The effect of antihypertensive therapy on dry eye

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Jun 18, 2014 - Schirmer I test, tear film break-up time (TBUT), fluorescein (FL) and rose bengal corneal staining patterns of the ...... Tear osmolality and ferning.
http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–7 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.912660

RESEARCH ARTICLE

The effect of antihypertensive therapy on dry eye disease Emine Kalkan Akcay1, Murat Akcay2, Gamze Dereli Can1, Nabi Aslan2, Betul Seher Uysal1, Basak Bostanci Ceran3, Pinar Koseahya1, and Nurullah Cagil1 1

Department of Ophthalmology, Yildirim Beyazit Universty Medical Faculty Ankara Ataturk Training and Research Hospital, Ankara, Turkey, Department of Cardiology, Yildirim Beyazit Universty Medical Faculty Ankara Ataturk Training and Research Hospital, Ankara, Turkey, and 3 Department of Ophthalmology, Antalya Education and Research Hospital, Antalya, Turkey

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Abstract

Keywords

Context: There is a generalization that ‘‘antihypertensive (antiHT) therapy causes Dry Eye Syndrome’’, which has been claimed for years however most of the publications are epidemiological studies. We performed a clinical study to investigate the effects of antiHT agents on tear function. Objective: The aim of this article is to evaluate the effects of different classes of antiHT medications on tear osmolarity, ocular surface problems and dry eye symptoms. Materials and methods: Prospective, non-randomized a clinical study. A total of 71 patients who would be initiated antiHT medication due to elevated systemic blood pressure were included in the study. Thirty of these patients were given antiHT drugs containing diuretic (diuretic +), and 41 of them were given diuretic-free drugs (diuretic ). While the number of the patients medicated in the group that received Angiotensin Converting Enzyme inhibitors (ACE inh)/ Angiotensin receptor blockers (ARB) (ACE/ARB +) was 29, the number of those medicated in the ACE/ARB-free group (ACE/ARB ) was 42. Ocular surface disease index scores, tear osmolarity, Schirmer I test, tear film break-up time (TBUT), fluorescein (FL) and rose bengal corneal staining patterns of the patients were analyzed. The patients were examined through the repetition of all the tests in the 1st and the 3rd month. Results: The participants (n ¼ 71) comprised 38 males and 33 females with a mean age of 51.8 ± 10.4. When the first (0–1st month) and the third month (0–3rd months) control measurements between diuretics (+) and diuretics () groups before and after antiHT therapies were compared, a statistically significant difference was not found in any of the tests applied. When the 0–1st month measurements of ACE/ARB (+) and ACE/ARB () groups were compared, it was observed that staining with FL in ACE/ARB (+) group decreased in a statistically significant manner (p ¼ 0.035) and there was a significant increase in TBUT values (p ¼ 0.022). Discussion and conclusion: The use of antiHT drugs containing diuretic had no adverse effect on the tear function tests, but using drugs that contain ACE/ARB could have a positive impact.

Antihypertension medicals, dry eye, tear osmolarity

Introduction The ocular surface needs a tear film covering the whole surface in order to maintain its health and function. Dry eye syndrome (DES) is a disorder of the tear film that occurs as a result of decreased tear production or increased tear film evaporation, and that leads to the damage of the ocular surface together with various symptoms and discomforts. DES may develop because of the reduction in the amount of tear, defect in the distribution of tear on the surface of the

Address for correspondence: Dr. Emine Kalkan Akcay, Department of Ophthalmology, Yildirim Beyazit Universty Medical Faculty Ankara Ataturk Training and Research Hospital, Ankara, Turkey. E-mail: [email protected]

History Received 11 March 2014 Revised 27 March 2014 Accepted 02 April 2014 Published online 18 June 2014

cornea and conjunctiva, corneal wetting problems, corneal epithelial irregularities or may be due to abnormalities in the lipid layer of the tear1–4. In many publications in the literature, systemic medications have been examined in terms of ocular side effects, and most have been reported to cause DES. The agents that are accused to cause an increase in the signs and symptoms of DES are beta blockers (BB), angiotensin-converting enzyme inhibitors (ACE inh) and diuretics5–7. Although it is stated in epidemiological studies that in many patients using antihypertensive (antiHT) drugs, there is an increase in DES signs and symptoms, the controlled clinical studies on this subject are few5,6,8–11. The aim of this study is to evaluate the effect of these agents on tear osmolarity, ocular symptoms and tear function tests in the patients that were initiated different classes of antiHT medication due to hypertension (HT).

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Materials and methods The study included 71 patients (33 female, 38 male) who were started antiHT drug therapy [Diuretics, ACE inh., Angiotensin receptor blockers (ARB), BB, calcium channel blockers (CCB), and combination forms of these drugs]. Exclusion criteria included ocular topical treatment within the past 6 months, previous ocular laser or surgical treatment, history of ocular trauma, use of contact lenses within the past 12 months, active ocular infection, or other common ocular diseases, including pterygium, glaucoma, or retinal detachment and systemic disease other than HT. The study was in adherence to the tenets of the Declaration of Helsinki. All patients who agreed to participate in this study provided written informed consent. Patients who were evaluated in the Cardiology Clinic in Yildirim Beyazit University, Ataturk Education and Research Hospital and diagnosed with HT were performed ocular surface disease index (OSDI) scoring which was validated in Turkish prior to use of antihypertensive drugs12. The OSDI developed by the Outcomes Research Group at Allergan Inc. (Irvine, CA), is a 12-item questionnaire designed to provide a rapid assesment of the syptoms of ocular irritation consistent with DES and their impact on vision-related functioning. The 12 items in the OSDI are grouped into three scales which measure visual sensations (e.g. eyes feeling gritty, blurred vision), visual limitations on activities such as reading or driving at night, and sensitivity to conditions of wind or dry air. Items are answered on a scale from 0 (none of the time) to 4 (all of the time), and subscale scores and an overall score are calculated as the percentage of points out of the total possible, with higher scores representing greater disability13. OSDI was grouped as normal (0–12), mild (13–22), moderate (23–32) and severe (33–100) according to its severity14. Furthermore, the tear osmolarity was determined through Tear Lab (TearLab Corp, San Diego, CA). Tear Lab osmolarity system is a device capable of measuring tear osmolarity in seconds by using an amount of less than 50 Nano liters of tears. In this device, tear osmolarity is measured through a non-invasive chip, which is inserted at the end of the probe4,15–18. Tear osmolarity, which is over 308, was considered significant for the diagnosis of DES16,19. Schirmer I test, tear film break-up time (TBUT) and patterns of corneal staining with fluorescein (FL) and rose bengal (RB) were analyzed. The Schirmer I test without topical anesthesia was performed by inserting a sterile Schirmer test strip (Schirmer Tear Test Strips, Alcon Laboratories, Fort Worth, TX) into the inferior fornix at the junction of the middle and lateral third of the lower eyelid margin for 5 min. The result of the Schirmer I test was recorded in milimeter. The fact that the Schirmer I test was below 10 mm as the cut-off value was acknowledged to be meaningful (abnormal). Tear film stability was assessed with a TBUT. TBUT was evaluated after instillation of a FL strip impregnated with no preserved saline (fluorescein sodium 1 mg, Bio-tech, Vision Care Pvt. Ltd., Gujarat, India). Using a cobalt blue filter and slit-lamp microscope, the time interval between the last complete blink and the first appearance of a dry spot or disruption in the tear film was measured. The average of three

Cutan Ocul Toxicol, Early Online: 1–7

measurements was determined for each eye. We used a cut-off value of less than 10 s as an indicator for abnormality20. Corneal FL staining was observed through a slit-lamp with a cobalt blue filter and for RB conjunctival staining, RB strips (Bio vision Limited, Wayside, Tring Road, Wellhead, UK) were wetted with one drop of 0.9% sodium chloride and gently applied to the inferior fornix. Both staining were graded as 0 (no staining), 1 (mild staining with a few disseminated stains and limited to less than one third of the cornea), 2 (moderate staining with a severity between grades 1 and 3), or 3 (severe staining with confluent stains and occupying half of the cornea or more) using the Oxford Grading System Score (OGSS)21. The result of corneal FL and RB staining was defined as abnormal for grade 41 OGSS. The patients were initiated antiHT drugs, and we noted which agents were initiated. The most frequent classes of antihypertensive drugs used or prescribed to patients include diuretics and ACE inh. and ARB. Thiazide diuretics cause an inhibition of NaCl transport in the Distal Convoluted Tubule. Reduction in blood pressure is initially due to a reduction in extracellular volume and cardiac output. Angiotensin II, a potent vasoconstrictor, is produced by the action of ACE on the substrate angiotensin I. Antihypertensive effects of ACE inhibitors are due to the reduction in the amount of angiotensin II produced22. Since ACE inh. and ARB were reported to have a similar systemic mechanism of action in the literature, they were evaluated in the same group. The patients were examined at the end of the first and the 3rd months. The same tests were repeated at the control examinations. All measurements were performed to both eyes and the eye, which had higher tear osmolarity value, was taken for statistical analysis. Statistical analysis Data analysis was performed by using SPSS for Windows, version 11.5 (SPSS Inc., Chicago, IL). Whether the distributions of continuous and metric discrete data were normally or not was determined by Kolmogorov–Smirnov test. Continuous and metric discrete variables were shown as mean ± standard deviation (SD) or median (min–max), where applicable. While, the mean differences between groups were compared by Student’s t test, otherwise, Mann–Whitney U test was applied for comparisons of the median values. Nominal data were analyzed by Pearson’s Chi-square or Fisher’s exact test, where appropriate. While, the differences among baseline and 1st month regarding for median levels were evaluated by Wilcoxon Sign Rank test, otherwise, McNemar test was applied for nominal data comparisons. When the number of repeated measurements was more than two Friedman test was used instead of Wilcoxon Sign Rank test and Cochran’s Q test was applied instead of McNemar test. A p value less than 0.05 was considered statistically significant. But, all possible multiple comparisons the Bonferroni Correction was applied for controlling Type I error.

Antihypertensive therapy and dry eye

DOI: 10.3109/15569527.2014.912660

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Results Of the 71 patients included in the study, 41 were given diuretic containing (diuretic +) antiHT drugs and 30 of them were given diuretic free (diuretic ) antiHT drugs by the cardiology clinic. The mean age of the diuretic (+) group was 54.9 ± 10.4, and that of the diuretic () group was 49.4 ± 10.1. There was no statistically significant difference in gender distribution between the two groups (p ¼ 0.649) (Table 1). Fourty-two of the 71 patients included in the study were given ACE inh/ARB containing (ACE/ARB+), and 29 of them were given ACE inh/ARB-free (ACE/ARB ) antiHT drugs. The mean age of the ACE/ARB (+) group was 49.6 ± 11, and that of the ACE/ARB () group was 53.2 ± 10. The difference in gender distribution between the two groups was not statistically significant (p ¼ 0.801) (Table 2). Seventy-one patients included in the study were applied tests before starting medication and in the 1st month check in (01st month). When these tests were evaluated, OSDI scores and intensity, there was no statistically significant difference between diuretic (+) and diuretic () groups (p40.05) in terms of osmolarity measurement, Schirmer test, TBUT, FL, and RB staining. Additionally, there was no statistically significant difference among any of the tests of the 0–1st month assessments of the groups themselves (p40.025) (Table 3). Even though all of the patients included in the study were present in the 1st month examinations, the number of patients in the 3rd month examination fell to 52. When we evaluted the tests before medication and in the 3rd month after the medication started (0–3rd month), there was no statistically significant difference in any of them between diuretics (+) and diuretics () groups (p40.017). In addition, there was no statistically significant difference between 0 and 3rd month assessment in the groups themselves in all tests (p40.025) (Tables 4 and 5). Table 1. Demographic characteristics of patients with complete baseline and 1st month follow-up according to groups using diuretic or not. Variables

Diuretic free (n:41)

Using Diuretic (n:30)

p Value

Age Gender Female Male

49.4 ± 10.1

54.9 ± 10.4

0.028a 0.649b

20 (%48.8) 21 (%51.2)

13 (%43.3) 17 (%56.7)

a

Student’s t test, bPearson’s Chi-Square test.

Table 2. Demographic characteristics of patients with complete baseline and 1st month follow-up according to groups using ACE/ARB or not. Variables

ACE/ARB free (n:42)

Using ACE/ARB (n:29)

p Value

Age Gender Female Male

53.2 ± 10.0

49.6 ± 11.0

0.157a 0.801b

19 (%45.2) 23 (%54.8)

14 (%48.3) 15 (%51.7)

ACE/ARB: Angiotensin Converting Enzyme inhibitors-Angiotensin receptor blockers. a Student’s t test, bPearson’s Chi-Square test.

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However, when the 0–1st month tests of the ACE/ARB (+) and ACE/ARB () antiHT drugs given groups were compared, FL staining significantly decreased in the ACE/ ARB (+) group versus the ACE/ARB () group (p ¼ 0.035) (Table 6). Although there was not a change in the median staining score in ACE/ARB () at the end of the 1th month from the baseline, according to the Oxford classification it was seen that FL scores were increased by two grades or decreased by one grade. In ACE/ARB (+) group, FL scores were increased one grade and decrease two grade. So when we look at the minimum and maximum changes, the FL scores of the ACE/ ARB (+) has been reduced more. This has caused a statistically significant difference. Similarly, TBUT values increased in a statistically significant manner in the ACE/ARB (+) group compared to the ACE/ARB () group (p ¼ 0.022) (Table 7). When 0–3rd month tests of these two groups were compared within each group and between groups (p40.017) in terms of changes, no significant difference was found in any of the tests (p40.025) (Tables 8 and 9).

Discussion In this study, we examined the patients who were newly diagnosed with HT and started antiHT drugs, and we investigated the effect of this treatment on tear functions. Diuretic (hydrochlorothiazide) antiHT drugs do not show any negative effect on the tear functions, but the treatment containing ACE/ARB has been observed to have positive effects on some tear function tests. In a review, Blomquist wrote on the ocular complications of the systemic medications, he observed basing on his practical experience that patients were exposed to DES or aqueous tear deficiency because of the systemic drugs, and he reported that diuretics, b-blockers, antihistamines, antidepressants, anticholinergics and also antipsychotics cause DES with anticholinergic effects5. In their study with 668 participants, Smidt et al. asked participants whether they had had a daily ocular dryness, sandy and/or gritty sensation in their eyes for more than 3 months, and they agreed that the answer reflected and validated the ocular dryness problems. They have concluded that ocular dryness in cardiac agents is associated with thiazides, BB, CCB, ACE inh. / Angiotensin II antagonists and statins6. With their study in which they started with 5924 participants, Moss et al. sought to determine the incidence of DES, through 5-, 10- and 15-year follow-ups. According to the positive answers given by respondents to the question ‘‘For the past 3 months or longer, have you had dry eyes?’’, they identified the participants who had DES. They pointed out that diuretics are related to higher incidence; however, this difference did not quite reach statistical significance7. Additionally, people using diuretics have borderline higher risk 7. In their study, Schein et al. concluded that dry eye and dry mouth prevalence was, respectively, 1.12 and 1.52 times more in the participants that received multiple medication including diuretic and hipotensive agent as well11. Bergmann et al. in their study on 11 normal young human subjects using oral hydrochlorothiazide, applied Schirmer I test with anesthesia and identified a significant decrease in

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Table 3. Clinical measurement levels of cases with complete baseline and 1st month follow-up according to groups using (n ¼ 30) diuretic or not (n ¼ 41).

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Variables OSM4308 Diuretic () Diuretic (+) TBUT510 Diuretic () Diuretic (+) Abnormal OSDI Diuretic () Diuretic (+) FL Staining(n) Diuretic () Diuretic (+) RB Staining(n) Diuretic () Diuretic (+) SCH510 Diuretic () Diuretic (+)

Baseline

1st Month

p Valuea

Improvement

p Valueb 0.714c

22 (%53.7) 14 (%46.7)

15 (%36.6) 6 (%20.0)

0.143 0.039

12 (%29.3) 10 (%33.3)

23 (%56.1) 22 (%73.3)

20 (%48.8) 21 (%70.0)

0.629 1.000

10 (%24.4) 5 (%16.7)

23 (%56.1) 17 (%56.7)

23 (%56.1) 19 (%63.3)

1.000 0.687

3 (%7.3) 2 (%6.7)

9 (%22.0) 6 (%20.0)

10 (%24.4) 5 (%16.7)

1.000 1.000

4 (%9.8) 2 (%6.7)

9 (%22.0) 12 (%40.0)

9 (%22.0) 11 (%36.7)

1.000 1.000

3 (%7.3) 5 (%16.7)

15 (%36.6) 21 (%70.0)

14 (%34.1) 18 (%60.0)

1.000 0.508

4 (%9.8) 6 (%20.0)

0.431c

1.000d

1.000d

0.269d

0.304d

OSM, tear osmolarity; TBUT, Tear film break-up time; OSDI, ocular surface disease index; Fl, fluoroscein; RB, rose bengal; SCH, schirmer, aThe comparisons between baseline and 1st month within the groups of Diuretic (+) and diuretic (), the results of p value that 50.025 with McNemar’s test, according to the Bonferroni adjustment was considered statistically significant, bThe comparison of the amount of the change of clinical measurements from the baseline between diuretic + and  groups, the results of p value that50.05 was considered statistically significant, cPearson’s Chi-Square test, dFisher’s Exact Test.

Table 4. Clinical measurement levels of cases with complete follow-up according to groups using diuretic or not. Variables OSM Diuretic () (n:28) Diuretic (+) (n:24) TBUT Diuretic () (n:28) Diuretic (+) (n:24) OSDI Score Diuretic () (n:28) Diuretic (+) (n:24) OSDI Intensity Diuretic () (n:28) Diuretic (+) (n:24) FL Diu¨retik () (n:28) Diu¨retik (+) (n:24) RB Diuretic () (n:28) Diuretic (+) (n:24) SCH Diuretic () (n:28) Diuretic (+) (n:24)

Baseline

1st month

3rd month

p Valuea

307.5 (286–388) 308.5 (290–333)

304.5 (277–344) 303 (279–341)

304 (286–344) 315.5 (284–336)

0.168 0.093

5.5 (2–13) 6.5 (1–10)

9.5 (3–12) 6 (1–11)

9.5 (0–12) 6 (3–12)

0.033 0.717

20 (0–52) 17.5 (0–53)

20 (0–65) 15.5 (0–45)

23.5 (0–50) 13.5 (0–47)

0.223 0.909

2 (1–4) 2 (1–4)

2 (1–4) 2 (1–4)

2.5 (1–4) 2 (1–4)

0.843 0.704

0 (0–2) 0 (0–1)

0 (0–1) 0 (0–2)

0 (0–1) 0 (0–2)

0.097 0.289

0 (0–4) 0 (0–2)

0 (0–4) 0 (0–3)

0 (0–2) 0 (0–2)

0.479 0.294

10.5 (1–17) 6 (2–17)

11.5 (0–17) 8.5 (0–19)

11.5 (0–17) 7 (0–17)

0.729 0.253

OSM, tear osmolarity; TBUT, tear film break-up time; OSDI, ocular surface disease index; Fl, fluoroscein; RB, rose bengal; SCH, Schirmer, aAccording to the Friedman test, Bonferroni adjustment results for p50.025 was considered statistically significant.

basal tear production10. Rohrschneider and Koch measured the amount of tear secretion of 66 patients who were using acetazolamide and 20 people in the control group with Schirmer I test without anesthesia, and they stated that this treatment apperently reduces tear production13. In our study complaints of patients were questioned with OSDI survey, and osmolarity test which has been recognized as the gold standard in recent years, Schirmer I test to

determine the amount of tear, TBUT to evaluate the effects on evaporating, FL and RB staining to determine corneal surface damage were performed. To our knowledge, no systematic research in which objective tests are used so extensively in order to investigate this issue exists in the literature. Bergmann and Rohrschneider, separately, evaluated only the changes in the Schirmer I test in their study. Now, we know that the objective

Antihypertensive therapy and dry eye

DOI: 10.3109/15569527.2014.912660

Table 5. Distribution of improvement in the frequency of clinical measurements of cases with complete follow-up according to groups using diuretic or not.

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Variables

1st month – baseline

3rd month – baseline

8 (28.6%) 8 (33.3%) 0.711b

8 (28.6%) 3 (12.5%) 0.157b

7 (25.0%) 3 (12.5%) 0.309c

7 (25.0%) 2 (8.3%) 0.152c

4 (14.3%) 3 (12.5%) 1.000c

3 (10.7%) 4 (16.7%) 0.690c

3 (10.7%) 2 (8.3%) 1.000c

7 (25.0%) 3 (12.5%) 0.309c

3 (10.7%) 4 (16.7%) 0.690c

6 (21.4%) 7 (29.2%) 0.521b

3 (10.7%) 6 (25.0%) 0.272c

6 (21.4%) 6 (25.0%) 0.761b

OSM Diuretic () (n:28) Diuretic (+) (n:24) p Valuea TBUT Diuretic () (n:28) Diuretic (+) (n:24) p Valuea OSDI Diuretic () (n:28) Diuretic (+) (n:24) p Valuea FL Diuretic () (n:28) Diuretic (+) (n:24) p Valuea RB Diuretic () (n:28) Diuretic (+) (n:24) p Valuea SCH Diuretic () (n:28) Diuretic (+) (n:24) p Valuea

OSM, tear osmolarity; TBUT, tear film break-up time; OSDI, ocular surface disease index; Fl, fluoroscein; RB, rose bengal; SCH, schirmer, a According to the Bonferroni adjustment results for p50.017 was considered statistically significant, bPearson’s Chi-square test, cFisher’s exact Chi-square test.

and subjective tests especially osmolarity changes should be considered together for the diagnosis of dry eye20. In our study, between the groups using diuretics and the ones that do not, and within the groups during the 3-month follow-up there has not been a significant change in any tests. The systemic effects of antihypertensive drugs occur a few days after their use22. Therefore, follow-up of the patients in the 1st month is a sufficient time for the emergence of the effect of the systemic antihypertensive drugs on the tear. The use of a single dose acetazolamide is seen enough, and two hours after the use, the change in the amount of tear was examined in a clinical study13. Diuretics that are a part of combination treatment in current antihypertensive theraphy are mostly in the thiazid group diuretics, and loop diuretics, which are more powerful, are not used in antiHT treatment by themselves alone. Because diuretic effects of thiazide group is not very strong, they may not have affected tear functions clinically. There has been no difference in the results despite the fact that the number of the patients was more in the 1st month than it was in the 3rd month. The mechanisms by which medications may cause symptoms of dry eye and dry mouth are multifactorial (e.g. direct effect on gland function or dehydration)11. ACE inh and some other systemic medications may lead to oral and ocular dryness possibly through dysfunction of the saliwary and lacrimal glands. In the study of Smidith et al. ocular dryness was found to be inversely correlated with salivary flow rate6. On the other hand, while there are some studies saying that ACE inh. have a protective effect against the DES, there are also available studies claiming that ARBs do not have any

Table 6. Clinical measurement levels of cases with complete baseline and 1st month follow-up according to groups using (n ¼ 29) ACE/ARB or not (n ¼ 42). Variables OSM ACE/ARB () ACE/ARB (+) TBUT ACE/ARB () ACE/ARB (+) OSDI Score ACE/ARB () ACE/ARB (+) OSDI Intensity ACE/ARB () ACE/ARB (+) FL ACE/ARB () ACE/ARB (+) RB ACE/ARB () ACE/ARB (+) SCH ACE/ARB () ACE/ARB (+)

5

Baseline

1st Month

p Valuea

Variation

309 (286–334) 306 (290–388)

303 (279–341) 304 (277–344)

0.055 0.012

6 (47 to 43) 10 ( 53 to 31)

p Valueb 0.440

0.223 7 (1–10) 7 (2–13)

6 (1–12) 10 (3–12)

0.890 0.115

0 (6 to 5) 0 (7 to 8)

17.5 (0–53) 15 (0–57)

14 (0–53) 22 (0–65)

0.851 0.121

0 (29 to 22) 2 (24 to 31)

2 (1–4) 2 (1–4)

2 (1–4) 2 (1–4)

0.668 0.221

0 (2 to 2) 0 (3 to 2)

0 (0–1) 0 (0–2)

0 (0–2) 0 (0–1)

0.083 0.129

0 (1 to 2) 0 (2 to 1)

0 (0–2) 0 (0–4)

0 (0–3) 0 (0–4)

0.844 0.916

0 (1 to 3) 0 (4 to 3)

8 (2–17) 10 (1–17)

10 (0–19) 10 (0–17)

0.804 0.201

0 (15 to 14) 1 (7 to 11)

0.124

0.248

0.035

0.525

0.231

ACE/ARB, Angiotensin Converting Enzyme inhibitors-Angiotensin receptor blockers; OSM, Tear osmolarity; TBUT, Tear film break-up time; OSDI, Ocular Surface Disease Index; Fl, Fluoroscein; RB, rose bengal; SCH, Schirmer. aThe comparisons between baseline and 1st month within the groups of ACE-ARB (+) and ACEARB (), the results of p value that 50.025 with Wilcoxon signed-rank test, according to the Bonferroni adjustment was considered statistically significant, bThe Comparison of the amount of the change of clinical measurements from the baseline between ACE-ARB + and  groups, Mann–Whitney U test, the results of p value that 50.05 was considered statistically significant. Bold value is showing statistically significant value (p50.05).

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Table 7. Clinical measurement levels of cases with complete baseline and 1st month follow-up according to groups using (n ¼ 29) ACE/ARB or not (n ¼ 42).

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Variables OSM4308 ACE/ARB () ACE/ARB (+) TBUT510 ACE/ARB () ACE/ARB (+) Abnormal OSDI ACE/ARB () ACE/ARB (+) FL Staining ACE/ARB () ACE/ARB (+) RB Staining ACE/ARB () ACE/ARB (+) SCH510 ACE/ARB () ACE/ARB (+)

Baseline

1st Month

p Valuea

Improvement

p Value

b

0.607c 22 (%52.4) 14 (%48.3)

11 (26.2) 10 (%34.5)

0.013 0.388

14 (%33.3) 8 (%27.6)

27 (%64.3) 18 (%62.1)

30 (%71.4) 11 (%37.9)

0.581 0.092

5 (%11.9) 10 (%34.5)

0.022c 0.642d

23 (%54.8) 17 (%58.6)

24 (%57.1) 18 (%62.1)

1.000 1.000

4 (%9.5) 1 (%3.4)

8 (%19.0) 7 (%24.1)

11 (%26.2) 4 (%13.8)

0.453 0.375

2 (%4.8) 4 (%13.8)

14 (%33.3) 7 (%24.1)

13 (%31.0) 7 (%24.1)

1.000 1.000

6 (%14.3) 2 (%6.9)

24 (%57.1) 12 (%41.4)

20 (%47.6) 12 (%41.4)

0.344 1.000

7 (%16.7) 3 (%10.3)

0.218d 0.458d 0.511d

ACE/ARB, Angiotensin Converting Enzyme inhibitors-Angiotensin receptor blockers; OSM, Tear osmolarity; TBUT, Tear film break-up time; OSDI, Ocular Surface Disease Index; Fl, Fluoroscein; RB, rose bengal; SCH, Schirmer. aThe comparisons between baseline and 1st month within the groups of ACE-ARB (+) and ACE-ARB (), the results of p value that 50.025 with McNemar’s test, according to the Bonferroni adjustment was considered statistically significant, bThe comparison of the amount of the change of clinical measurements from the baseline between ACE-ARB + and  groups, the results of p value that 50.05 was considered statistically significant, cPearson’s Chi-Square test, dFisher’s Exact Test. Bold value is showing statistically significant value (p50.05). Table 8. Clinical measurement levels of cases with complete follow-up according to groups using ACE/ARB or not. Variables OSM ACE/ARB () (n:30) ACE/ARB (+) (n:22) TBUT ACE/ARB () (n:30) ACE/ARB (+) (n:22) OSDI Score ACE/ARB () (n:30) ACE/ARB (+) (n:22) OSDI Intensity ACE/ARB () (n:30) ACE/ARB (+) (n:22) FL ACE/ARB () (n:30) ACE/ARB (+) (n:22) RB ACE/ARB () (n:30) ACE/ARB (+) (n:22) SCH ACE/ARB () (n:30) ACE/ARB (+) (n:22)

Baseline

1st month

3rd month

p Value

308.5 (286–334) 307.5 (290–388)

303 (279–341) 304.5 (277–344)

312.5 (284–336) 304.5 (286–344)

0.242 0.051

5.5 (1–10) 6.5 (2–13)

6 (1–11) 10 (3–12)

6 (3–12) 9.5 (0–12)

0.597 0.141

17.5 (0–53) 20 (0–52)

13 (0–45) 26.5 (0–65)

12 (0–47) 25 (0–50)

0.372 0.284

2 (1–4) 2 (1–4)

2 (1–4) 2.5 (1–4)

1.5 (1–4) 3 (1–4)

0.859 0.552

0 (0–1) 0 (0–2)

0 (0–2) 0 (0–1)

0 (0–2) 0 (0–1)

0.542 0.066

0 (0–2) 0 (0–4)

0 (0–3) 0 (0–4)

0 (0–2) 0 (0–2)

0.211 0.581

7 (0–17) 11 (0–17)

0.378 0.850

8 (2–17) 10.5 (1–17)

10 (0–19) 10.5 (0–17)

a

ACE/ARB, Angiotensin Converting Enzyme inhibitors-Angiotensin receptor blockers; OSM, Tear osmolarity; TBUT, Tear film break-up time; OSDI, Ocular Surface Disease Index; Fl, Fluoroscein; RB, rose bengal; SCH, Schirmer, aAccording to the Friedman test, Bonferroni adjustment results for p50.025 was considered statistically significant.

effect7,9,23. Moss et al. are the first to state that ACE inh. have a protective effect on DES. They found in their study that persons using antidepressants were at higher risk for incidence of DES while those using ACE inh. were at lower risk. According to short-and long-term results of the use of ACE inhs, they also reported that ACE inhs have also a protective effect7. This may be due to the reported anti-

inflammatory effects of ACE inh24,25. In our study, consistent with this literature, we observed positive changes in FL and TBUT values in the ACE/ARB group between 0 and 1st month. The fact that the sample groups were not homogenous, that the sample size diminished during the transition from the 1st to the 3rd month because the patients did not came to

Antihypertensive therapy and dry eye

DOI: 10.3109/15569527.2014.912660

Table 9. Distribution of improvement in the frequency of clinical measurements of cases with complete follow-up according to groups using ACE/ARB or not.

Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Gazi Univ. on 12/23/14 For personal use only.

Variables OSM ACE/ARB ACE/ARB p Valuea TBUT ACE/ARB ACE/ARB p Valuea OSDI ACE/ARB ACE/ARB p Valuea FL ACE/ARB ACE/ARB p Valuea RB ACE/ARB ACE/ARB p Valuea SCH ACE/ARB ACE/ARB p Valuea

1st month – baseline

3rd month – Baseline

() (n:30) (+) (n:22)

10 (33.3%) 6 (27.3%) 0.640b

5 (16.7%) 6 (27.3%) 0.495c

() (n:30) (+) (n:22)

3 (10.0%) 7 (31.8%) 0.075c

3 (10.0%) 6 (27.3%) 0.144c

() (n:30) (+) (n:22)

5 (16.7%) 2 (9.1%) 0.685c

5 (16.7%) 2 (9.1%) 0.685c

() (n:30) (+) (n:22)

2 (6.7%) 3 (13.6%) 0.639c

4 (13.3%) 6 (27.3%) 0.290c

() (n:30) (+) (n:22)

5 (16.7%) 2 (9.1%) 0.685c

8 (26.7%) 5 (22.7%) 0.746b

() (n:30) (+) (n:22)

7 (23.3%) 2 (9.1%) 0.272c

6 (20.0%) 6 (27.3%) 0.539b

ACE/ARB: Angiotensin Converting Enzyme inhibitors-Angiotensin receptor blockers; OSM, tear osmolarity; TBUT, Tear film break-up time; OSDI, Ocular Surface Disease Index; Fl, Fluoroscein; RB, rose bengal; SCH, Schirmer, aAccording to the Bonferroni adjustment results for p50.017 was considered statistically significant, bPearson’s chi-square test, cFisher’s exact Chi-square test.

control examination, and that no comments on the medications can be made since the number of CCB and BB users was too low for them to create separate groups are the limitations of this study.

Conclusion In the light of these outcomes, rethinking is needed on the generalization that ‘‘antiHT therapy causes DES’’, which has been claimed for years, and more comprehensive clinical studies are required to be carried out in the future.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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