Abstract
Purpose
To investigate the possible effect of statin in preventing proliferative vitreoretinopathy (PVR) after successful repair of rhegmatogenous retinal detachment (RRD) by either vitrectomy or scleral buckling.
Patients and Methods
103 patients with RRD were included in this randomized controlled trial. After successful repair of RRD, patients were randomly assigned into two groups. One group received statin (Atorvastatin 40 mg daily for 3 months) while the other group stayed untreated. Regular follow-up examinations were conducted up to 6 months after surgery.
Results
PVR occurred in 3.8% of patients in the statin group compared to 22% in the untreated group (p=0.005). In the subgroup analysis, a significantly lower rate of PVR was observed in the statin group exclusively among patients who underwent vitrectomy with silicone oil tamponade (p=0.010), while no significant difference was detected in those who underwent scleral buckling (p=0.217). Other variables including gender, smoking, alcohol consumption, diabetes, hypertension, tear size, tear location and lens status had no statistically significant impact on occurrence of PVR. There was no statistically significant difference regarding age, duration of symptoms before surgery, intraocular pressure, visual acuity before surgery, choroidal thickness before and after surgery and the number of tears between patients with and without PVR. Post-op visual acuity was significantly worse in patients who developed PVR (p-value < 0.001).
Conclusion
In this study, post operative use of Atorvastatin 40 mg daily for 3 months was associated with significantly lower rate of PVR formation during 6 months follow up after successful repair of RRD, particularly in patients who underwent pars plana vitrectomy with silicone oil tamponade. No statistically significant effect was observed in the scleral buckling subgroup.
Keywords: statin, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, PVR
Introduction
Retinal detachment (RD) is a vision-threatening condition with a variety of etiologies which occurs in approximately 12.4 in 100,000 people per year.1,2 Rhegmatogenous retinal detachment (RRD) is the most common type and poses a significant threat to vision if untreated. In primary vitrectomy for RRD, a functional and anatomical success rate of 90% is achieved.3 However, the incidence of recurrent RRD is approximately 17.8%. Failure of primary vitrectomy for RRD is attributed to various risk factors, with proliferative vitreoretinopathy (PVR) being the cause of failure in 75% of cases. PVR is a well-recognized postoperative complication of RRD repair, reported to occur in up to 26% of cases.4 Additional risk factors for recurrent RRD include the time elapsed between the onset of primary RRD and primary vitrectomy surgery as well as the extent of quadrants involved in primary RRD.5–7 The rate of surgical failure due to PVR after primary scleral buckling for RRD has been reported to be approximately 5%. PVR-associated failure is more common in eyes with preoperative vitreous hemorrhage, preoperative PVR and in smokers.8
In PVR, excessive wound healing and fibrosis lead to the formation of proliferative membranes on the retinal surface, extending into the vitreous and causing tractional detachment.9 These membranes consist of various cells including hyalocytes, retinal pigment epithelial cells, glial cells, and fibroblast-like cells.10–13 Transforming growth factor-beta 2 (TGF- β2) plays a pivotal role in tissue fibrosis and its overexpression in the epiretinal membrane and vitreous of PVR patients correlates with intraocular fibrosis.14–17 The combination of hyalocytes and TGF- β2 is implicated in the pathogenesis of PVR. Recently angiopoietins, potent regulators of endothelial cell interactions, have been suggested as potential therapeutic targets in PVR with elevated levels of angiopoietin-2 implicated in human RRD.18
PVR is categorized into three grades: Grade A, characterized by vitreous haze and pigment clumps; Grade B, defined by wrinkling of the inner retinal surface, retinal stiffness, and vessel tortuosity; and Grade C, defined by full-thickness retinal folds in one or more quadrants.
Despite surgical advancements, PVR remains the most common cause of failure and blindness after RD repair. Pharmacologic interventions targeting inflammation, cell proliferation, and fibrosis have been explored but long-term success is limited. Steroids, anti-VEGF agents, and antineoplastic agents have shown promise in preclinical models but often fall short in human clinical trials, indicating the ongoing challenge in managing PVR.19,20
Statins, inhibitors of HMG-CoA reductase and primarily known for reducing cholesterol synthesis, exhibit diverse effects including immune-modulating and anti-inflammatory properties.21,22 Studies suggest potential benefits of statins in the eye, such as preventing PVR formation by reducing TGF- β2 levels, improving visual prognosis, and aiding reattachment in eyes post-vitrectomy.23 The mevalonate pathway, inhibited by statins, influences the Rho/Rho-kinase pathway, affecting cellular events related to cell morphology and contraction.24 Statins possess anti-inflammatory, anti-oxidative, and anti-fibroproliferative pleiotropic properties, potentially influencing photoreceptor survival, retinal wound healing, and PVR formation. Atorvastatin is a lipophilic statin, which enables it to penetrate lipid-rich membranes including the blood-brain barrier and potentially the blood-retinal barrier.25 Beyond its well-established role in the management of hyperlipidemia — as recommended by the 2018 American Heart Association guidelines — atorvastatin has attracted growing interest for its various effects, including anti-inflammatory and antifibrotic properties that may extend its therapeutic utility beyond cardiovascular disease.
Pars plana vitrectomy and scleral buckling are the two principal surgical approaches for rhegmatogenous retinal detachment and differ substantially in their effects on the intraocular environment. Vitrectomy with silicone oil tamponade is commonly used in more complex cases and is associated with greater disruption of the blood-retinal barrier and increased intraocular inflammation. In contrast, scleral buckling preserves the vitreous cavity and results in less alteration of the ocular microenvironment. These biological differences may influence both the development of proliferative vitreoretinopathy (PVR) and the response to pharmacological interventions targeting inflammatory and fibrotic pathways.
The current study aims to investigate the potential effects of statins, specifically Atorvastatin, in mitigating PVR after successful repair of RRD by either vitrectomy or scleral buckling.
Materials and Methods
This pilot randomized controlled trial (RCT) was conducted at Rasoul-Akram Hospital, Tehran, Iran from January 2023 to 2025. Participants in this project adhered to all Helsinki principles. This research was approved by the Research Ethics Committee of Iran University of Medical Sciences under the ethics code number IR.IUMS.REC.1398.980. This study was registered in Iranian registry of clinical trials (IRCT registration number: IRCT20191207045645N1). Written informed consent was obtained from all participants prior to enrollment in the study. This study included patients with primary RRD who underwent either pars plana vitrectomy with silicone oil as tamponade or scleral buckling. This pilot randomized controlled trial employed consecutive sampling, in which all patients meeting the inclusion criteria during the study period were enrolled. A total of 103 patients were selected and after successful reattachment surgery, they were randomly assigned to two groups: statin (53 patients) or no statin (50 patients). All surgeries were performed by a single experienced vitreoretinal surgeon (F.A) using a standardized surgical protocol to minimize inter-surgeon variability and reduce potential confounding due to differences in surgical technique or skill. Participants were randomly assigned to the statin or untreated group using a computer-generated random sequence with block randomization (block size = 4). The randomization sequence was generated by an independent statistical analyst who was not involved in patient enrollment, treatment, or outcome assessment. Allocation concealment was maintained by having the statistical analyst disclose each patient’s group assignment individually, at the time of assignment, to the physician responsible for allocation; the assigning physician had no advance knowledge of upcoming allocations in the sequence. Given the absence of a placebo (statin vs no treatment), the study was open-label, and both the assigning physician and the patient were aware of group allocation following assignment. However, the attending physician who examined patients and assessed PVR development postoperatively was blinded to treatment allocation throughout follow-up. The statin group received atorvastatin 40 mg (manufactured by Actover Company) once daily for 3 months. Regular follow-up examinations were conducted at various intervals (first day, first week, months 1, 3, and 6) up to 6 months post-surgery. In all patients, the demographic information, the details related to the number, size, and location of the breaks, the patient’s refraction status (eg high myopia), the patient’s lens status (eg phakic/pseudophakic), the patient’s smoking status (current or past use) and alcohol consumption, intraocular pressure (IOP) status, duration of RD symptoms before primary surgery (less than/more than 14 days) and PVR formation after surgery were recorded. Baseline tests including CBC, ESR, CRP, BUN, Cr, FBS, ALT, and AST were performed before starting statin and re-evaluated three months later. Enhanced depth imaging OCT (EDI-OCT) was used to measure choroidal thickness in the subfoveal area. Inclusion criteria encompassed patients over 40 years old who underwent either pars plana vitrectomy with silicone oil as tamponade or scleral buckling with successful reattachment by a skilled surgeon experienced in treating retinal detachment and subsequent PVR. Exclusion criteria involved combined RD, recurrent RD, giant tear-induced RD, secondary RD unrelated to PVR, surgery complications, other concurrent eye diseases (eg glaucoma, Central serous chorioretinopathy (CSCR), retinal dystrophies), PVR grade C, pregnancy, breastfeeding, systemic steroid use and interference with statins due to specific drugs. Considerations for statin use including dosage, potential complications, and duration were aligned with the 2018 AHA guideline and monitored under the supervision of an internal medicine specialist throughout the study.
Chi-square and Fisher’s exact test were conducted to assess the impact of various parameters such as gender, smoking, alcohol consumption, diabetes, hypertension, tear size, tear location, lens status, and statin use on the development of PVR. Independent samples t-test and Mann–Whitney test were used to compare age, duration of symptoms, IOP, pre-op and post-op visual acuity and choroidal thickness and break number. A p-value < 0.05 was considered significant.
Results
The detailed results of this study are presented in the following tables. A total of 103 patients were included in the study and were randomly divided into two groups: statin (53 patients) or no statin (50 patients) group. Table 1 and Table 2 compare the baseline characteristics of the two groups. The only factors that differed significantly between the groups were the prevalence of smoking, which was lower in the statin group and break number which was higher in statin group.
Table 1.
Basic Characteristics of the Statin and No Treatment Group (Qualitative Variables)
| Statin | P-value | OR | |||
|---|---|---|---|---|---|
| No | Yes | ||||
| Gender | Male | 47.9% | 52.1% | 0.850* | 0.921 |
| Female | 50.0% | 50.0% | |||
| Smoking | No | 44.6% | 55.4% | 0.006* | 0.089 |
| Yes | 90.0% | 10.0% | |||
| Alcohol | No | 49.5% | 50.5% | 0.515† | 1.960 |
| Yes | 33.3% | 66.7% | |||
| DM | No | 48.1% | 51.9% | 0.730* | 0.844 |
| Yes | 52.4% | 47.6% | |||
| HTN | No | 46.3% | 53.7% | 0.273* | 0.576 |
| Yes | 60.0% | 40.0% | |||
| Break size | Less than 1 hour | 48.2% | 51.8% | 0.721* | 0.827 |
| More than 1 hour | 52.9% | 47.1% | |||
| Break location | Nasal | 50.0% | 50.0% | 0.994 † | - |
| Inferior | 0.0% | 100.0% | |||
| Temporal | 40.0% | 60.0% | |||
| Superior | 100.0% | 0.0% | |||
| Inferonasal | 50.0% | 50.0% | |||
| Inferotemporal | 56.3% | 43.8% | |||
| Superotemporal | 47.5% | 52.5% | |||
| Superonasal | 47.8% | 52.2% | |||
| Lens | Phakic | 51.4% | 48.6% | 0.362* | 1.495 |
| Pseudophakic | 41.4% | 58.6% | |||
| Operation | Vitrectomy | 45.7% | 54.3% | 0.264* | 0.582 |
| Scleral buckling | 59.1% | 40.9% | |||
| Macula status | On | 62.5% | 37.5% | 0.281* | 1.958 |
| Off | 46% | 54% | |||
Notes: * Chi-Square Test; † Fisher’s Exact Test.
Table 2.
Basic Characteristics of the Statin and No Treatment Group (Quantitative Variables)
| Statin | N | Mean | SD | P-value | |
|---|---|---|---|---|---|
| Age | No | 50 | 55.32 | 12.13 | 0.226* |
| Yes | 52 | 52.12 | 14.28 | ||
| Duration of symptoms | No | 46 | 11.00 | 25.87 | 0.476† |
| Yes | 52 | 15.98 | 33.36 | ||
| IOP | No | 50 | 12.54 | 1.84 | 0.919† |
| Yes | 52 | 12.60 | 2.33 | ||
| Preop VA | No | 42 | 1.98 | 1.21 | 0.463† |
| Yes | 47 | 2.17 | 1.06 | ||
| Preop choroidal thickness | No | 34 | 264.38 | 94.79 | 0.458* |
| Yes | 45 | 246.71 | 110.74 | ||
| Break numbers | No | 1.55 | 1.04 | 0.026† | |
| Yes | 2.12 | 1.54 |
Notes: * Independent Samples t-Test; † Mann–Whitney Test.
3.8% of patients in the statin group developed PVR grade C compared to 22% in the untreated group (p=0.005, OR=0.14). Use of statin was associated with no progression to PVR in 96.2% of patients. Other variables including gender, smoking, alcohol consumption, diabetes, hypertension, tear size, tear location and lens status had no statistically significant impact on occurrence of PVR (Table 3). Odds of observing PVR in women was 2.36 times higher in comparison with men but it was not statistically significant. Also, odds of getting PVR was higher about 1.88 times in patients with diabetes mellitus (DM) and 2.03 in patients with hypertension (HTN), but these were not statistically significant. The OR for assessing the relation between break size and PVR was 0.41 which demonstrated that odds of PVR in eyes with break size of less than an hour was lower but it was not statistically significant.
Table 3.
Effect of Different Variables on Development of PVR After Successful RRD Repair
| Variables | PVR | p-value | OR | ||
|---|---|---|---|---|---|
| No | Yes | ||||
| Gender | Male | 90.40% | 9.60% | 0.148* | 2.36 |
| Female | 80.00% | 20.00% | |||
| Smoking | No | 87.00% | 13.00% | 0.784* | 0.74 |
| Yes | 90.00% | 10.00% | |||
| Alcohol | No | 86.90% | 13.10% | 0.661† | 0.87 |
| Yes | 100.00% | 0.00% | |||
| DM | No | 88.90% | 11.10% | 0.331* | 1.88 |
| Yes | 81.00% | 19.00% | |||
| HTN | No | 89.00% | 11.00% | 0.278* | 2.03 |
| Yes | 80.00% | 20.00% | |||
| Eye | OD | 89.50% | 10.50% | 0.476* | 1.53 |
| OS | 84.80% | 15.20% | |||
| Break size | Less than 1 hour | 86.70% | 13.30% | 0.394* | 0.41 |
| More than 1 hour | 94.10% | 5.90% | |||
| Break location | Nasal | 75.00% | 25.00% | 0.956† | |
| Inferior | 100.00% | 0.00% | |||
| Temporal | 100.00% | 0.00% | |||
| Superior | 100.00% | 0.00% | |||
| Inferonasal | 90.00% | 10.00% | |||
| Inferotemporal | 87.50% | 12.50% | |||
| Superotemporal | 87.50% | 12.50% | |||
| Superonasal | 87.00% | 13.00% | |||
| Lens | Phakic | 87.80% | 12.20% | 0.823* | 1.16 |
| Pseudophakic | 86.20% | 13.80% | |||
| Statin use | No | 78.00% | 22.00% | 0.005* | 0.14 |
| Yes | 96.20% | 3.80% | |||
Notes: * Chi-Square Test; † Fisher’s Exact Test.
There was no statistically significant difference regarding age, duration of symptoms before surgery, IOP, visual acuity before surgery, choroidal thickness before and after surgery and the number of tears between patients with and without PVR. Post-op visual acuity was significantly worse in patients who developed PVR (p-value < 0.001) (Table 4).
Table 4.
Comparison of Different Variables Between Eyes with and without PVR Development
| PVR | N | Mean | SD | P-value | |
|---|---|---|---|---|---|
| Age | No | 89 | 52.90 | 13.69 | 0.118* |
| Yes | 13 | 59.08 | 8.94 | ||
| Duration of symptoms | No | 86 | 14.62 | 31.92 | 0.879† |
| Yes | 12 | 6.67 | 3.37 | ||
| IOP | No | 89 | 12.51 | 2.11 | 0.416† |
| Yes | 13 | 13 | 2.04 | ||
| Preop VA | No | 76 | 2.02 | 1.13 | 0.180† |
| Yes | 13 | 2.48 | 1.09 | ||
| Postop VA | No | 76 | 0.71 | 0.63 | 0.001† |
| Yes | 13 | 1.46 | 0.83 | ||
| Preop choroidal thickness | No | 70 | 253.94 | 107.25 | 0.930* |
| Yes | 9 | 257.22 | 77.79 | ||
| Postop choroidal thickness | No | 67 | 222.61 | 93.05 | 0.65* |
| Yes | 8 | 238.5 | 95.72 | ||
| Break numbers | No | 88 | 1.85 | 1.40 | 0.694† |
| Yes | 12 | 1.75 | 0.87 |
Notes: * Independent Samples t-Test; † Mann–Whitney Test.
A multivariate logistic regression analysis was also performed, and again the results showed a significantly lower PVR rate in the statin group (p value: 0.016)
In the subgroup analysis according to the type of surgery, we found that among patients who underwent scleral buckling, none in the statin group (0 of 9 patients) developed PVR, whereas 15.4% in the no-statin group (2 of 11 patients) developed PVR. This difference was not statistically significant. However, in the vitrectomy subgroup, 24.3% of patients in the no-statin group (9 of 37 patients) developed PVR compared with only 4.5% in the statin group (2 of 44 patients), which was significantly lower (p = 0.01; OR = 0.148) (Table 5 and Table 6).
Table 5.
Subgroup Analysis of Proliferative Vitreoretinopathy (PVR) Formation in Patients Who Underwent Pars Plana Vitrectomy
| PVR | Total | OR | |||
|---|---|---|---|---|---|
| No | yes | ||||
| Statin | No | 28 | 9 | 0.010* | 0.148 |
| 75.7% | 24.3% | ||||
| Yes | 42 | 2 | |||
| 95.5% | 4.5% | ||||
| Total | 70 | 11 | |||
| 86.4% | 13.6% | ||||
Note: * p- value.
Table 6.
Subgroup Analysis of Proliferative Vitreoretinopathy (PVR) Formation in Patients Who Underwent Scleral Buckle Surgery
| PVR | Total | OR | |||
|---|---|---|---|---|---|
| No | yes | ||||
| Statin | No | 11 | 2 | 0.217* | 0.846 |
| 84.6% | 15.4% | ||||
| Yes | 9 | 0 | |||
| 100.0% | 0.0% | ||||
| Total | 20 | 2 | |||
| 90.9% | 9.1% | ||||
Note: * p- value.
When stratified by both surgical approach and smoking status, the protective effect of statins remained statistically significant among non-smoking patients who underwent vitrectomy (4.7% vs 25.8%, p=0.014, OR=0.140), and the Mantel-Haenszel analysis confirmed this association after adjustment for smoking within the vitrectomy subgroup (MH OR=0.140, p=0.023). In contrast, no significant association was observed in the scleral buckling subgroup regardless of smoking status (MH OR=0.000, p=0.568).
Discussion
The results of our study showed that use of Atorvastatin 40 mg daily for 3 months significantly reduced the rate of PVR after successful repair of RRD by vitrectomy and using silicone oil as tamponade, suggesting that the beneficial role of statins in preventing PVR may be specific to this surgical context and should not be extrapolated to all RRD repair techniques. Notably, despite having a significantly higher number of retinal breaks at baseline — a well-established risk factor for PVR — the statin group demonstrated a significantly lower rate of PVR development, further supporting the potential protective role of postoperative statin therapy.
Atorvastatin 40 mg once daily for three months was selected as it represents a moderate- to high-intensity dose with a well-established safety profile, in line with the 2018 AHA guidelines. All patients were managed under the supervision of an internal medicine specialist, with laboratory monitoring at baseline and three months. The three-month duration was chosen to cover the critical early postoperative window during which inflammation and fibrosis — the key drivers of PVR — are most active. Of note, Atorvastatin belongs to the lipophilic statin class, along with Simvastatin, which allows it to cross biological barriers including the blood-retinal barrier. This property may underlie its potential protective effect against PVR, and whether lipophilic statins offer advantages over hydrophilic agents in this context remains an interesting question for future research.
Vitrectomy with silicone oil tamponade is typically reserved for more complex retinal detachments, and this complexity comes at a biological cost. The procedure tends to cause greater disruption of the blood-retinal barrier, exposes retinal pigment epithelial cells more extensively to the vitreous cavity, and creates an environment rich in inflammatory and profibrotic mediators — all conditions that favor PVR development. It is perhaps in this more hostile biological setting that the anti-inflammatory and antifibrotic properties of statins find their greatest utility. Scleral buckling, on the other hand, leaves the vitreous intact and is generally employed in less complex cases, which may inherently carry a lower PVR risk and could explain why the protective effect of statins was less apparent in this subgroup.
There are some cytokines and biomarkers related to PVR formation which can be addressed by statins. Tuuminen et al exhibited effective pleiotropic actions for statins, potentially offering benefits in the clinical context of RRD. Statin-treated patients with retinal detachment displayed significantly lower intravitreal levels of Angiopoietin 2 (ANGPT-2), VEGF, and MMP-2 compared to non-statin-treated RRD patients. The observed reduction in MMP-2 levels, associated with basement membrane breakdown and fibroproliferation, suggests that preoperative statin treatment may modify the inflammatory process and prevent PVR.26
Other studies have been done seeking a new milieu in preventing PVR in a similar way as statins do. Edward et al identified several antiproliferative agents associated with PVR including 5-FU, Daunorubicin, Doxorubicin, Taxol, Colchicine, and Methotrexate. While daunorubicin and 5-FU have shown promise in animal models, clinical studies yielded inconsistent results.27 Daunorubicin has been deemed safe for perioperative use, contributing to reduced reoperation rates in patients undergoing retinal surgery for PVR; However, despite this treatment, patients did not exhibit significant differences in visual acuity or reattachment rates after one year.28 Similarly, 5-FU therapy for PVR detachment did not lead to significant improvements in anatomical or visual outcomes, and it even resulted in worse visual outcomes for specific patients with macular-sparing PVR retinal detachments.29 Taxol and colchicine, inhibiting microtubule formation, demonstrated efficacy in preventing PVR in vitro and in vivo, but further clinical studies are awaited. Our data also suggest that statin use may impact re-vitrectomy rates after retinal detachment. A pharmacokinetics study on intravitreal statin delivery found effective therapeutic concentrations against inflammation induced by bacterial lipopolysaccharide in vitro.30 However, large-scale retrospective studies and clinical trials are needed to precisely understand statins’ effects on PVR pathology. Combining different drug classes may address various PVR pathways synergistically, reflecting the complex nature of multifactorial pathologies like PVR.
Another study explored the varying potentials of statins, such as Simvastatin, in patients with diabetic retinopathy (DR).31 Despite similar lipid-lowering effects among statins, their capacity for direct vasculoprotection and blood–brain barrier penetration, notably observed in lipophilic statins like Simvastatin and Atorvastatin, set them apart.32–34 Simvastatin treatment not only preserved the integrity of the blood-retinal barrier (BRB) but also hindered leukocyte accumulation, telangiectatic vessel development, ganglion cell vacuolar degeneration, and the progression of PVR and diabetic macular edema (DME) in a DR experimental model.24,35,36 Moreover, studies indicate that simvastatin-treated neuronal cells demonstrate increased resistance to in vitro toxicity and ischemia/oxidative stress-induced death.37,38 Clinical studies supporting these results reveal improved retinal blood flow with simvastatin administration.39 Additionally, simvastatin stabilized visual fields in clinic patients with normal-tension glaucoma.40
In a retrospective cohort study from a Finnish population that evaluated the rate of re-vitrectomy (not limited to PVR) in patients undergoing vitreoretinal surgery, preoperative statin use was associated with a 28% lower risk of re-vitrectomy. This effect was not observed in vitreoretinal surgeries performed for indications other than RRD.41
Limitations
One limitation of this study is the absence of a placebo control. Participants were randomized to either statin therapy or no treatment. Future studies with placebo control would help confirm these findings with greater rigor.
A principal limitation is the sample size. With about 50 participants per arm, power to detect the pre-specified 10 percentage point absolute difference is low. Enrollment was limited by recruitment timeframe and single-center capacity. Given these resource limits, the study was intentionally designed as a pilot to estimate effect sizes and inform the planning and sample-size calculations of a future definitive RCT.
Conclusion
In this study, postoperative use of Atorvastatin 40 mg daily for 3 months was associated with a significantly lower rate of PVR formation during 6-month follow-up after successful repair of RRD, particularly in patients who underwent pars plana vitrectomy with silicone oil tamponade. No significant effect was observed in the scleral buckling subgroup. This study suggests a potential beneficial role of statins in preventing PVR following vitrectomy. However, the small sample size was a limitation. This study may serve as a basis for future larger-scale randomized controlled trials to confirm and extend these results.
Funding Statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data Sharing Statement
The authors confirm that the data supporting the findings of this study are available upon reasonable request. Individual deidentified participant data, along with relevant study documents, will be made available to researchers who provide a methodologically sound proposal. Requests for data access may be directed to the corresponding author via the contact details provided in the manuscript. Data will be available after publication and for a period of 2 years thereafter.
Disclosure
The authors report no conflicts of interest in this work.
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Associated Data
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Data Availability Statement
The authors confirm that the data supporting the findings of this study are available upon reasonable request. Individual deidentified participant data, along with relevant study documents, will be made available to researchers who provide a methodologically sound proposal. Requests for data access may be directed to the corresponding author via the contact details provided in the manuscript. Data will be available after publication and for a period of 2 years thereafter.