Onset and progression of atherosclerosis in patients with melanoma treated with immune checkpoint inhibitors
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* Daan C H van Dorst
* Tom J J Uyl
* Astrid A M Van der Veldt
* Timy Andrawes
* Arjen Joosse
* Esther Oomen-De Hoop
* Alexander HJ Danser
* Ron H J Mathijssen
* Daniel Bos
* Jorie Versmissen

## Abstract

**Background** Immune checkpoint inhibitors (ICIs) are effective anticancer agents but significantly increase cardiovascular risk. This could be due to its potential to induce or worsen atherosclerosis. We evaluated the onset and progression of atherosclerosis during ICI treatment in patients with melanoma and investigated risk factors for substantial (>10%/year) atherosclerotic plaque growth in five segments of the arterial tree.

**Methods** Onset and yearly progression of atherosclerosis were assessed in the aortic arch, descending thoracic aorta, abdominal aorta, left and right iliac arteries via CT scans performed prior to and 1 year (±3 months) after ICI therapy initiation in patients with melanoma in the adjuvant (resected melanoma) and advanced disease (irresectable stage III and stage IV) setting. The primary outcome was defined as yearly progression of maximal plaque thickness in each arterial segment. Secondary outcomes were changes in the number of plaques, incidence of arterial thrombosis (ATE), and factors associated with substantial plaque growth in the descending thoracic aorta.

**Results** In total, 244 patients were included. Plaque thickness increased significantly in all aortic segments, ranging from 3.0% to 8.0% per year (all p<0.001). In 75% of included patients, substantial plaque growth in ≥1 segment occurred. Number of plaques remained identical in 64–86% of arterial segments. Three (1.2%) developed ATE within 1 year after ICI initiation. ICI combination therapy demonstrated a trend towards increased risk of substantial plaque growth compared with monotherapy (OR 2.10 (95% CI, 0.95 to 4.66; p=0.068)), whereas antihypertensive drug usage was associated with a lower risk (OR 0.48 (95% CI, 0.24 to 0.95; p=0.036)).

**Conclusion** The majority of patients with melanoma experience substantial atherosclerotic plaque growth during ICI therapy. The number of plaques remained relatively stable, suggesting that ICIs could particularly affect pre-existing plaques.

*   Immune Checkpoint Inhibitors
*   Melanoma

#### WHAT IS ALREADY KNOWN ON THIS TOPIC

*   Immune checkpoint inhibitors (ICIs) increase the risk of developing cardiovascular disease by accelerating atherosclerosis. However, it remains unclear whether this effect is applicable across various segments of the arterial system or whether it only influences pre-existing plaques or also contributes to the formation of new atherosclerotic lesions.

#### WHAT THIS STUDY ADDS

*   In this study involving patients with melanoma, significant atherosclerotic plaque growth was observed in all five examined aortic segments during immune checkpoint inhibitor therapy. Additionally, the majority of patients exhibited substantial plaque progression in at least one aortic segment. The number of atherosclerotic plaques remained relatively stable, which could indicate that ICIs have the most profound pro-atherosclerotic effects on pre-existing plaques.

#### HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

*   Future research should characterize atherosclerotic progression and investigate possible preventive anti-atherosclerotic strategies during ICI treatment in a prospective manner.

## Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized treatment outcomes for various types of malignancies. ICIs stimulate a T-cell-mediated antitumor response by inhibition of immunosuppressive immune checkpoints, including anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed death 1 (PD-1) or its ligand. This leads to durable treatment responses and improved survival outcomes in a notable proportion of patients. Apart from the advanced disease setting, ICIs are increasingly used in curative treatment settings (neoadjuvant, adjuvant) as well.1 

Next to the beneficial anticancer effects, ICIs can also induce serious immune-related adverse events through enhanced immune-system activation, which may affect the cardiovascular system.2 The acute cardiovascular side effects of ICIs, including myocarditis and pericarditis, are usually well-recognized by physicians in current practice.3 However, the longer-term cardiovascular sequelae have only recently gained attention, as it was shown that ICI treatment predisposed patients with cancer to a threefold higher risk of developing a cardiovascular event, including myocardial infarction and ischemic stroke, compared with matched non-ICI users.4 5 Given the improvements in cancer-specific survival rates and the prescription of ICIs in the adjuvant setting for the treatment of melanoma, it is vital to further study the mechanisms that underlie their potential influence on cardiovascular risk in the longer-term.6 

One of the mechanisms underlying the increased cardiovascular risk in patients receiving ICIs is their reported potential to stimulate atherosclerosis by inhibition of immune checkpoints. Normally, these immune checkpoints are critical negative regulators of atherosclerosis and attenuate the progression of atherosclerosis by limiting immune cell infiltration into atherosclerotic plaques.7 By blocking these atheroprotective checkpoints, ICIs may predispose patients with cancer to atherosclerosis and atherosclerotic cardiovascular events, which has also been demonstrated mechanistically in preclinical studies.5 8 9 Furthermore, ICI therapy was shown to accelerate atherosclerotic plaque growth in the thoracic aorta by >3-fold in a clinical imaging study,5 but this conclusion was drawn from a subanalysis in only 40 patients with melanoma. Moreover, the growth of atherosclerotic plaques was assessed in the thoracic aorta only, while it is known that there is a modest (0.3–0.5) correlation between the presence of atherosclerosis within various arterial segments.10 It is known that the exact location of atherosclerosis and calcifications in the arterial tree is an important predictor of future cardiovascular risk.11 Therefore, we evaluated the progression and onset of atherosclerosis in multiple segments of the arterial tree and assessed possible risk factors for atherosclerotic progression in patients with melanoma who receive ICI therapy.

## Methods

### Patient population

Patients with melanoma who received anti-PD-1 monotherapy (nivolumab or pembrolizumab), anti-CTLA-4 monotherapy (ipilimumab), or anti-PD-1/anti-CTLA-4 combination therapy (ipilimumab plus nivolumab) as standard of care were included in the current single-center study. Patients were treated in either the adjuvant (stage III and IV, after complete resection) or advanced (irresectable stage III or stage IV) disease setting based on their stage at baseline. Patients were not restaged longitudinally during the course of this study (eg, in case of recurrence or progression). The current retrospective cohort study was a secondary analysis of patients who were included between April 5, 2016, and September 9, 2021, in the prospective multicenter MULTOMAB study conducted at the Erasmus MC University Medical Center (International Clinical Trials Registry Platform, NTR7015).12 The aim of the MULTOMAB study is to set-up a prospective database of oncology patients treated with monoclonal antibodies. In this study, MULTOMAB patients who received ICI treatment in the Erasmus MC were screened for analysis.

### Data collection

The following covariates of interest were collected via the electronic medical records: general characteristics at baseline (age, sex, WHO performance status, body mass index, estimated glomerular filtration rate), tumor characteristics (melanoma stage, presence of brain metastases at baseline, lactate dehydrogenase (LDH) levels), type of first ICI therapy (anti-PD-1, anti-CTLA-4, combination therapy), initiation of prednisone treatment during ICI therapy (as a surrogate marker for clinically relevant ICI-induced immune-related adverse events), prior anticancer therapy (BRAF/MEKI, chemotherapy, radiotherapy), cardiovascular risk factors (diabetes mellitus, smoking status), history of cardiovascular disease (myocardial infarction, stroke, transient ischemic attack), and cardiovascular medications at baseline (antihypertensives, statins, aspirin). Data was collected manually from medical records by individual screening of records. Follow-up was initiated on the day of ICI initiation, and the follow-up period was defined as the interval between the initiation of ICI therapy and scan 1.

### Image analysis

In general, standard-of-care CT scans were acquired at baseline prior to the start of ICI treatment and after every 3–4 months for treatment response evaluation. The protocol used for CT scan acquisition is described in online supplemental table 1. Patients were included if CT scans within 3 months prior to the first ICI administration (scan 0) and 1 year (±3 months) after the first ICI administration (scan 1) were available. Positron Emission Tomography-CT scans and CT scans with slice thickness of >3 mm were excluded. Atherosclerotic plaque burden and progression were monitored by serial measurement of the number of plaques and maximal atherosclerotic plaque thickness on standard-of-care, contrast-enhanced CT scans in the following arterial segments: aortic arch, descending thoracic aorta, abdominal aorta, left iliac artery and right iliac artery according to a standardized manner. The ascending aorta was not included in the current study due to frequent motion artifacts.

### Supplementary data

[[jitc-2024-011226supp001.pdf]](pending:yes) 

Atherosclerotic plaque burden was measured by manual counting of the number of atherosclerotic plaques per arterial segment and maximal plaque thickness per arterial segment was measured in a standardized fashion in axial direction perpendicular to the vascular wall using an electronic caliper by two independent reviewers (DCHvD, TA), under supervision of a radiology expert (DB), who were blinded to the sequence of the images. A plaque was defined as the presence of vessel wall calcifications, vessel wall irregularity or the presence of an apparent thickening of the vessel wall with a hypodense aspect. In case of multiple plaques per segment, the plaque with the largest thickness was selected for analysis. Subsequently, the change in plaque burden was assessed between scan 0 and scan 1 and the change in plaque thickness was computed as the change per year (annualized) and expressed as the percentage change in total plaque thickness. The intraobserver and interobserver variability of the measurements of maximal plaque thickness was assessed by analyzing a randomly taken subset of 40 patients twice by the same observer with a delay of 1 month and once by a second observer. The intraobserver and interobserver variability are presented as the intraclass correlation coefficient (ICC). All images were assessed using Vue PACS software (V.12.2.8.3000185).

### Study outcomes

The primary outcome was the annual progression of maximal plaque thickness per arterial segment. Secondary outcomes included alterations in the number of atherosclerotic plaques and the identification of factors associated with substantial plaque growth. We defined a threshold of ≥10% growth as substantial plaque growth after initiation of ICI therapy.

Although general consensus on the exact magnitude that is indicative of substantial plaque growth is lacking, we based this threshold on previous publications that defined ≥10% growth in coronary artery atherosclerosis as progression.13–15 In addition, in a small previous clinical study, the median annual growth of atherosclerotic plaque volume was 2.1% prior to initiation of ICI therapy.5 The occurrence of an arterial thromboembolism (ATE) was monitored in the period between initiation of ICI therapy and scan 1. An ATE was defined as the occurrence of either myocardial infarction, coronary artery disease requiring coronary revascularization, ischemic stroke or peripheral arterial thrombosis/embolism.

### Statistical analysis

Continuous variables were reported as mean and SD or median and IQR. Categorical variables were described as counts and percentages. Proportions were compared by χ2 tests, and median values were compared by independent-samples Mann-Whitney U test. Factors associated with substantial growth of atherosclerotic plaque thickness were studied by dichotomizing growth (presence or absence of ≥10% growth) and performing a univariable logistic regression to calculate ORs. For this, on condition that no significant differences in absolute atherosclerotic plaque growth were found between the different analyzed arterial segments, the descending thoracic aorta will be selected as the analyzed segment due to its reduced susceptibility to motion artifacts, which is also in line with a previous study.5 In case of significant variables in the univariable analysis, a multivariable analysis will be performed with additional incorporation of known general cardiovascular risk factors in a multivariable model. The parameter ICI combination therapy was analyzed in the advanced disease cohort specifically, given that this combination treatment is exclusively administered in this disease setting. All statistical analyses were performed using SPSS V.28.0.1.0 software (IBM SPSS, Chicago, Illinois, USA) and GraphPad Prism Software V.8.0 (GraphPad Software, San Diego, California, USA). All p values were two-sided, CIs were set at the 95% level and p values<0.05 were considered to indicate statistical significance.

## Results

### Study population

In total, 388 patients with melanoma who were included in the MULTOMAB trial between April 5, 2016, and September 9, 2021, were screened, of whom 244 patients were eligible and had adequate CT scans available for inclusion in the current study (figure 1). Baseline characteristics of the included patients are displayed in table 1. The majority of included patients received ICI treatment in the advanced disease setting (n=165, 67%), whereas the adjuvant cohort consisted of n=79 (33%) patients. In both cohorts, most patients were male and had a WHO performance status of 0 (fully active without restriction). 72% of the patients in the advanced disease cohort and all patients in the adjuvant cohort received anti-PD-1 monotherapy. In both cohorts, 4% of included patients had a history of myocardial infarction. More patients in the advanced disease than in the adjuvant cohort had a history of stroke (5% vs 1%, respectively) or transient ischemic attack (6% vs 1%, respectively).

![Figure 1](http://jitc.bmj.com/https://jitc.bmj.com/content/jitc/13/4/e011226/F1.medium.gif)

[Figure 1](http://jitc.bmj.com/content/13/4/e011226/F1)

Figure 1 
Flowchart of included patients. ICIs, immune checkpoint inhibitors.

View this table:
[Table 1](http://jitc.bmj.com/content/13/4/e011226/T1)

Table 1 
Baseline characteristics

### Evaluation of atherosclerotic plaque thickness during ICI treatment

In the advanced disease cohort and adjuvant cohorts, respectively, 156 (95%) and 71 (90%) of included patients had an assessable plaque present in at least one of the analyzed segments. The number of patients with evaluable plaques per analyzed segment in the advanced disease and adjuvant cohorts is shown in online supplemental table 2. Assessment of intraobserver and interobserver variability demonstrated excellent reliability for measurements of maximal plaque thickness, with ICCs of 0.92 and 0.93, respectively. Given that between the advanced disease and adjuvant cohorts there was no difference in the proportion of plaques that demonstrated progression (p>0.05 for all segments, online supplemental table 2) nor in the absolute annual growth rates (p>0.05 for all segments, online supplemental table 3) both cohorts were combined for further analyses.

In the total cohort, the median time interval between CT scans on which atherosclerotic plaque progression and the change in the number of plaques was assessed was 376 (49) days. The median annual growth rates in plaque thickness per arterial segment are displayed in table 2. Plaque thickness increased significantly in all segments of the arterial tree, ranging from a 3.0% annual increase in the abdominal aorta to an 8.0% annual increase in the aortic arch (p<0.001 vs 0 for all). Substantial plaque growth (≥10%) was observed in 31–45% of the segments analyzed and 183 (75%) of included patients demonstrated substantial plaque growth in at least one of the segments analyzed. If only segments with growth ≥10% were analyzed, the median annual change was 19.0–21.7% per year (table 2). There was no overall significant difference in terms of absolute growth rate (p=0.063) or growth rate in segments with ≥10% growth (p=0.37) between the analyzed segments.

View this table:
[Table 2](http://jitc.bmj.com/content/13/4/e011226/T2)

Table 2 
Change in maximal plaque thickness in the total cohort

3 (1.2%) out of the 244 included patients developed an ATE within 1 year after starting ICI treatment. Two of these patients received ICI treatment in the advanced disease and one in the adjuvant treatment setting. These events are further specified in online supplemental table 4, which occurred after 58, 96, and 156 days after the initiation of ICI treatment. Two of these patients with ATE had substantial growth in four out of five included segments, and one patients experienced substantial growth in all segments investigated.

### Number of atherosclerotic plaques during ICI treatment

In the majority of patients, the number of plaques remained identical in each analyzed arterial segment. This ranged from 64% of patients with no change in the number of plaques in the descending aorta to 86% with no change in the number of plaques in the right iliac artery. The percentage of patients with an increased number of plaques ranged from 8.5% in the abdominal aorta to 26.7% in the descending aorta. In most of these patients, this concerned one new atherosclerotic lesion within 1-year follow-up.

### Factors associated with substantial plaque growth

Factors associated with substantial (≥10%) annual atherosclerotic plaque growth were analyzed in the descending thoracic aorta, given that there were no significant differences in growth between the different included arterial segments. Factors indicating a higher disease burden (LDH>upper limit of normal) or ICI-related toxicity (requirement of prednisone) were not associated with substantial plaque growth (table 3). The odds of having substantial atherosclerotic growth in the descending aorta were significantly lower in patients receiving antihypertensive drugs at baseline (OR: 0.47 (95% CI, 0.26 to 0.86; p=0.014)). Baseline use of aspirin was associated with lower odds of substantial plaque growth, although this did not reach statistical significance (OR: 0.29 (95% CI, 0.08 to 1.03; p=0.055)). Patients who used statins at baseline did not have a significantly lower risk of having substantial growth (OR: 0.57, (95% CI, 0.29 to 1.13; p*=*0.11)), nor were other cardiovascular risk factors (eg, smoking, age, body mass index (BMI)≥25, and diabetes mellitus) associated with substantial plaque growth (table 3). In the multivariable model that included both the use of antihypertensive drugs and known cardiovascular risk factors (ie, age ≥65 years, BMI≥25, and history of myocardial infarction, stroke, TIA and diabetes mellitus), the usage of antihypertensive drugs remained associated with a lower risk of substantial plaque growth (OR: 0.48 (95% CI, 0.24 to 0.95; p=0.036)).

View this table:
[Table 3](http://jitc.bmj.com/content/13/4/e011226/T3)

Table 3 
Logistic regression analysis of risk factors for substantial growth in plaque thickness in the descending thoracic aorta during ICI therapy in the total cohort

In the advanced disease cohort, patients treated with ICI combination therapy (n=35) demonstrated a trend towards higher odds of developing substantial plaque growth compared with monotherapy in the descending aorta (OR 2.10 (0.95–4.66; p=0.068)). Factors associated with substantial growth in plaque thickness in any of the analyzed segments are shown in online supplemental tables 5-9.

## Discussion

### Observed growth rate in atherosclerotic plaques

In this study assessing the burden and progression of atherosclerosis during ICI treatment, we observed substantial plaque growth in a notable proportion of patients, regardless of the arterial segment analyzed or the treatment setting in which the ICI was administered. Substantial (≥10%) plaque growth was observed in 31–45% of the segments analyzed, and 75% of included patients demonstrated substantial growth in at least one of the segments analyzed. The median observed growth in the analyzed arterial segments ranged from 3.0% to 8.0% per year. Although a previous study analyzed yearly changes in plaque volume rather than plaque thickness, our observed growth rates are similar to the previously observed threefold increase in atherosclerotic progression to 6.7% per year in patients after initiation of ICI therapy and higher than the reported 2.1% yearly increase prior to ICI treatment initiation.5 Patient characteristics between studies were generally comparable, with the exception that fewer patients were using statins at baseline in our study (24% here vs 43% in Drobni *et al*,5 respectively). Our observed plaque growth also points towards substantial atherosclerotic progression during ICI therapy. This could be an important factor for the increased cardiovascular risk in patients receiving ICIs.

We found that the number of plaques across the different segments of the arterial tree did not increase significantly during ICI therapy. Although our follow-up period was relatively short given that new atherosclerotic lesions may require multiple years to develop, this finding could suggest that the increased cardiovascular risk during the first years of ICI therapy might be determined by the effect of ICIs on pre-existing plaques.16 This might be informative in the identification of patients at the highest risk of developing cardiovascular events during ICI treatment, which could be patients with the highest atherosclerotic burden at baseline.5 17 To thoroughly assess the impact of ICIs on the development of new atherosclerotic lesions and on the occurrence of overt cardiovascular disease, additional research involving extended follow-up periods will be necessary.

### Risk factors for atherosclerotic progression

Although not significant, ICI combination therapy exhibited a trend toward more frequent substantial atherosclerotic plaque growth compared with monotherapy. This may be expected, as combination therapy is associated with increased immune-related adverse events, likely due to the enhanced immune activation from concurrent PD-1 and CTLA-4 blockade.18 19 In addition, ICI combination therapy is more frequently prescribed to patients with a higher tumor burden. Although we found no association between baseline LDH levels and increased atherosclerotic progression, further investigation of ICI combination therapy as a possible risk factor for atherosclerotic progression is required as ICI combination therapy might also be prescribed to patients with resectable stage III melanoma in the neoadjuvant setting in the future as well.20 

In contrast with Drobni *et al*,5 statin use was not associated with significantly lower odds of substantial plaque growth in patients included in our study. Possible explanations for this finding are that fewer patients in our study used statins at baseline and that we analyzed the risk of developing substantial plaque growth (>10%) rather than differences in absolute plaque volume changes. However, baseline use of antihypertensives was associated with lower odds of substantial atherosclerotic growth in the descending aorta. This could point towards either direct atheroprotective effects of antihypertensives or more optimally controlled hypertension in these patients, given that adequate blood pressure control is known to be protective against atherosclerotic progression.21 22 Unfortunately, routine measurements of blood pressure were not available for most included patients. Due to the retrospective design of the current study, the observed associations of statins, antihypertensives and other commonly known cardiovascular risk factors have to be interpreted with caution. These observations could be confounded by indication, as all included patients on statins and/or antihypertensives had a previous indication based on their baseline cardiovascular risk. Given the well-established role of antihypertensives and statins in preventing atherosclerotic cardiovascular disease, prospective research is warranted to explore their potential protective effects in this setting.

### Limitations

To the best of our knowledge, this is the largest study performed to date to evaluate the clinical burden and progression of atherosclerosis in a real-world population of ICI-treated patients with melanoma. Yet, our study has some limitations. First, due to its retrospective design, we could not perform an intrapatient comparison of plaque growth before and after initiation of ICI therapy due to the unavailability of multiple scans prior to baseline, nor could we compare growth rates to a matched non-ICI control group. Therefore, we evaluated the growth rates in our cohort with those of a previous study.5 Second, despite using a method that demonstrated excellent intraobserver and interobserver agreement,23 24 the included CT scans were acquired as standard-of-care and were not ECG-triggered. Consequently, we were unable to quantify the progression of atherosclerosis in the coronary arteries, nor were we able to distinguish between calcified or non-calcified plaques or to quantify plaque volumes. However, given that a larger total thickness of atherosclerotic aortic plaques correlates with clinical vascular events,25–27 our main outcome is of clear clinical relevance. Third, the progression of atherosclerosis was quantified for 1 year after initiation of ICI therapy only. Despite this relatively short follow-up period, we still found substantial plaque growth in a considerable proportion of patients. A previous study in patients with melanoma with more than 2 years of follow-up found a slower growth rate of calcified plaque volume during ICI treatment whereas total plaque mass did not change.28 Given that calcified plaque growth is inversely related to cardiovascular events,29 this indicates that ICIs modify the plaque composition towards a more rupture-prone plaque over a longer period of time. It would be of great value to prospectively assess the progression of atherosclerosis with a longer follow-up period, both during and after the eventual completion of ICI treatment in future studies.

In conclusion, our study provides important new insights into the onset and progression of atherosclerosis during ICI therapy. Within 1 year of ICI treatment, substantial atherosclerotic plaque growth was found in a considerable number of patients with an indication that this growth initially occurs in pre-existing plaques. Future prospective research should be conducted to compare atherosclerotic growth rates with matched non-ICI-treated patients and to identify patients at the highest cardiovascular risk. In addition, possible preventive strategies (eg, statins and antihypertensives) should be investigated to minimize cardiovascular events with the maintenance of the beneficial effects of ICI therapy in patients with cancer.

## Data availability statement

Data are available upon reasonable request.

## Ethics statements

### Patient consent for publication

Not applicable.

### Ethics approval

This study was conducted in accordance with the Declaration of Helsinki and the International Standards of Good Clinical Practice. This study was approved by the Medical Ethics Committee of Erasmus University Medical Center (MEC 16-011). Participants gave informed consent to participate in the study before taking part.

## Footnotes

*   Contributors DCHvD, AHJD, RHJM, DB and JV were involved in the design of the study. DCHvD, TA, RHJM, and DB were involved in the acquisition of data. DCHvD, TJJU, AAMVdV, EO-DH, RHJM, and JV were involved in the data analysis. DCHvD, TJJU, AAMVdV, TA, AJ, EO-DH, AHJD, RHJM, DB and JV were involved in the interpretation of the results. All authors were involved in the preparation of the manuscript and approved its final version. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. As guarantor, JV accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests None of the authors have a competing interest in relation to the current manuscript. RHJM received funding for investigator initiated research (all paid to the institute) from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Deuter Oncology, Nordic Pharma, Novartis, Pamgene, Pfizer, Roche, Sanofi and Servier.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

*   Accepted April 14, 2025.


*   © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

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