increase in peak aortic velocity was 0.24±0.30 m/s per year in the control group and 0.04±0.38 m/s per year in the rosuvastatin group (P=0.007). In addition, in our separate previous study ²⁶ on the progression of AS, the median interval between the first and last echocardiogram was 601 (interquartile range, 353–909) days. After the observation period, the peak aortic velocity increased from 3.51±0.76 to 3.88±0.85 m/s. Patients in the high monocyte group had more rapid progression in peak aortic velocity (0.24 [0.09–0.43] versus 0.08 [0.04–0.23] m/s per year). Based on these data, we estimated conservatively that PCSK9 inhibitors would result in a 0.1 m/s per year greater reduction in peak aortic velocity compared with the control group, with an assumed SD of ±0.2 m/s per year for the annual change in peak velocity. We used a 1‐sided superiority test (α=0.025, Δ=0) and used the Superiority by a Margin module in PASS 15 to calculate a sample size of 128 patients, ensuring 80% statistical power to detect a significant difference between the groups. Accounting for a potential 20% dropout rate during follow‐up, the study required a total of 160 enrolled patients, with 80 participants allocated to each group.

Analysis Methods

The study population will be categorized as follows:

The full analysis set: This set will include all participants who provide informed consent and are randomized, and will be analyzed according to the intention‐to‐treat principle.

The per protocol set: This set will comprise participants who complete the trial without major protocol violations (defined as deviations from the study's inclusion or exclusion criteria).

The safety set: This set will include participants who sign informed consent, are randomized, and received at least 1 dose of the investigational drug (PCSK9 inhibitor).

Efficacy analyses will be conducted based on the full analysis set and per protocol set. Baseline demographic data will be analyzed using the full analysis set, whereas safety evaluations will be performed on the safety set.

We will use SAS (version 9.3; SAS Institute, Cary, NC) and R statistical software (version 4.1.1; R studio) for data description and statistical analyses. Continuous variables will be expressed as mean±SD.

For the primary outcome and numerical secondary outcomes, we plan to use a linear regression model for primary analysis. However, for subgroup analyses considering the potential repeated‐measures nature of the data and the need to more precisely evaluate treatment effect changes over time, a linear mixed‐effects model may be used. This model will include fixed effects for the treatment group, time point (baseline and 24 months), the treatment‐by‐time interaction, and a random intercept for each patient.

For binary secondary outcomes (eg, valve surgery) and adverse events, we will report the counts and proportions for each treatment group. Intergroup comparisons will be performed using Fisher tests.

We will conduct stratified analyses based on baseline characteristics, including body mass index (< 28 or ≥28 kg/m²) and the presence or absence of diabetes, hypertension, coronary artery disease, and renal function impairment, for the analysis of the primary outcome.

All analyses will adhere to the intention‐to‐treat principle. Additionally, to address the missing 2‐year peak aortic jet velocity values, we plan to use multiple imputations methods, with baseline characteristics as covariates, to repeat the analysis of the primary outcome. All tests will be 2‐sided, with a significance level set at P≤0.05.

DISCUSSION

Currently, clinical and mechanistic research on PCSK9 inhibitors primarily focuses on atherosclerosis. Notably, the EPISODE study is the first global RCT to investigate the impact of actively lowering Lp(a) levels using PCSK9 inhibitors on the progression of AS. Small et al ²⁷ summarized ongoing clinical trials evaluating medical therapies for primary valvular heart disease, including our study. Additionally, an ongoing clinical trial is investigating the use of pelacarsen to mitigate AS progression by reducing Lp(a) levels (NCT05646381). Currently, there are no effective medical treatments for AS; however, lipid‐lowering therapy represents a potential therapeutic target. The EPISODE study may provide novel insights into the management of this condition.

LIMITATIONS

This study faced several limitations due to restrictions on the use of PCSK9 inhibitors in current drug guidelines and the need to maintain consistency in baseline characteristics. Specifically, our inclusion criteria targeted patients with elevated LDL‐C levels despite regular statin therapy. Some patients had uncontrolled blood lipid levels at enrollment and were randomized to the control group. During follow‐up, patients may switch therapies, such as adding PCSK9 inhibitors to intensify lipid‐lowering, which could potentially lead to premature trial termination. Additionally, PCSK9 inhibitors are administered via subcutaneous injection, are more costly than statins, may reduce patient compliance, and consequently impact study outcomes. Furthermore, although this study used an evaluator‐blinded design, this choice may affect the quality of the study compared with a double‐blind randomized controlled trial. An open‐label design was chosen due to practical considerations; 1 group received both subcutaneous injections and oral medications, whereas the other only received oral medications. Given that patients self‐administered subcutaneous injections and no pharmaceutical company support for placebos was available, a double‐blind design was not feasible. Although this may introduce potential bias, we believe this approach remains valuable for generating clinical data in the current context. Finally, the EPISODE trial is a single‐center study with only 160 eligible patients enrolled at Anzhen Hospital, which may lead to selection bias. To improve the generalizability of the findings, future multicenter studies involving patients from diverse geographic regions are necessary.

CURRENT STATUS

This RCT is ongoing at this time. It is in the stage of recruiting patients.

CONCLUSIONS

The EPISODE trial represents the first global randomized controlled trial to evaluate the therapeutic efficacy of PCSK9 inhibitors in CAVS. The results may offer valuable insights into the prevention and treatment of CAVS, potentially enabling early interventions to slow disease progression, reduce mortality, and decrease the need for valve replacement, thereby alleviating the associated health care and societal burdens.

Sources of Funding

This study was supported by government health care authorities: the Capital Health Research and Development of Special (2022‐2‐1052) funded by the Beijing Municipal Health Commission, and the Beijing Hospitals Authority's Ascent Plan (DFL20240601) funded by the Beijing Hospitals Authority.

Disclosures

This study has no conflict of interest.