Silodosin as a predisposing factor of intraoperative floppy iris syndrome (IFIS): an observational propensity score-matching cohort study

To evaluate the correlation between silodosin and intraoperative floppy iris syndrome (IFIS) and compare it with other a1-adrenergic receptor antagonists (a1-ARAs) and other factors predisposing to IFIS. From the patients who underwent phacoemulsification between 2014 and 2020, we identified all patients who, during their preoperative assessment, reported an a1-ARAs intake (exposed group). These patients were matched utilizing a propensity score matching analysis with an otherwise homogenous group of patients (control group) based on demographics and systemic/ocular comorbidities. A total of 350 patients were included in each group. In the exposed group, 177 (50.6%) patients were exposed to tamsulosin, 105 (30%) to alfuzosin, 43 (12.2%) to silodosin. Regarding IFIS, it was observed in 21.5% of patients on tamsulosin (38/177), 11.4% on alfuzosin (12/105), 37.2% on silodosin (16/43), and 3.4% in the controlled group (12/350). In a multiple regression model analysis, the only two factors significantly associated with IFIS development were silodosin and tamsulosin yielding an adjusted odds ratio of 8.471 (95%CI 4.005–17.920) and 3.803 (95%CI 2.231–6.485), respectively. Silodosin has been demonstrated as a predisposing factor, strongly correlated with IFIS development. These results should increase cataract surgeons’ awareness to assess their patients preoperatively for exposure to silodosin carefully and employ the appropriate prophylactic measures to ameliorate the impact of silodosin intake on the surgical outcome.


Introduction
Intraoperative floppy iris syndrome (IFIS) was defined in 2005 by Chang and Campbell as the occurrence of the following triad of signs during phacoemulsification: an iris which billows and ripples in response to phaco fluidics, a pupil that progressively contracts and poorly responds to mydriatic agents, and finally, an iris stroma which tends to prolapse through the incisions [1]. IFIS is classified based on the above signs' presence as mild, moderate, or severe (presence of one, two, or all three signs respectively) [2]. In the original report, IFIS was utterly attributed to the intake of tamsulosin, a uroselective a1-adrenergic receptor antagonist (a1-ARA), which is commonly prescribed to men as treatment of benign prostate hyperplasia (BPH) [1]. IFIS mostly became apparent after the revised clinical guidelines of BPH's treatment, which replaced surgical intervention with a1-ARAs as the first-line treatment [3]. However, IFIS has subsequently been correlated with a plethora of predisposing factors, including demographics (male gender and advanced age), arterial hypertension and antihypertensive drugs, a poorly dilated pupil, and other medications such as other a1-ARAs (besides tamsulosin), finasteride, antipsychotics, and benzodiazepines [4][5][6][7][8][9][10]. Nevertheless, up to date, tamsulosin remains the predisposing factor that is most strongly correlated with IFIS occurrence.
This strong correlation between tamsulosin and IFIS could be attributed to tamsulosin's strong affinity for the a1 A sub-type of the adrenergic receptor (a1 A -AR), which is significantly more robust than other a1-ARAs such as alfuzosin, doxazosin, prazosin, and terazosin [11][12][13][14]. The a1 A -AR regulates the tone of the musculus dilatator pupillae [15]. Therefore, the inhibition of these receptors interferes with the iris's dilation, while their long-term use leads to the alteration of the iris' anatomy, specifically the dilator muscle's atrophy that is irreversible and independent of a1-ARAs cessation [16][17][18].
Silodosin is the newest member of the a1-ARAs family, granted approval by the Food and Drug Administration in 2008 [19]. Silodosin is a uroselective a1-ARA with a high affinity for the a1 A -AR. Therefore, it is fair to believe that silodosin could significantly be correlated to IFIS. However, the literature investigating the correlation between the intake of silodosin and IFIS development is limited [20][21][22][23]. Our study aims to evaluate the correlation between silodosin and IFIS. To the best of our knowledge, it represents the first attempt to estimate the power of this correlation, compare it with other a1-ARAs, while adjusting for other predisposing factors linked to IFIS.

Study design and patient selection
We conducted a retrospective observational cohort study in accordance with the STROCSS 2019 Guidelines and the tenets of the Declaration of Helsinki after approval of the Institutional Review Board with a waiver of consent [24]. The study pool consisted of all patients who underwent phacoemulsification at a tertiary ophthalmology department during a 6-year period (2014-2020). Initially, we identified all patients, who during their preoperative assessment (7 days preoperatively), reported an a1-ARAs intake (exposed group). We then conducted a propensity score matching analysis using variables (potential risk factors) included in our standard preoperative assessment to match the patients with a1-ARAs intake with an otherwise homogenous group of patients (control group) [25]. Specifically, patients were matched based on: gender, age, diabetes mellitus, arterial hypertension, preceded vitrectomy, corneal opacities, shallow anterior chamber (\ 2.5 mm), posterior polar cataract, white/brunescent cataract, pseudoexfoliation, iridodonesis/phacodonesis, glaucoma, deep-set eye, monocularity, and finally, poor compliance of the patient.

Data collection and definition of outcomes
All study data were retrieved after carefully assessing the patients' medical files and the respective electronic operating records. We thoroughly reviewed all folders regarding the exposure to risk factors predisposing to IFIS. Specifically, for patients on a1-ARAs, we recorded which particular drug they were administrated, including finasteride. For all patients, we also identified which patients were exposed to benzodiazepines, neuromodulating drugs (including antidepressants, antipsychotics, cholinergic drugs, and dopaminergic drugs), and antihypertensive drugs (angiotensin II receptor inhibitors, b-blockers). We considered a positive exposure, any drug intake, independently of the duration of intake or drug cessation. Finally, for each patient, we recorded the IFIS status. Positive status was considered the occurrence of any of the three signs of IFIS. IFIS was also classified as mild, moderate, and severe (based on the incidence of one, two, or three signs, respectively).

Surgical procedure
On surgery's day, our protocol included a preoperative dilation with tropicamide 0.5%, phenylephrine hydrochloride 2.5%, and cyclopentolate 1% eye drops. Regarding anesthesia, topical anesthesia was achieved with proparacaine hydrochloride 0.5%, while intracameral anesthesia was achieved with an ophthalmic viscosurgical device containing 1% sodium hyaluronate and 1% lidocaine (Visthesia, Zeiss Meditec, Germany). The operation was performed using a 2.4 mm clear corneal incision and two side ports. For all cases, the same gravity-fluids torsional phacoemulsification device was used (Infiniti Vision System, Alcon Laboratories, Inc.).

Statistical analysis
Statistical analysis was conducted using SPSS software (Version 26.0, IBMÒ). The confidence interval (CI) was set at 95% and the level of statistical significance at p \ 0.05. Categorical variables were described using frequencies and percentages while continuous variables using mean ± standard deviation. Categorical variables were compared using the Pearson Chi-square test, with post hoc pairwise comparisons, where appropriate. For continuous variables, Kolmogorov-Smirnov was used as a normality test. Non-normally distributed continuous variables were compared using the Mann-Whitney U test or Kruskal-Wallis H test with post hoc pairwise comparisons, as appropriate. Finally, a multiple regression model was used to estimate each predisposing factor's adjusted odds ratio in developing IFIS.

Study population and baseline characteristics
We identified 376 patients exposed to a1-ARAs at the time of operation. Following a propensity score casematching analysis, 26 patients remained unmatched, while 350 patients (exposed group) were matched with 350 patients in our cataract database based on the variables of our standard preoperative assessment. Therefore, 700 patients were included, 692 males (98.9%) and eight females (1.1%), with a mean age of 75.33 ± 6.96 years. Table 1 summarizes the differences in the distribution of the baseline characteristics between the exposed and control group, following the case-matching by propensity scores. Notably, no statistically significant differences in the baseline characteristics were observed between the two groups.
Exposure to a1-ARAs and IFIS occurrence In the exposed group, 177 (50.6%) patients were exposed to tamsulosin, 105 (30%) to alfuzosin, 43 (12.2%) to silodosin, 3 (0.9%) to doxazosin, 1 (0.3%) to terazosin, and finally, 45 (12.86%) patients were exposed to finasteride. Table 2 demonstrates the IFIS rates of patients on silodosin, tamsulosin, and alfuzosin, as well as the mean preoperative dilated pupil diameter and the rate of utilization of preoperative prophylactic intracameral epinephrine in each subgroup compared to the control group. Notably, the preoperative dilated pupil was significantly smaller in the silodosin and tamsulosin groups than in the alfuzosin and control groups (p = 0.01 and p \ 0.001 for silodosin, respectively). The use of prophylactic intracameral epinephrine did not differ significantly among the three a1-ARA groups, while predictably, it was significantly higher than the control group (p \ 0.001). Interestingly, IFIS rates of the silodosin subgroup were significantly higher compared to the control group and the alfuzosin group (p \ 0.001) but not compared to the tamsulosin group (p = 0.31). IFIS rates were also significantly higher in the tamsulosin group than the alfuzosin group (p = 0.04).
None of the patients on doxazosin presented signs of IFIS, while the patient on terazosin presented a mild IFIS (iris billowing). Four patients were exposed both to tamsulosin and alfuzosin, and one was exposed both to tamsulosin and silodosin. None of these five patients presented IFIS signs. Finally, of the 45 patients who were exposed to finasteride, 11 (24.4%) showed IFIS signs, 3 (6.7%) mild, 5 (11.1%) moderate, and 3 (6.7%) severe IFIS.

Multiple regression model
A multiple regression model analysis was conducted to estimate the OR of each a1-ARA in correlation with IFIS development. Other predisposing factors were included in the model to reach an adjusted estimation of the OR. Specifically, we included the intake of finasteride, benzodiazepines, neuromodulators, and antihypertensive drugs. Antihypertensives were furtherly divided into angiotensin II receptor inhibitors, b-blockers, or other antihypertensives (including diuretics, calcium channel blockers, and angiotensinconverting enzyme inhibitors). The intake of doxazosin and terazosin was not included in the model since very few patients were exposed to these a1-ARAs to conduct any meaningful analysis. Table 3 presents the adjusted ORs of each predisposing factor in the model along with 95% confidence intervals (CI). Notably, the only two factors that were significantly associated with IFIS development were silodosin and tamsulosin (p \ 0.001).

Discussion
In this study, we evaluated the correlation between silodosin intake and IFIS development. We managed to quantify this correlation by estimating an odds ratio while adjusting for covariates reported as factors predisposing to IFIS development. Notably, the control group was homogenous to the exposed group regarding demographics, systematic comorbidities, and ocular comorbidities. Our study demonstrated silodosin as a factor strongly predisposing to IFIS development.
The studies that have already investigated the correlation between silodosin intake and IFIS are limited. Specifically, some case reports have identified silodosin as the predisposing factor of IFIS, with the most recent one reporting a bilateral IFIS occurrence [20][21][22]. In addition, a recent retrospective cohort à: In mean mm ± standard deviation study, with 19 patients exposed to silodosin, reported an IFIS occurrence rate in this sub-group of patients of 79% (15/19), which was higher than the rate of IFIS reported in their tamsulosin sub-group of patients (63%, 10/16) [23]. In our study, the rate of IFIS development in the silodosin sub-group was also found higher than the rate of IFIS in the tamsulosin sub-group (37.2% vs. 21.5%).
To this day, tamsulosin remains the predisposing factor that is most strongly correlated to IFIS occurrence. Univariate analyses and multiple regression models report unadjusted odds ratios for IFIS occurrence when exposed to tamsulosin between 10.67 and 206.5 [6,26,27] and adjusted odds ratios between 5.78 and 4058 [4,6,26,28]. For this reason, a joint statement by the American Society of Cataract and Refractive Surgery and the American Academy of Ophthalmology advocates either to initiate tamsulosin following cataract surgery or to use a non-selective a1-ARA for BPHs treatment in phakic patients [29].
Silodosin is prescribed for the treatment of symptomatic BPH and lower urinary tract symptoms (LUTS). When compared to tamsulosin, in a recent meta-analysis, based on 13 studies including 2129 randomized participants, both drugs were found equally effective in the management of symptomatic BPH and LUTS [30]. Along with the prolongation of life expectancy, a larger population of patients on these a1-ARAs will inevitably require cataract surgery in the near future. When silodosin is prescribed to phakic patients, it is highly recommended that the patient's ophthalmologist be informed accordingly.
IFIS, especially unanticipated, is correlated with significant intraoperative complications [1,8,31,32]. Fortunately, when patients are appropriately assessed preoperatively to stratify the surgical risk adequately and the necessary prophylactic measures are employed for high-risk patients, complication rates return to their baseline [33]. Therefore, we recommend that all physicians and medical personnel involved in the preoperative evaluation of cataract patients should record the intake of a1-ARAs, and particularly the intake of tamsulosin and silodosin.
The surgical risk is not linear. This statement is implemented particularly in IFIS. The vast majority of IFIS cases are correlated with a handful of already identified risk factors. Therefore, the cornerstone in addressing IFIS is first to be familiar with these predisposing factors, then assess them properly preoperatively, and finally, employ the necessary prophylactic measures to ameliorate their impact on the surgical outcome [34].
Our study has several limitations. First, its retrospective nature could have introduced information bias in our study. In addition, due to our study's retrospective nature, the subgroups of each a1-ARA differ in size, which could have impacted our conclusion. Furthermore, several patients identified as highrisk patients due to their exposure to one or more predisposing factors received intracameral epinephrine preoperatively. Therefore, our analysis probably has underestimated the actual risk associated with exposure to predisposing factors. Finally, despite our best efforts to adjust for covariates, unknown cause/effect relations could have impacted our results.
On the other hand, the large sample size and the utilization of propensity scores case-matching significantly strengthen our results. To the best of our knowledge, our study is the first in the literature that has linked silodosin with IFIS, managing to quantify the power of the correlation between silodosin and IFIS by estimating an odds ratio while adjusting for other risk factors by using two homogenous groups of patients achieved by propensity scores case-matching.
In conclusion, silodosin, a uroselective a1-ARA, has been demonstrated in this study as a predisposing factor strongly correlated with IFIS development. These results should increase cataract surgeons' awareness to assess their patients preoperatively for exposure to silodosin carefully and employ the appropriate prophylactic measures to ameliorate the impact of silodosin intake on the surgical outcome.
Funding No funding was received for this research. No financial grants or funds were received in support of the study.

Declarations
Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. No proprietary interest in any of the products mentioned in the study. No conflict of interest.
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the (place name of institution and/or national research committee) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent Informed consent was obtained from all individual participants included in the study.

Consent for publication
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