The present was a prospective nonrandomized cohort study. The study followed the STROBE guidelines. (32) All patients diagnosed with exfoliation glaucoma attending the Ophthalmology Department at the Skaraborg’s Hospital were asked if they wanted to participate in the study. In case of an affirmative answer, patients were called to a special recruiting appointment. To diminish “recall bias” patients were advised about the nature of the study before the recruitment appointment. The recruiting period was from January 2014 until December 2018 (five years).
Inclusion criteria:
1. Patients diagnosed with exfoliation glaucoma. Exfoliation glaucoma was defined according to the European Glaucoma Society. (33)
2. Age ≤ 85 years at recruiting.
Exclusion criteria:
1. Patients who could not perform at least five reliable visual fields three years after recruiting. Reliable visual fields were: false positives ≤ 15% and/or false negatives ≤ 20%, and/or fixation losses ≤ 30%.
2. Patients with advanced visual field deterioration, defined as mean deviation (MD) ≥ -18 dB and/or visual field index (VFI) ≤40%, were excluded. Patients with damaged visual fields were excluded to avoid "floor effects.(34, 35)
3. Patients who were operated on glaucoma surgery during the follow-up period. Uneventful cataract surgery and/or selective laser treatment (SLT) were not considered exclusion criteria.
4. Patients suffering from another eye disease during the follow-up period that could modify visual fields, i.e., central vein occlusion, retinal diseases, etc.
5. Patients dropping out of the control period for different reasons like dementia, moving to another city, etc.
6. Patients who administrated nicotine through other ways than cigarette smoking, like chewing tobacco, smoking pipes, pills, etc., both at the recruiting visit and during the three-year follow-up period.
The risk factors studied at recruiting were smoking, age, sex, unilateral/bilateral glaucoma, visual acuity, refractive errors, IOP at diagnosis and recruitment, number of medications, central corneal thickness (CCT) measurement, gonioscopy evaluation: depth and pigmentation, cup-disc (C/D) ratio, diabetes, hypertension, cardiovascular diseases (including angina, heart attacks, heart failure, stroke, TIA and peripheral arterial diseases), migraine and family history for glaucoma.
Risk factors studied during the three years were: IOP reduction, SLT treatment, cataract operation, and the number of medications used.
At the recruiting visit, all participants filled out a questionnaire regarding smoking. The questions were as follows: 1) Did you smoke once in your life? (Yes/No). 2) Did you smoke more than 100 cigarettes in your life? (Yes/No). 3) Are you still smoking? (Yes/No). 4) How many cigarettes per day have you smoked? 5) When did you begin smoking? 6) When did you quit smoking? The total number of cigarettes smoked in the whole life was calculated as the number of cigarettes per day x 365 x smoking years. Smoking was studied and classified according to the definitions of the Centers for Disease Control and Prevention (CDC) National Health Interview Services (Division of Health Interview Statistics. National Center for Health Statistics. 3311 Toledo Rd Hyattsville, USA). Current smoker: An adult who has smoked 100 cigarettes in their lifetime and who currently smokes cigarettes. Former smoker: An adult who has smoked at least 100 cigarettes in their lifetime but who had quit smoking at the time of the interview. No smoker: An adult who has never smoked, or who has smoked less than 100 cigarettes in their lifetime. (https://www.cdc.gov/nchs/nhis/tobacco/tobacco_glossary.htm)
Furthermore, the questionnaire included questions regarding hypertension, cardiovascular diseases, diabetes, migraine, and a family history of glaucoma. Hypertension was studied as "using medicines against high blood pressure" (Yes/No). Cardiovascular diseases (angina, heart attack, heart failure, stroke, TIA, and peripheral artery diseases) were registered as present/absent (Yes/No). Diabetes was classified as "using medicines against diabetes" (Yes/No). Migraine was described as "suffered from migraine" (Yes/No). Finally, a family history of glaucoma was defined as having near relative suffering from glaucoma. Near relative was defined: as father and/or mother and/or siblings. The answer was registered as "Yes/No."
Every patient was ophthalmological examined at the recruiting visit. Age was registered as age at the recruiting visit and age at diagnosis based on the patient's records. Sex was registered as male/female. In addition, the unilateral/bilateral presence of glaucoma was recorded. If both eyes were suffering from glaucoma, both eyes were registered, but only one eye, chosen at random, was included in the study.
The best-corrected visual acuity (BCVA) was tested using a Snellen chart. Refractive errors were registered based on the information sent by the optician/optometrist. The IOP was measured with an applanation tonometer. The central corneal thickness (CCT) values were obtained using an ultrasound device (Tomey Pachymetry; Tomey Corp, Nagoya 451–0051, Japan). A gonioscopy was performed using a goniolens with undilated pupils to assess the trabecular meshwork. Gonioscopy was classified using the Shaffer's system (0-4). The pigmentation of the trabecular meshwork was ranked 0-3. Afterwards, the patient's pupils were dilated with 2.5 % Phenylephrine and Tropicamide 0.5% (Bausch & Lomb UK Ltd, 106 London Road-Kingston-upon-Thames-Surrey-KT2 6TN-England). The presence of exfoliation was recorded. In the case of pseudophakia, if exfoliation was not present at recruitment, patients were included if exfoliation was registered at least twice in patients’ medical records. The appearance of the optic nerve was studied using a 90-D lens, and the average vertical cup-to-disc ratio (C/D ratio) was measured.
The risk factors for progression under the three-year follow-up were measured: IOP reduction was calculated as the difference in IOP between the IOP at diagnosis and the IOP three years after recruitment. The SLT treatment was measured as present or absent per patient (Yes/No). Cataract operation was counted as present or absent (Yes/No). Eye drops at the end of the three years were measured as the number of medications (compounds).
The primary endpoint of the study was the visual field's progress. All patients were examined using the Humphrey Field Analyzer device (Carl Zeiss, Carl-Zeiss-Straße 22, 73447 Oberkochen, Germany) and the test point pattern 24-2. A trained ophthalmic nurse did the examinations. Visual field progression was assessed in three different ways.
The first approach was based on the "mean deviation" (MD) values. The difference in MD values was calculated from the beginning to the end of the study. Higher MD values indicated higher progression. The MD parameter was chosen since several studies still use MD as an indicator of progression. (36-39) However, cataract development can also modify MD values.
The second method used to analyze progression was based on the "visual field index" (VFI) values. The machine calculated the VFI and performed a regression analysis calculating the "rate of progression" (ROP). The device calculated the ROP as the percentage of VFI deterioration (%)/year. The ROP calculation is a "trend analysis."
Finally, guided progression analysis (GPA) was the third progression method. The GPA is included in the device and performed automatically (GPA Alert). The GPA differs from the ROP because it is an "event analysis." The machine compares every single point to similar points detected in prior examinations. The GPA alert showed: no, possible or likely progression. In the present study, the results were evaluated as "no progression" or "progression," The term “progression” included both "possible" and "likely" progression.
Statistics
The SPSS statistical software was used for statistical analysis (IBM, 1 New Orchard Road Armonk, NY 10504, USA). All the studied variables were tested in two steps. The first step used univariate linear regression analysis for continuous endpoint variables (MD and ROP). Meanwhile, the dichotomous endpoint (GPA) used a univariate logistic regression. The variables that showed significant values in the univariate analysis model were included as covariates in a multivariate analysis. Multivariate linear regression analysis was used in case the endpoints were continuous (MD and ROP). In the case of a dichotomous variable (GPA), a multivariate logistic regression analysis was performed. In addition, a subgroup analysis among the smokers using a similar strategy was done. The significance level was set at 0.05.
A post-hoc power calculation was done using the "PS free software" of the Vanderbilt University (https://biostat.app.vumc.org/wiki/Main/PowerSampleSize).