Evolocumab-associated haemorrhagic pericarditis with cardiac tamponade: case report

Abstract

Background

Evolocumab, a fully humanized monoclonal antibody that inhibits proprotein convertase subtilisin/kexin Type 9 (PCSK9), is one of the most widely used lipid-lowering therapies for atherosclerotic cardiovascular disease. It is generally well tolerated, but immune-mediated inflammatory reactions may occur with monoclonal antibodies. Among common adverse effects associated with evolocumab, pericardial disease associated with PCSK9 inhibitors is extremely rare.

Case summary

A man in his late 70s on evolocumab for 2 months presented to the hospital for atrial flutter and moderate pericardial effusion. He was treated with amiodarone and discharged with colchicine and indomethacin. Ten days later, the patient represented with worsening shortness of breath, malaise, and jugular venous distension with echocardiographic evidence of tamponade physiology. Emergent pericardiocentesis drained about 1 L of sanguineous fluid. Autoimmune, infectious, and malignant aetiologies were systematically excluded. Evolocumab was discontinued, and the patient remained asymptomatic without recurrence.

Discussion

This case illustrates a probable immune-mediated pericarditis with haemorrhagic effusion and tamponade seen with evolocumab use. Clinicians should remain vigilant for this rare monoclonal antibody–associated pericardial inflammation as a potentially serious adverse reaction to evolocumab, particularly when other common causes have been excluded. Continued pharmacovigilance is essential as the use of PCSK9 inhibitors expands.

Learning points.

• Evolocumab, a fully humanized proprotein convertase subtilisin/kexin Type 9 inhibitor with low immunogenicity, can rarely cause immune-mediated complications, such as haemorrhagic pericarditis.

• Drug-induced pericardial effusion should be suspected when new effusion develops weeks to months after therapy initiation and other causes (infectious, malignant, autoimmune) have been excluded.

• Management involves discontinuation of the offending agent, with consideration of alternative lipid-lowering therapies, such as inclisiran.

Introduction

Evolocumab is a fully humanized immunoglobulin G2 (IgG2) monoclonal antibody that binds to proprotein convertase subtilisin/kexin Type 9 (PCSK9). Proprotein convertase subtilisin/kexin Type 9 normally binds to the low-density lipoprotein receptor (LDL-R) and directs it to lysosomal degradation, leading to lower low-density lipoprotein cholesterol (LDL-C) clearance.¹ Evolocumab acts by directly binding to PCSK9, decreasing LDL-R degradation and increasing LDL-Cclearance. According to the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, in patients with established atherosclerotic cardiovascular disease (ASCVD) receiving background statin therapy, evolocumab lowered LDL-C by ∼60% and reduced major cardiovascular events by 15%.²

Structurally, evolocumab is a recombinant and fully human antibody, which theoretically reduces the risk of anti-drug antibody formation and serum sickness-like reactions.^3,4 It reaches steady state after three to four doses and is administered subcutaneously every 2 weeks or monthly.¹ While common adverse reactions, such as injection-site reactions are mild, there have been rare reports of life-threatening immune-mediated inflammations. We present a patient who developed haemorrhagic pericarditis with tamponade physiology while on evolocumab.

Summary figure

Date	Setting	Key events and findings	Management/outcome	Evolocumab (Repatha) exposure and timing
2 April 2025	Outpatient pharmacy	Evolocumab dispense recorded (140 mg/mL SureClick, 84-day supply)	—	140 mg subcutaneous every 2 weeks (six doses)
April–Mid-June, 2025 (approx.)	Outpatient	On evolocumab for ∼2.5 months prior to first ED presentation (per case history)	–	Ongoing q2-week injections; exact last injection date before symptom onset not documented but expected to be mid-June as per dosing and frequency
19–22 July 2025	Emergency department (ED) → CCU admission	Presented with palpitations; HR 140 s with new onset Atrial Flutter; POCUS showing moderate circumferential pericardial effusion	Admitted to the CCU, initiated on amiodarone, and underwent cardioversion with placement of an implantable loop recorder (ILR); discharged with amiodarone, Eliquis, colchicine, indomethacin, and a planned 1-week follow-up TTE to monitor the pericardial effusion	–
2 August 2025	Hospitalization (re-presentation)	Outpatient TTE (done on 2 August 2025) showed increased pericardial fluid with tamponade physiology; admitted for drainage	Pericardial drainage performed followed by atrial flutter ablation performed after	–
Post-procedure follow-up	Outpatient	Clinical improvement with no additional palpitation or shortness of breath. Follow-up 2- and 6-month post-drainage TTE without evidence of pericardial effusion	Evolocumab identified as suspected culprit and discontinued	Evolocumab stopped; alternative lipid-lowering strategy being considered

Case presentation

A man in his late 70s who is a never-smoker and a former painter with hyperlipidaemia on evolocumab for 2 months presented with 2 days of palpitations (see Summary figure). He had previously been treated with atorvastatin 10 mg daily but developed myalgias, after which he was switched to evolocumab; other home medications included amlodipine 5 mg daily, vitamin D supplementation, and famotidine 20 mg as needed. On arrival, he was tachycardic (140–145 b.p.m.) with electrocardiogram showing atrial flutter. Laboratory workup showed mild normocytic anoemia, and bedside transthoracic echocardiography (TTE) showed moderate circumferential pericardial effusion without tamponade. He was admitted to the cardiac care unit, treated with amiodarone, and underwent cardioversion. He was discharged on colchicine 0.6 mg twice a day and indomethacin 50 mg for the treatment of pericardial effusion with follow-up TTE scheduled in a week. Given new-onset atrial flutter, therapeutic enoxaparin was initiated inpatient and transitioned to apixaban on discharge.

About a week later, the patient was referred back to the hospital after an outpatient TTE showed severe pericardial effusion with tamponade physiology (see Supplementary material online, Video S1). Repeat TTE in the ED confirmed right atrial and right ventricular diastolic collapse with a plethoric inferior vena cava (IVC) (see Figure 1A). Physical exam was notable for jugular venous distension and muffled heart sounds.

Figure 1.

Transthoracic echocardiographic findings demonstrating cardiac tamponade physiology. (A) Subcostal view showing a markedly dilated inferior vena cava with diminished inspiratory collapse, consistent with elevated right atrial pressure (RAP). (B) Apical four-chamber view demonstrating diastolic collapse of the right atrial wall, indicating early right-sided pressure compromise. (C) Parasternal long-axis view showing diastolic compression of the right ventricle (arrow), confirming haemodynamically significant tamponade physiology. (D) Subcostal view showing a circumferential pericardial effusion surrounding the heart. (E) Parasternal short-axis view quantifying a large pericardial effusion measuring 2.21 cm in diastole.

The patient underwent emergent pericardiocentesis, draining 955 mL of bloody fluid, and subsequently underwent atrial flutter ablation. Repeat TTE the following day showed resolution of the effusion (see Supplementary material online, Video S2). Infectious evaluation was negative, including no growth on peripheral blood cultures at 5 days, a negative respiratory pathogen polymerase chain reaction (PCR) panel (including Chlamydia pneumoniae and Mycoplasma pneumoniae), and negative pericardial fluid bacterial cultures and AFB/mycobacterial studies; Rickettsia and Coxiella serologies, as well as Borrelia burgdorferi (Lyme) IgM/IgG testing, were not obtained because there were no epidemiologic risk factors or exposure history suggestive of these infections. Autoimmune and rheumatologic evaluation was unrevealing, with negative antinuclear antibody (ANA), anti-dsDNA, rheumatoid factor (RF), anti-Smith, anticardiolipin antibody, anti-cyclic citrullinated peptide (CCP), and anti-Sjögren syndrome-related antigens A and B (SSA/SSB) testing; erythrocyte sedimentation rate (ESR) was 30 mm/h (reference ≤ 19 mm/h), and C-reactive protein was 18 mg/L (reference ≤ 4 mg/L). Body imaging was also unremarkable, with no abnormalities or suspicious findings for malignancy. Evolocumab was identified as the potential culprit and discontinued. No other drugs or chronic medications were associated with, or had a clear temporal relationship to, the syndrome. At 2 months of follow-up, the patient remained asymptomatic and in sinus rhythm; a 6-month follow-up TTE also demonstrated no recurrence of pericardial effusion.

Discussion

This case describes haemorrhagic pericarditis progressing to tamponade temporally associated with evolocumab exposure, adding to the limited reports of PCSK9 inhibitor–associated serosal inflammation. The overall pattern—delayed onset, absence of an alternative unifying diagnosis after appropriate evaluation, and sustained resolution after drug discontinuation—supports a probable drug-related adverse reaction. Anticoagulation (therapeutic enoxaparin inpatient, transitioned to apixaban on discharge) for new-onset atrial flutter may have contributed to the sanguineous character of the pericardial fluid, but would not be expected to account for the development and progression of a large effusion with tamponade physiology. A key limitation is the lack of pericardial biopsy, as tissue sampling is not routinely obtained in emergent tamponade unless malignancy or infiltrative disease is strongly suspected; therefore, the mechanistic pathways discussed below are biologically plausible but inferential.

One potential mechanism is immune-complex formation. While evolocumab is a fully human IgG2 monoclonal antibody with a low risk of anti-drug antibody (ADA) development, immunogenicity is not zero. Anti-drug antibodies may still form and bind evolocumab to form circulating immune complexes that deposit in serosal membranes and activate the classical complement pathway.^4,5 Generation of C3a and C5a increases vascular permeability and recruits inflammatory cells, while formation of the membrane attack complex (C5b–9) can directly injure endothelial cells, potentially resulting in haemorrhagic effusion⁶ (see Figure 2). This mechanism is well described with other therapeutic monoclonal antibodies and offers a plausible explanation for the haemorrhagic nature of this patient’s pericardial effusion.

Figure 2.

Proposed immune-mediated mechanisms of evolocumab-associated haemorrhagic pericarditis leading to cardiac tamponade. (A) A humoral immune pathway in which subcutaneous evolocumab administration leads to anti-drug antibody formation and circulating immune complexes, triggering complement activation with generation of C3a/C5a and assembly of the membrane attack complex (C5b–9). Complement-mediated endothelial injury increases vascular permeability, resulting in inflammatory leakage of blood and fluid into the pericardial space, thus resulting in large pericardial effusion and tamponade physiology. (B) A cellular immune pathway, whereby proprotein convertase subtilisin/kexin Type 9 inhibition reduces lysosomal degradation of major histocompatibility complex Class I, increasing surface major histocompatibility complex Class I expression and presentation of cryptic self-antigens. This enhanced antigen presentation may activate cytotoxic CD8⁺ T cells, leading to localized immune-mediated endothelial injury and pericardial inflammation. Together, these complementary mechanisms provide a biologically plausible explanation for delayed-onset haemorrhagic pericarditis temporally associated with evolocumab use, as observed in the present case.

Beyond complement-mediated injury, PCSK9 also modulates inflammatory signalling. Experimental studies suggest that PCSK9 interacts with Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB), regulating downstream cytokines, including IL-6, IL-1β, and TNF-α.⁷ Inhibition of PCSK9 may disrupt this regulatory axis, particularly in genetically susceptible individuals or those with endothelial dysfunction due to diabetes, ageing, or autoimmune predisposition. Such localized immune dysregulation could explain why this patient demonstrated only mildly elevated ESR and C-reactive protein, consistent with inflammation confined to the pericardium rather than a systemic inflammatory reaction.

Another proposed mechanism involves major histocompatibility complex Class I (MHC-I) regulation.⁸ Under physiological conditions, PCSK9 promotes lysosomal degradation of MHC-I molecules, limiting their surface expression. Inhibition by evolocumab increases MHC-I density on cell surfaces, potentially exposing a broader repertoire of self-peptides, including ‘cryptic’ antigens not encountered during thymic negative selection.⁹ Presentation of these peptides may activate cytotoxic CD8+ T cells and trigger autoimmune-like tissue injury (see Figure 2). This phenomenon has been leveraged therapeutically in oncology, where PCSK9 inhibition enhances tumour immunogenicity and improves responses to immune checkpoint inhibitors.⁸ In non-cancer settings, however, this same mechanism could theoretically predispose to localized autoimmune inflammation, such as pericarditis.

Although rare, similar cases have been reported. Pavlovic et al. (2024) described patients with familial hypercholesterolaemia who developed concurrent pleural and pericardial effusions while receiving evolocumab, which resolved promptly after discontinuation.¹⁰ Bimal et al. reported a comparable presentation with moderate serosal effusions that improved over several months following drug withdrawal.¹¹ Immune-mediated pericardial disease has also been described with other monoclonal antibodies, including nivolumab, where pericardial biopsies demonstrated CD4-predominant lymphocytic infiltration and cases of tamponade.

Given the suspected drug-related pericardial inflammation temporally associated with a monoclonal PCSK9 inhibitor in this patient, subsequent lipid lowering should prioritize achieving ASCVD LDL-C targets while minimizing re-exposure to antibody-based therapies. Depending on baseline LDL-C and prior statin tolerance, alternatives include ezetimibe and bempedoic acid, with escalation as needed. If further LDL-C reduction is required, inclisiran may be a reasonable option because it lowers PCSK9 via siRNA-mediated suppression of hepatic PCSK9 synthesis rather than circulating antigen–antibody binding; this mechanism may plausibly lessen the likelihood of ADA formation and immune-complex–mediated reactions compared with monoclonal antibodies, although definitive comparative data for this specific adverse event are lacking.^12,13 The regimen should be individualized with shared decision-making and clinical follow-up.

Conclusion

Recent case reports show a consistent clinical pattern of delayed-onset effusion occurring within weeks to months of drug initiation and complete resolution after discontinuation. Although the exact mechanism remains unclear, evidence suggests a pathway of immune dysregulation characterized by complement activation, cytokine amplification, and endothelial injury. This case underscores the importance of clinical vigilance for pericardial complications in patients receiving PCSK9 inhibitors.

Lead author biography

Born and raised in Korea, Aaron Y. Kim, MD is a PGY3 internal medicine resident at New York Presbyterian Brooklyn Methodist Hospital with an interest in cardiology and cardiac imaging. A true Korean BBQ lover and coffee addict, he is always chasing good vibes and even better food. When he is not working, you will probably find him grilling and hanging out in Flushing for some late-night Asian eats.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Author contributions

Aaron Y. Kim (Conceptualization, Formal analysis, Investigation, Writing—original draft [lead]), Laura Bradel (Conceptualization, Formal analysis, Writing—review & editing [equal], Supervision [lead]), Nimrah Hossain (Conceptualization, Formal analysis, Writing—review & editing [equal], Supervision [lead]), and Brian Wong (Conceptualization, Formal analysis, Writing—review & editing [equal], Supervision [lead])

Consent: The authors confirm that written informed consent for the submission and publication of this case report, including images and associated text, has been obtained from the patient in line with the COPE guidelines.

Funding

None declared.

Data availability

The data underlying this article are included within the article and its Supplementary material. No additional datasets were generated or analysed.