Abstract
Importance
Retinal vessel diameters are being measured to examine their relationship to ocular and systemic disease, and in some studies are used to calculate the risk of disease. Important factors that directly impact retinal vessel diameters, such as medication use, should be considered when estimating these associations.
Objective
To quantify the association of selected medications and supplements and retinal vessel diameters.
Design
Prospective cohort study.
Setting
General adult population.
Participants
There were 4,926 participants in the Beaver Dam Eye Study aged 43–86 years at baseline, who were seen every 5 years over 20 years of follow-up from 1988–2010.
Main Outcome Measure
Central retinal arteriolar equivalent and central retinal venular equivalent measured from Early Treatment Diabetic Retinopathy Study fundus photograph field 1.
Results
The use of any blood pressure medication (β=0.73, P=0.04), specifically calcium channel blockers (β=1.52, P<0.01 after Bonferroni correction), was significantly associated with wider central retinal arteriolar equivalent adjusting for refraction, photograph focus, age, systolic blood pressure, height, examination phase, education level, smoking and drinking histories, and presence of diabetes and emphysema. Use of prostaglandin analogues was marginally associated with narrower central retinal arteriolar equivalent (β=−2.04, P=0.09) while beta blockers (β=−1.02, P=0.10) and oral steroids (β=2.13, P=0.07) were marginally associated with changes in the central retinal venular equivalent.
Conclusion and Relevance
Several medications were associated with central retinal arteriolar and venular equivalents. Prostaglandin analogues, calcium channel blockers, and oral steroids have the largest relative effects. After applying Bonferroni correction, the use of calcium channel blockers was most strongly associated with change in the central retinal arteriolar equivalent. The presence of factors that are associated with retinal vessel diameters should be considered when using retinal vessel diameter as an outcome, or when using these measures to assess risk of systemic or ocular disease.
Retinal vessel diameters (RVDs) are associated with cardiovascular diseases such as hypertension, myocardial infarction and cardiovascular mortality.1–3 Many factors affect retinal vessel diameters. Men tend to have larger RVDs than women and older individuals tend to have narrower RVDs than younger individuals.4,5 Other systemic factors, e.g., blood pressure, glycemia, lipid levels, obesity, smoking, renal function and chronic inflammation also affect RVDs.6–9
RVDs are also associated with ocular characteristics and diseases.10–14 Wider retinal venules are associated with severity of diabetic retinopathy10 and open angle glaucoma.12 One study has reported evidence of an association of RVDs and age-related macular degeneration.15
A class of exposures that is often ignored in examining associations between cardiovascular endpoints and RVDs is use of medications and supplements. Many different classes of drugs have the potential to alter RVDs. Medication associations with vessel diameters may include not only those cardiovascular medications classified as vasodilators but may also include other blood pressure medications, systemic medications for other conditions, and herbal supplements.16–18 Of particular interest are relatively new medications such as phosphodiesterase 5 inhibitors, angiotensin receptor blocking agents, and angiotensin converter enzyme agents as well as medications that act as anti-oxidants and others that have anti-inflammatory actions.19,20 These medications have potential to alter RVDs as well as the associations of RVDs to cardiovascular disease. In addition, garlic extract or powder, taken as a non-vitamin, non-mineral dietary supplement may have direct effects on hypertension21 which may be secondarily associated with smaller retinal arteriolar diameters. Garlic may also decrease oxidative stress that could affect vessel diameters.17
Because of the potential of RVDs to be associated with diseases not only in the eye but in other organs, exposures that are related to these diameters may be related to health outcomes. The following is a report of the findings regarding the use of medications and their effects with concurrent retinal venular and arteriolar diameters from the Beaver Dam Eye Study, a population cohort study seen over 20 years of follow-up.
METHODS
There were 4,926 persons 43–86 years of age who participated in the baseline examination of the Beaver Dam Eye Study in 1988–1990. Ninety-nine percent of the population was of European ancestry. Informed consent was obtained from participants before each examination and all examinations followed a similar protocol that was approved by the institutional Human Subjects Committee of the University of Wisconsin and which conformed to the tenets of the Declaration of Helsinki.
Data regarding anthropometric measurements, health history, education, and lifestyle factors were collected at each examination. Blood samples were obtained. Diabetes was defined as self-report (use of insulin or diet to control blood sugar) and confirmed by glycosylated hemoglobin level above 6.5% or by absence of self-report with glycosylated hemoglobin level above 7%. Cardiovascular disease (CVD) was defined as self-report of stroke, myocardial infarction or angina. Smoking status was defined as never, past (smoked >100 cigarettes in lifetime but not currently smoking) or current. Ever heavy drinking was defined as self-report of ever drinking more than four alcoholic beverages daily on a regular basis. Refraction was measured according to a modification of The Early Treatment Diabetic Retinopathy Study protocol22 to obtain the best corrected visual acuity when the automated refraction yielded visual acuity of 20/40 or worse. Serum creatinine was measured on frozen samples from a subset of participants at the baseline, 5-, 10-, and 15-year examinations. It was not measured at the 20-year examination. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation23 and dichotomized into ≥60 or <60 mL/min/1.73 m2.
Participants were asked to bring all current medications to the examination. If a participant was not taking any medications, this was recorded. Examiners followed up with participants by phone in order to verify the name of any medication that was reported but not brought to the examination. All medication names were recorded by trained examiners and American Hospital Formulary Service (AHFS) coding was used to classify all medications. Vasodilators were identified by AHFS code 2412 or as being a direct vasodilator, such as minoxidil or hydralazine. Medication form was recorded; however, frequency of use, dose consumed, length of time the medication has been used and, for ocular medication, the eye in which medication was used were not specified or recorded.
Stereoscopic 30° color retinal photographs of the optic disc were converted to digital images by a high-resolution scanner (Nikon LS2000, Nikon Inc., Japan) using standard settings for all photographs. Images were displayed on 21-inch monitors set to a screen resolution of 1600 × 1200 pixels. The diameters of all arterioles and venules coursing through a standard area 0.5 to 1.0 disc diameters from the optic disc margin (Zone B) were measured using a custom computer program.24 Photograph focus was subjectively determined by a trained grader to be “good”, “fair” or “poor”. For these analyses vessel measurements from the right eye were used and a participant was required to have data for both central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE).
To be included in analyses, participants had to have been seen at one or more of the five examination phases of the Beaver Dam Eye Study. Of the 15,898 total person-visits, 1,282 visits were excluded for missing or ungradable photographs. An additional 1,534 person-visits were excluded because of having had cataract surgery in the right eye. Beyond having complete data for vessel measurement in the right eye and medication use, participants included in analyses were also required to have complete data for age, sex, height, systolic blood pressure, smoking history, diabetes history, history of emphysema, right eye refraction, and a graded measure of retinal photograph focus. An additional 1,104 person-visits were excluded due to missing information for one or more covariate. After exclusions, there were 11,978 person-visits remaining for analyses. Medications and supplements included in primary analyses were restricted to those used by at least 40 persons at a minimum of one visit (i.e., ranging from <1% at the baseline visit in 1988–1990 to 2.5% at the most recent visit in 2008–2010).
To analyze the immediate impact of vasodilating medications on RVDs, we explored the relationship between vessel diameters and concurrent medication use cross-sectionally at each examination using a mixed modeling approach to account for the correlation between the repeated measurements for a person seen at multiple visits over 20 years of follow-up. P-values for categorical variables are given for each category as compared to the reference category. The overall P-value for a categorical variable is a type-3 P-value that tests for any difference between any of the categories, while the test of trend models categorical variables as continuous in order to identify a linear trend with RVDs for the ordered categories. The beta estimate reported for the effect of medications on CRAE and CRVE represent the change in RVDs associated with taking a medication, as compared to not taking the given medication. We tested for significant multiplicative interactions between medications and examination phase, and between medications and inferred indication for the medication use. Any interaction that was significant at the alpha=0.05 level in the minimally adjusted model is reported. Bonferroni corrections25 for multiple comparisons are reported along with calculated P-value without such corrections. For the major categories of medications (vasodilator, prostaglandin analogue, any NSAID, any blood pressure medication, beta blocker, any diuretic, steroid, herbal vasodilator and garlic supplement) a correction was made for 9 comparison groups. For all sub-categories, a correction was made for 29 comparison groups. SAS version 9.3 was used for all analyses.
Age, sex, height, systolic blood pressure, refraction, and photograph focus affect vessel measurement from photographic images; therefore, these covariates were included in the minimally adjusted model. We also adjusted for examination phase, as there may be time trends associated with medication use (e.g., changing indications for use of medication) which may in turn affect RVDs. The maximally adjusted model includes all factors in the minimally adjusted model as well as education, smoking, emphysema, ever heavy drinking, and diabetes.
Although specific reason for medication use was not reported, medical history including emphysema, diabetes and cardiovascular disease was obtained and analyses for confounding by inferred indication were performed. Stratified analyses were used to identify relationships that may have been due to illness rather than the given medication. Results were confirmed by testing for interactions between medication use and illness status to identify significant differences in the effect of the given medication on RVD between those with and those without the specified illness.
A subset of analyses was performed to examine the effect of renal function (eGFR≥60 vs. eGFR<60 mL/min/1.73 m2) on the minimally and maximally adjusted models. Approximately 13% of the person-visits included in our primary analysis were missing a measure of serum creatinine.
RESULTS
Participants whose data contributed to these analyses, as reflected in person-visits over all examination phases, tended to be younger, have higher BMIs, higher diastolic blood pressures, and fewer co-morbidities such as diabetes, history of cardiovascular disease, and emphysema than those whose data were excluded (Table 1).
Table 1.
Characteristics of Participants for all Person-Visits Included and Excluded from Analyses.
| Included | Excluded | Age-Sex Adjusted | |||||
|---|---|---|---|---|---|---|---|
| Characteristic | N Person- Visits |
% or Mean (SD) |
N Person- Visits |
% or Mean (SD) |
ORa | P Valuea | Type 3 P Valueb |
| CRAE (µm; OR per 10) | 11978 | 148.8 (14.6) | 2728 | 144.9 (16.9) | 1.15 | <.001 | |
| CRVE (µm; OR per 10) | 11978 | 225.6 (23.0) | 2716 | 217.6 (26.7) | 1.10 | <.001 | |
| Age (y; OR per 10) | 11978 | 645.0 (10.1) | 3920 | 73.9 (11.4) | 0.42 | <.001 | |
| Height (in; OR per 6) | 11978 | 65.3 (3.7) | 3473 | 64.3 (3.9) | 0.88 | 0.04 | |
| Body mass index (kg/m2; OR per 1) | 11963 | 29.7 (5.7) | 3464 | 29.1 (6.1) | 1.01 | 0.05 | |
| Systolic BP (mmHg; OR per 10) | 11978 | 130.5 (19.3) | 3558 | 132.9 (20.4) | 1.01 | 0.16 | |
| Diastolic BP (mmHg; OR per 10) | 11974 | 76.1 (10.7) | 3556 | 72.3 (11.6) | 1.06 | 0.004 | |
| Sex | |||||||
| Female | 6628 | 55.3 | 2475 | 63.1 | Ref | ||
| Male | 5350 | 44.7 | 1445 | 36.9 | 1.17 | 0.003 | |
| Photograph focus quality | |||||||
| Good | 7896 | 65.9 | 1504 | 44.0 | |||
| Fair | 3310 | 27.6 | 733 | 21.4 | |||
| Poor | 772 | 6.5 | 439 | 12.8 | |||
| Cannot grade | 0 | 0.0 | 745 | 21.8 | |||
| Refraction | |||||||
| Myopic | 3294 | 27.5 | 361 | 26.8 | Ref | 0.12 | |
| Emmetropic | 2746 | 22.9 | 247 | 18.3 | 1.20 | 0.04 | |
| Hyperopic | 5938 | 49.6 | 739 | 54.9 | 1.09 | 0.27 | |
| History of cataract surgery | |||||||
| No | 11978 | 100.0 | 2038 | 52.4 | |||
| Yes | 0 | 0.0 | 1818 | 46.8 | |||
| Other | 0 | 0.0 | 32 | 0.8 | |||
| Education, y | |||||||
| < 12 | 2494 | 20.8 | 1105 | 28.7 | Ref | 0.20 | |
| 12 | 5651 | 47.2 | 1619 | 42.1 | 0.99 | 0.91 | |
| 13–15 | 1887 | 15.8 | 587 | 15.3 | 0.91 | 0.26 | |
| ≥ 16 | 1946 | 16.3 | 538 | 14.0 | 0.85 | 0.07 | |
| Diabetes present | |||||||
| No | 10402 | 86.8 | 2572 | 77.3 | Ref | <.001 | |
| Suspected | 305 | 2.6 | 97 | 2.9 | 0.94 | 0.58 | |
| Yes | 1271 | 10.6 | 658 | 19.8 | 0.60 | <.001 | |
| History of CVD | |||||||
| No | 10253 | 86.2 | 2933 | 75.9 | Ref | ||
| Yes | 1649 | 13.9 | 930 | 24.1 | 0.78 | <.001 | |
| History of emphysema | |||||||
| No | 11595 | 96.8 | 3673 | 95.2 | Ref | ||
| Yes | 383 | 3.2 | 186 | 4.8 | 0.79 | 0.02 | |
| Smoking status | |||||||
| Never | 5481 | 45.8 | 1938 | 49.7 | Ref | 0.01 | |
| Past | 4751 | 39.7 | 1565 | 40.2 | 0.86 | 0.007 | |
| Current | 1746 | 14.6 | 393 | 10.1 | 0.83 | 0.03 | |
| History of heavy drinking | |||||||
| No | 10055 | 84.0 | 3336 | 86.3 | Ref | ||
| Yes | 1923 | 16.1 | 532 | 13.8 | 0.83 | 0.004 | |
| eGFR<60 mL/min/1.73 m2 c | |||||||
| No | 8961 | 85.5 | 1819 | 72.0 | Ref | ||
| Yes | 1522 | 14.5 | 707 | 28.0 | 0.92 | 0.14 | |
BP, blood pressure; CRAE, central retinal arteriolar equivalent; CRVE, central retinal venular equivalent; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; OR, odds ratio; SD, standard deviation.
Percentages do not always total 100% due to rounding.
For included vs. excluded.
Tests for any difference in included vs. excluded among multiple categories.
Measured at examinations 1–4 only.
Characteristics other than medication status associated with RVD are summarized in Table 2. Mean CRAE was narrower in the presence of increased age, greater body mass index, more education, and higher systolic and diastolic blood pressures. Mean CRAE was wider in the presence of a history of CVD, current smoking, emphysema, diabetes, poor focus of the fundus photo, and more hyperopic refractive error. The mean CRVE was narrower in the presence of increased age, more education, and higher systolic blood pressure. Mean CRVE was wider in the presence of greater height, male sex, history of CVD, current smoking, heavy drinking, diabetes, poorer focus of the fundus photo, and more hyperopic refraction.
Table 2.
Mean Retinal Vessel Diameters by Participant Characteristics Over All Person-visits.
| Central Retinal Arteriolar Equivalent | Central Retinal Venular Equivalent | |||||
|---|---|---|---|---|---|---|
| Participant Characteristics | Mean (SD) | Type 3 P valuea |
P value for trend |
Mean (SD) | Type 3 P valuea |
P value for trend |
| Age, y | ||||||
| < 65 | 149.8 (14.6) | <.001 | <.001 | 228.0 (22.6) | <.001 | <.001 |
| 65–69 | 148.1 (14.3) | 225.1 (22.9) | ||||
| 70–74 | 148.3 (14.4) | 224.2 (22.9) | ||||
| 75–79 | 147.8 (14.7) | 223.0 (23.4) | ||||
| 80–84 | 147.6 (14.8) | 219.6 (23.1) | ||||
| ≥ 85 | 146.5 (14.0) | 216.9 (20.8) | ||||
| Height, in | ||||||
| <60 | 148.6 (15.1) | 0.62 | 0.96 | 223.1 (24.6) | <.001 | <.001 |
| 60–63 | 149.0 (14.6) | 222.8 (22.7) | ||||
| 63–66 | 149.0 (14.5) | 225.0 (22.9) | ||||
| 66–69 | 149.2 (14.3) | 227.6 (22.5) | ||||
| 69–72 | 148.1 (15.0) | 228.3 (23.1) | ||||
| ≥ 72 | 148.1 (14.1) | 225.9 (22.1) | ||||
| Sex | ||||||
| Women | 149.1 (14.6) | 0.07 | 0.07 | 223.0 (22.9) | <.001 | <.001 |
| Men | 148.5 (14.4) | 228.8 (22.6) | ||||
| History of CVD present | ||||||
| No | 148.7 (14.6) | 0.04 | 0.04 | 225.2 (22.8) | <.001 | <.001 |
| Yes | 149.8 (14.4) | 227.5 (24.0) | ||||
| Body mass index, kg/m2 | ||||||
| <25 | 150.5 (14.5) | <.001 | <.001 | 223.8 (22.9) | 0.64 | 0.83 |
| 25–29.9 | 148.8 (14.6) | 225.4 (22.6) | ||||
| 30–39.9 | 148.2 (14.5) | 226.7 (23.1) | ||||
| ≥ 40 | 148.0 (14.8) | 225.8 (24.1) | ||||
| Education, y | ||||||
| < 12 | 150.5 (14.4) | <.001 | <.001 | 229.5 (24.2) | <.001 | <.001 |
| 12 | 149.1 (14.8) | 225.6 (22.7) | ||||
| 13–15 | 148.3 (14.2) | 224.3 (22.4) | ||||
| ≥ 16 | 146.6 (14.2) | 221.7 (21.8) | ||||
| Smoking status | ||||||
| Never | 147.2 (14.1) | <.001 | <.001 | 220.2 (21.7) | <.001 | <.001 |
| Past | 148.3 (14.4) | 226.4 (21.6) | ||||
| Current | 155.4 (14.7) | 240.4 (23.7) | ||||
| History of heavy drinking | ||||||
| No | 148.9 (14.5) | 0.97 | 0.97 | 224.6 (22.8) | <.001 | <.001 |
| Yes | 148.7 (15.1) | 230.9 (23.1) | . | . | ||
| Systolic BP, mmHg | ||||||
| <140 | 150.3 (14.4) | <.001 | <.001 | 226.0 (22.8) | <.001 | <.001 |
| 140–159 | 145.8 (14.1) | . | . | 225.3 (23.3) | . | . |
| ≥ 160 | 143.8 (15.0) | . | . | 222.7 (23.8) | . | . |
| Diastolic BP, mmHg | ||||||
| < 90 | 149.4 (14.5) | <.001 | <.001 | 225.5 (23.0) | 0.45 | 0.25 |
| 90–94 | 144.9 (14.2) | 226.1 (22.5) | ||||
| ≥ 95 | 141.4 (13.6) | 226.9 (23.1) | ||||
| History of emphysema | ||||||
| No | 148.7 (14.5) | 0.01 | 0.01 | 225.3 (22.8) | 0.36 | 0.36 |
| Yes | 152.7 (14.8) | 234.4 (25.3) | ||||
| Diabetes present | ||||||
| No | 148.7 (14.5) | 0.03 | 0.01 | 225.5 (22.8) | <.001 | <.001 |
| Suspect | 150.1 (14.0) | 225.9 (22.6) | ||||
| Yes | 150.0 (14.8) | 226.1 (24.6) | ||||
| eGFR < 60 mL/min/1.73 m2 b | ||||||
| No | 149.3 (14.5) | 0.04 | 0.04 | 227.1 (22.9) | <.001 | <.001 |
| Yes | 147.9 (15.0) | 223.0 (22.8) | ||||
| Photo focus quality | ||||||
| Good | 148.1 (14.3) | <.001 | <.001 | 224.4 (22.5) | <.001 | <.001 |
| Fair | 149.9 (14.6) | 227.8 (23.4) | ||||
| Poor | 152.2 (16.4) | 228.4 (24.7) | ||||
| Refraction | ||||||
| Myopic | 144.5 (15.3) | <.001 | <.001 | 217.4 (22.5) | <.001 | <.001 |
| Emmetropic | 149.1 (13.9) | 225.9 (21.6) | ||||
| Hyperopic | 151.1 (13.9) | 230.0 (22.6) | ||||
BP, blood pressure; CVD, cardiovascular disease; SD, standard deviation.
Tests for any difference among multiple categories.
Measured at examinations 1–4 only.
Medication use varied by study visit (Table 3). Vasodilators were being taken at 624 person-visits. Medications that are hypothesized to have vasodilating effects, other than those so classified by the AHFS, were relatively commonly used at some visits (e.g., anti-hypertensives, diuretics, NSAIDs, prostaglandin analogues). Within medication categories the patterns of use of medications vary over time, which is attributable in part to the availability of some (usually newer) medications.
Table 3.
Medication Use by Study Visit and Over All Person-visits.
| N (%) Using Medication | ||||||
|---|---|---|---|---|---|---|
| Medication | Exam 1 (1988–1990) N=3992 |
Exam 2 (1993–1995) N=3045 |
Exam 3 (1998–2000) N=2141 |
Exam 4 (2003–2005) N=1682 |
Exam 5 (2008–2010) N=1118 |
Total Person-Visits N=11978 |
| Vasodilator | 258 (6.5) | 135 (4.4) | 109 (5.1) | 72 (4.1) | 50 (4.5) | 624 (5.2) |
| Isosorbide | 31 (0.8) | 36 (1.2) | 37 (1.7) | 18 (1.1) | 15 (1.3) | 137 (1.1) |
| Oral nitroglycerin | 104 (2.6) | 58 (1.9) | 56 (2.6) | 24 (1.4) | 17 (1.5) | 259 (2.2) |
| Topical nitroglycerin | 37 (0.9) | 32 (1.1) | 24 (1.1) | 20 (1.2) | 9 (0.8) | 122 (1.0) |
| Prostaglandin analogue | 1 (0.0) | 4 (0.1) | 41 (1.9) | 75 (4.5) | 44 (3.9) | 165 (1.4) |
| Any NSAID | 1291 (32.3) | 1796 (59.0) | 1524 (71.2) | 1289 (76.6) | 867 (77.6) | 6767 (56.5) |
| Aspirin | 920 (23.1) | 1212 (40.0) | 1131 (52.8) | 990 (58.9) | 711 (63.6) | 4964 (41.4) |
| Non-aspirin | 489 (12.3) | 809 (26.6) | 686 (32.0) | 631 (37.5) | 405 (36.2) | 3020 (25.2) |
| Cyclooxygenase 2 | 0 (0.0) | 0 (0.0) | 24 (1.1) | 112 (6.7) | 23 (2.1) | 159 (1.3) |
| Any BP medication | 1427 (35.8) | 1232 (40.5) | 1091 (51.0) | 1033 (61.4) | 772 (69.1) | 5555 (46.4) |
| Calcium channel blocker | 173 (4.3) | 348 (11.4) | 315 (14.7) | 267 (15.9) | 201 (18.0) | 1304 (10.9) |
| ACE inhibitor | 257 (6.4) | 359 (11.8) | 375 (17.5) | 436 (25.9) | 346 (31.0) | 1773 (14.) |
| ARB | 0 (0.0) | 0 (0.0) | 48 (2.2) | 105 (6.2) | 97 (8.7) | 250 (2.1) |
| ACE inhibitor or ARB | 257 (6.4) | 359 (11.8) | 423 (19.8) | 538 (32.0) | 441 (39.5) | 2018 (16.9) |
| Any beta blocker | 454 (11.4) | 344 (11.3) | 390 (18.2) | 448 (26.6) | 367 (32.8) | 2003 (16.7) |
| Beta blocker-eye | 51 (1.3) | 46 (1.5) | 41 (2.0) | 23 (1.4) | 19 (1.7) | 180 (1.5) |
| Beta blocker-oral | 408 (10.2) | 303 (10.0) | 352 (16.4) | 430 (25.6) | 353 (31.6) | 1846 (15.4) |
| Any diuretic | 998 (25.0) | 631 (20.7) | 500 (23.4) | 529 (31.5) | 410 (36.7) | 3068 (25.6) |
| Loop diuretic | 169 (4.2) | 142 (4.7) | 128 (6.0) | 114 (6.8) | 96 (8.6) | 649 (5.4) |
| Potassium sparing diuretic | 361 (9.0) | 210 (6.9) | 135 (6.3) | 123 (7.3) | 77 (6.9) | 906 (7.6) |
| Thiazide diuretic | 780 (19.5) | 456 (15.0) | 365 (17.1) | 404 (24.0) | 315 (28.2) | 2320 (19.4) |
| Any steroid | 202 (5.1) | 204 (6.7) | 337 (15.7) | 228 (13.6) | 162 (14.5) | 1133 (9.5) |
| Steroid-oral | 73 (1.8) | 61 (2.0) | 153 (7.2) | 64 (3.8) | 39 (3.5) | 390 (3.3) |
| Steroid-nasal | 64 (1.6) | 77 (2.5) | 127 (6.0) | 88 (5.2) | 51 (4.6) | 407 (3.4) |
| Steroid-topical | 29 (0.7) | 38 (1.3) | 33 (1.5) | 22 (1.3) | 24 (2.2) | 146 (1.2) |
| Steroid-inhaled | 36 (0.9) | 56 (1.8) | 67 (3.1) | 93 (5.5) | 66 (5.9) | 318 (2.7) |
| Steroid-eye | 26 (0.7) | 14 (0.5) | 15 (0.7) | 7 (0.4) | 11 (1.0) | 73 (0.6) |
| Herbal vasodilator | 8 (0.2) | 20 (0.7) | 129 (6.0) | 40 (2.4) | 20 (1.8) | 217 (1.8) |
| Garlic supplement | 43 (1.1) | 92 (3.0) | 151 (7.1) | 105 (6.2) | 45 (4.0) | 436 (3.6) |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; NSAID, nonsteroidal anti-inflammatory drug.
Unadjusted mean RVDs by medication use, the effects of medication use on concurrent RVDs in the minimally and maximally adjusted models, and results of Bonferroni correction are presented in Tables 4 and 5 for CRAE and CRVE, respectively. Use of prostaglandin analogues was associated with CRAE in the minimally and maximally adjusted models; however, after correction for multiple comparisons, the use of prostaglandin analogues was only marginally associated with CRAE (β=−2.04, corrected P=0.09). There was a significant interaction between the use of any blood pressure medication and examination phase and between the use of calcium channel blockers and examination phase. For each of these medications, taking the medication was associated with increased CRAE at each examination phase and the impact of taking the medication was stronger at later examination phases. Therefore, the adjusted main effects of taking any blood pressure medication and calcium channel blockers are presented in the tables. After correction for multiple comparisons, the effect of use of any blood pressure medications (β=0.73, P=0.04), specifically calcium channel blockers, was associated with wider CRAE (β=1.52, P<0.001).
Table 4.
Unadjusted Mean CRAE by Medication Use and Effect Thereof on CRAE in the Minimally and Maximally Adjusted Models with and without Bonferroni Correction.
| Unadjusted | Minimally Adjusted Modela | Maximally Adjusted Modelb | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean | P value | Mean | P value | ||||||||
| Medication | Not Using Med. |
Using Med. | Not Using Med. |
Using Med. |
β Estimate (95% CI) |
Orig | Adj | Not Using Med. |
Using Med. |
β Estimate (95% CI) |
Orig | Adj |
| Vasodilatorc | 148.8 (14.5) | 150.3 (14.8) | 149.9 | 151.0 | 1.10 (0.17,2.03) | 0.02 | 0.18 | 151.9 | 152.8 | 0.88 (−0.05,1.80) | 0.06 | 0.54 |
| Isosorbided | 148.8 (14.6) | 152.0 (13.9) | 149.9 | 151.4 | 1.51 (−0.36,3.39) | 0.11 | >0.99 | 152.0 | 153.3 | 1.31 (−0.56,3.17) | 0.17 | >0.99 |
| Oral nitroglycerind | 148.8 (14.5) | 152.5 (14.9) | 149.9 | 151.6 | 1.65 (0.28,3.01) | 0.02 | 0.53 | 151.9 | 153.2 | 1.31 (−0.06,2.67) | 0.06 | >0.99 |
| Topical nitroglycerind | 148.8 (14.6) | 152.5 (15.3) | 149.9 | 151.8 | 1.87 (0.01,3.74) | 0.05 | >0.99 | 152.0 | 153.6 | 1.62 (−0.24,3.48) | 0.09 | >0.99 |
| Prostaglandin analoguec | 148.9 (14.6) | 144.9 (14.2) | 150.0 | 148.0 | −1.99 (−3.52,−0.45) | 0.01 | 0.10 | 152.1 | 150.0 | −2.04 (−3.56,−0.51) | 0.01 | 0.09 |
| Any NSAIDc | 149.6 (14.6) | 148.3 (14.5) | 150.2 | 149.8 | −0.35 (−0.74,0.05) | 0.08 | >0.99 | 152.2 | 151.9 | −0.31 (−0.71,0.08) | 0.12 | >0.99 |
| Aspirind | 149.2 (14.6) | 148.3 (14.5) | 150.0 | 149.9 | −0.05 (−0.44,0.35) | 0.82 | >0.99 | 152.0 | 152.0 | −0.04 (−0.43,0.35) | 0.84 | >0.99 |
| Non-aspirind | 149.1 (14.6) | 148.1 (14.5) | 150.1 | 149.6 | −0.57 (−1.00,−0.14) | 0.01 | 0.27 | 152.2 | 151.6 | −0.52 (−0.94,−0.09) | 0.02 | 0.58 |
| Cyclooxygenase 2d | 148.9 (14.6) | 146.8 (14.0) | 150.0 | 149.8 | −0.12 (−1.52,1.29) | 0.87 | >0.99 | 152.0 | 152.0 | −0.02 (−1.42,1.38) | 0.97 | >0.99 |
| Any BP medicationc e | 149.9 (14.5) | 147.7 (14.6) | 149.4 | 150.2 | 0.78 (0.28,1.27) | 0.002 | 0.02 | 151.5 | 152.2 | 0.73 (0.24,1.23) | 0.004 | 0.04 |
| Calcium channel blockerd e | 148.9 (14.6) | 148.3 (14.1) | 149.7 | 151.3 | 1.54 (0.88,2.21) | <.001 | <.001 | 151.8 | 153.3 | 1.52 (0.86,2.18) | <.001 | <.001 |
| ACE inhibitord | 149.2 (14.5) | 146.9 (14.6) | 149.9 | 150.3 | 0.40 (−0.17,0.97) | 0.17 | >0.99 | 151.9 | 152.2 | 0.28 (−0.29,0.85) | 0.33 | >0.99 |
| ARBd | 148.9 (14.6) | 148.5 (14.7) | 149.9 | 150.9 | 1.03 (−0.20,2.26) | 0.10 | >0.99 | 152.0 | 152.9 | 0.90 (−0.33,2.13) | 0.15 | >0.99 |
| ACE or ARBd | 149.2 (14.5) | 147.0 (14.6) | 149.8 | 150.4 | 0.52 (−0.03,1.07) | 0.06 | >0.99 | 151.9 | 152.3 | 0.39 (−0.16,0.95) | 0.17 | >0.99 |
| Any beta blockerc | 149.0 (14.5) | 147.9 (14.6) | 149.8 | 150.4 | 0.54 (−0.02,1.10) | 0.06 | 0.54 | 151.9 | 152.4 | 0.51 (−0.05,1.06) | 0.07 | 0.63 |
| Beta blocker-eyed | 148.9 (14.5) | 145.7 (16.7) | 150.0 | 148.9 | −1.03 (−2.74,0.68) | 0.24 | >0.99 | 152.0 | 150.9 | −1.10 (−2.80,0.60) | 0.20 | >0.99 |
| Beta blocker-orald | 149.0 (14.6) | 148.1 (14.4) | 149.8 | 150.5 | 0.67 (0.09,1.24) | 0.02 | 0.70 | 151.9 | 152.5 | 0.64 (0.06,1.21) | 0.03 | 0.87 |
| Any diureticc | 149.3 (14.5) | 147.6 (14.6) | 149.9 | 150.0 | 0.03 (−0.47,0.53) | 0.90 | >0.99 | 152.0 | 152.0 | 0.04 (−0.46,0.54) | 0.87 | >0.99 |
| Loop diureticd | 148.8 (14.6) | 149.0 (14.6) | 149.9 | 150.4 | 0.51 (−0.39,1.40) | 0.27 | >0.99 | 152.0 | 152.4 | 0.38 (−0.51,1.28) | 0.40 | >0.99 |
| Potassium sparing diureticd | 149.0 (14.6) | 147.2 (14.6) | 150.0 | 149.4 | −0.65 (−1.43,0.14) | 0.11 | >0.99 | 152.1 | 151.5 | −0.55 (−1.33,0.23) | 0.17 | >0.99 |
| Thiazide diureticd | 149.2 (14.5) | 147.3 (14.7) | 150.0 | 150.0 | 0.02 (−0.51,0.54) | 0.95 | >0.99 | 152.0 | 152.1 | 0.07 (−0.45,0.59) | 0.79 | >0.99 |
| Any steroidc | 148.9 (14.6) | 148.8 (14.5) | 150.0 | 150.0 | −0.05 (−0.68,0.59) | 0.89 | >0.99 | 152.0 | 152.1 | 0.10 (−0.54,0.74) | 0.77 | >0.99 |
| Steroid-orald | 148.8 (14.6) | 149.9 (14.2) | 150.0 | 150.5 | 0.61 (−0.39,1.60) | 0.23 | >0.99 | 152.0 | 152.7 | 0.71 (−0.28,1.70) | 0.16 | >0.99 |
| Steroid-nasald | 148.9 (14.6) | 147.5 (14.4) | 150.0 | 149.1 | −0.93 (−1.97,0.12) | 0.08 | >0.99 | 152.1 | 151.3 | −0.78 (−1.82,0.26) | 0.14 | >0.99 |
| Steroid-topicald | 148.9 (14.6) | 147.4 (14.1) | 150.0 | 148.9 | −1.03 (−2.57,0.52) | 0.19 | >0.99 | 152.0 | 151.0 | −0.99 (−2.53,0.55) | 0.21 | >0.99 |
| Steroid-inhaledd | 148.8 (14.6) | 148.9 (15.0) | 150.0 | 149.4 | −0.54 (−1.79,0.72) | 0.40 | >0.99 | 152.0 | 151.7 | −0.33 (−1.60,0.95) | 0.61 | >0.99 |
| Steroid-eyed | 148.9 (14.6) | 148.3 (13.6) | 150.0 | 149.7 | −0.26 (−2.50,1.98) | 0.82 | >0.99 | 152.0 | 151.8 | −0.21 (−2.44,2.02) | 0.85 | >0.99 |
| Herbal vasodilatorc | 148.9 (14.6) | 147.6 (14.2) | 150.0 | 149.4 | −0.61 (−1.86,0.65) | 0.34 | >0.99 | 152.0 | 151.5 | −0.55 (−1.79,0.70) | 0.39 | >0.99 |
| Garlic supplementc | 148.9 (14.6) | 146.5 (13.8) | 150.0 | 149.4 | −0.62 (−1.59,0.35) | 0.21 | >0.99 | 152.0 | 151.4 | −0.64 (−1.60,0.33) | 0.19 | >0.99 |
ACE, angiotensin-converting enzyme; Adj, adjusted; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; CRAE, central retinal arterial equivalent; Med., medication; NSAID, nonsteroidal anti-inflammatory drug; Orig, original; SD, standard deviation.
A participant must have had complete data for CRAE and CRVE measures, medication use, and been free from cataract surgery to be included in analyses at a given examination. In addition, they must have had data for refraction, focus quality, education, height, systolic BP, smoking history, diabetes (glycosylated hemoglobin), emphysema and history of heavy drinking.
Minimally adjusted model adjusts for refraction, focus quality, age, systolic BP, and height and examination phase.
Maximally adjusted model adjusts for refraction, focus quality, age, systolic BP, height, education, smoking, emphysema, ever heavy drinking, diabetes and examination phase.
Bonferroni adjustment made for 9 comparisons.
Bonferroni adjustment made for 29 comparisons.
Interacts with visit (examination phase); estimates for main effect are shown.
Table 5.
Unadjusted Mean CRVE (µm) by Medication Use and Effect Thereof on CRVE in the Minimally and Maximally Adjusted Models with and without Bonferroni Correction.
| Unadjusted | Minimally Adjusted Modela | Maximally Adjusted Modelb | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean | P value | Mean | P value | ||||||||
| Medication | Not Using Med. |
Using Med. | Not Using Med. |
Using Med. |
β Estimate (95% CI) |
Orig | Adj | Not Using Med. |
Using Med. |
β Estimate (95% CI) |
Orig | Adj |
| Vasodilatorc | 225.5 (22.8) | 226.8 (25.3) | 225.9 | 226.0 | 0.14 (−1.18,1.46) | 0.83 | >0.99 | 229.0 | 229.0 | 0.04 (−1.27,1.36) | 0.95 | >0.99 |
| Isosorbided | 225.6 (22.9) | 226.1 (24.4) | 225.9 | 227.6 | 1.72 (−0.92,4.36) | 0.20 | >0.99 | 229.0 | 230.4 | 1.46 (−1.17,4.09) | 0.28 | >0.99 |
| Oral nitroglycerind | 225.5 (22.9) | 229.1 (25.1) | 225.9 | 225.1 | −0.81 (−2.74,1.12) | 0.41 | >0.99 | 229.1 | 227.9 | −1.14 (−3.06,0.79) | 0.25 | >0.99 |
| Topical nitroglycerind | 225.5 (22.9) | 230.9 (25.1) | 225.9 | 228.0 | 2.15 (−0.47,4.76) | 0.11 | >0.99 | 228.9 | 231.3 | 2.33 (−0.27,4.94) | 0.08 | >0.99 |
| Prostaglandin analoguec | 225.7 (22.9) | 214.8 (22.7) | 225.9 | 223.7 | −2.27 (−4.39,−0.14) | 0.04 | 0.33 | 229.1 | 226.7 | −2.34 (−4.46,−0.22) | 0.03 | 0.28 |
| Any NSAIDc | 227.1 (22.8) | 224.5 (23.0) | 225.8 | 225.9 | 0.15 (−0.40,0.7) | 0.60 | >0.99 | 228.9 | 229.1 | 0.19 (−0.35,0.74) | 0.49 | >0.99 |
| Aspirind | 226.2 (22.8) | 224.7 (23.1) | 225.6 | 226.2 | 0.66 (0.12,1.21) | 0.02 | 0.51 | 228.7 | 229.4 | 0.70 (0.16,1.25) | 0.01 | 0.34 |
| Non-aspirind | 226.4 (22.9) | 223.2 (23.1) | 226.1 | 225.4 | −0.62 (−1.22,−0.03) | 0.04 | >0.99 | 229.2 | 228.6 | −0.58 (−1.17,0.01) | 0.05 | >0.99 |
| COX 2d | 225.7 (22.9) | 216.1 (22.8) | 225.9 | 225.4 | −0.53 (−2.46,1.39) | 0.59 | >0.99 | 229.0 | 228.4 | −0.61 (−2.53,1.31) | 0.53 | >0.99 |
| Any BP medicationc | 226.8 (22.5) | 224.2 (23.4) | 226.0 | 225.8 | −0.17 (−0.84,0.5) | 0.61 | >0.99 | 229.0 | 229.0 | 0.05 (−0.61,0.72) | 0.87 | >0.99 |
| Calcium channel blockerd | 225.7 (22.9) | 224.3 (23.7) | 225.9 | 225.7 | −0.18 (−1.07,0.72) | 0.69 | >0.99 | 229.0 | 228.9 | −0.12 (−1.01,0.77) | 0.80 | >0.99 |
| ACE inhibitord | 226.0 (22.9) | 223.3 (22.9) | 225.9 | 225.8 | −0.07 (−0.87,0.73) | 0.86 | >0.99 | 229.0 | 229.0 | 0.02 (−0.78,0.82) | >0.99 | >0.99 |
| ARBd | 225.7 (23.0) | 220.9 (22.4) | 225.9 | 225.4 | −0.53 (−2.23,1.17) | 0.54 | >0.99 | 229.0 | 228.5 | −0.49 (−2.19,1.22) | 0.58 | >0.99 |
| ACE or ARBd | 226.1 (22.9) | 223.0 (22.9) | 225.9 | 225.7 | −0.19 (−0.97,0.58) | 0.63 | >0.99 | 229.0 | 228.9 | −0.09 (−0.87,0.69) | 0.82 | >0.99 |
| Any beta blockerc | 226.2 (22.7) | 222.7 (23.9) | 226.1 | 225.0 | −1.07 (−1.86,−0.28) | 0.01 | 0.07 | 229.2 | 228.2 | −1.02 (−1.81,−0.24) | 0.01 | 0.10 |
| Beta blocker-eyed | 225.7 (22.9) | 218.9 (25.5) | 225.9 | 224.9 | −0.97 (−3.39,1.45) | 0.43 | >0.99 | 229.0 | 227.8 | −1.22 (−3.63,1.18) | 0.32 | >0.99 |
| Beta blocker-orald | 226.1 (22.8) | 223.1 (23.8) | 226.1 | 225.1 | −1.03 (−1.85,−0.22) | 0.01 | 0.38 | 229.2 | 228.2 | −0.95 (−1.76,−0.14) | 0.02 | 0.63 |
| Any diureticc | 226.0 (22.7) | 224.5 (23.6) | 225.7 | 226.3 | 0.56 (−0.15,1.27) | 0.12 | >0.99 | 228.8 | 229.5 | 0.78 (0.08,1.49) | 0.03 | 0.27 |
| Loop diureticd | 225.6 (22.8) | 225.0 (25.1) | 225.9 | 225.7 | −0.20 (−1.46,1.07) | 0.76 | >0.99 | 229.0 | 229.1 | 0.06 (−1.21,1.32) | 0.93 | >0.99 |
| Potassium sparing diureticd | 225.7 (23.0) | 224.2 (22.2) | 225.9 | 226.0 | 0.08 (−1.03,1.18) | 0.89 | >0.99 | 229.0 | 229.3 | 0.34 (−0.76,1.44) | 0.54 | >0.99 |
| Thiazide diureticd | 225.9 (22.9) | 224.2 (23.3) | 225.8 | 226.3 | 0.50 (−0.24,1.24) | 0.19 | >0.99 | 228.9 | 229.5 | 0.66 (−0.08,1.39) | 0.08 | >0.99 |
| Any steroidc | 225.6 (22.9) | 225.1 (23.4) | 225.9 | 225.9 | 0.03 (−0.86,0.91) | 0.95 | >0.99 | 228.9 | 229.3 | 0.33 (−0.56,1.22) | 0.46 | >0.99 |
| Steroid-oralc | 225.5 (22.9) | 227.0 (23.6) | 225.8 | 227.8 | 1.95 (0.57,3.33) | 0.01 | 0.16 | 228.9 | 231.0 | 2.13 (0.76,3.51) | 0.002 | 0.07 |
| Steroid-nasalc | 225.7 (23.0) | 223.3 (21.5) | 225.9 | 225.0 | −0.95 (−2.39,0.50) | 0.20 | >0.99 | 229.0 | 228.3 | −0.70 (−2.14,0.74) | 0.34 | >0.99 |
| Steroid-topicalc | 225.6 (23.0) | 225.3 (23.5) | 225.9 | 224.4 | −1.48 (−3.62,0.65) | 0.17 | >0.99 | 229.0 | 227.5 | −1.52 (−3.64,0.61) | 0.16 | >0.99 |
| Steroid-inhaledc | 225.6 (22.9) | 224.3 (24.3) | 225.9 | 225.1 | −0.83 (−2.59,0.93) | 0.36 | >0.99 | 229.0 | 228.8 | −0.27 (−2.06,1.52) | 0.77 | >0.99 |
| Steroid-eyec | 225.6 (23.0) | 226.9 (24.8) | 225.9 | 226.6 | 0.71 (−2.40,3.82) | 0.65 | >0.99 | 229.0 | 229.9 | 0.92 (−2.18,4.02) | 0.56 | >0.99 |
| Herbal vasodilatord | 225.6 (23.0) | 222.6 (20.4) | 225.9 | 226.1 | 0.26 (−1.46,1.97) | 0.77 | >0.99 | 229.0 | 229.3 | 0.34 (−1.38,2.05) | 0.70 | >0.99 |
| Garlic supplementd | 225.7 (23.0) | 222.3 (22.0) | 225.9 | 226.0 | 0.09 (−1.25,1.43) | 0.90 | >0.99 | 229.0 | 229.0 | 0.03 (−1.31,1.37) | 0.96 | >0.99 |
ACE, angiotensin-converting enzyme; Adj, adjusted; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; CRVE, central retinal venular equivalent; Med., medication; NSAID, nonsteroidal anti-inflammatory drug; Orig, original; SD, standard deviation.
To be included in analyses at a given examination, a participant must have complete information for CRAE and CRVE measures, medication use, and be free from cataract surgery. In addition, they must have information for refraction, focus quality, education, height, systolic BP, smoking history, diabetes (glycosylated hemoglobin), emphysema and history of heavy drinking.
Minimally adjusted model adjusts for refraction, focus quality, age, systolic BP and height and examination phase.
Maximally adjusted model adjusts for refraction, focus quality, age, systolic BP, height, education, smoking, emphysema, ever heavy drinking, diabetes and examination phase.
Bonferroni adjustment made for 9 comparisons.
Bonferroni adjustment made for 29 comparisons.
For CRVE, beta blockers (β=−1.02, P=0.01) were associated with CRVE in the minimally and maximally adjusted models, but were only marginally associated (β=−1.02, corrected P=0.10) after correction for multiple comparisons. Use of oral steroids, while relatively uncommon, was marginally associated with CRVE after Bonferroni correction (β=2.13, corrected P=0.07).
Stratified analyses were performed to examine confounding by presumed indication. The effect of vasodilators (P=0.82), oral nitroglycerin (P=0.25), blood pressure medications (P=0.22), calcium channel blockers (P=0.34), and oral beta blockers (P=0.10) on CRAE were not found to be significantly different between those with and without self-reported cardiovascular disease. The effects of beta blockers (P=0.20), oral beta blockers (P=0.06) and diuretics (P=0.60) on CRVE were also not significantly different in persons with and without self-reported cardiovascular disease. The effect of oral steroids on CRVE was not significantly different between persons with and without diabetes (P=0.95) or between those with and without emphysema (P=0.86).
A subset of analyses was performed to examine the effect of renal function, captured by eGFR≥60 vs. <60 mL/min/1.73 m2, on the relationships between medications and RVDs in the maximally adjusted model. The addition of this variable did not significantly alter the effects of medications on RVDs as compared to the results of analyses for the full population (data not shown).
COMMENT
This analysis of associations between medications and RVDs in multivariable adjusted models over 20 years in a population-based study showed several significant (P<0.05) and marginally significant (P<0.10) associations following Bonferroni correction for multiple comparisons.
Calcium channel blockers appear to have relatively large associations with increased CRAE and should be considered when examining effects of other exposures on CRAE. These medications are widely used, especially in older adults, and therefore may be more important on a population basis. A possible mechanism for the widening effect of calcium channel blockers on CRAE is their reported relaxation effect on the microcirculation.26,27
The changing effect of any blood pressure medication, specifically calcium channel blockers, over the 20-year period of follow-up may be due, in part, to the evolving definition of clinical hypertension. Lower systolic and diastolic blood pressures have been shown to be significantly associated with having wider CRAE, and as persons are currently prescribed anti-hypertensive medication at lower and lower blood pressure measures than in the past,28–30 the association of the medication appears to become stronger (wider CRAE) over the course of the examination.
The relationship of prostaglandin analogues to CRAE is in the opposite direction from these medications, although the significant relationship was attenuated when adjusting for multiple comparisons. This class of medications is relatively widely used in persons with suspected and confirmed glaucoma to reduce intraocular pressure. It should be noted that this association was found after adjustment for age and blood pressure. A researcher might attribute smaller CRAE solely to blood pressure and/or age when part of the effect may actually be due to use of this category of medications.
Use of oral steroids was marginally associated with wider CRVE in models that included other characteristics found to be associated with wider CRVE, such as diabetes and smoking. Although relatively few persons were taking these medications, the effect was relatively large and suggests the need to stratify by such usage in analyses that are aimed at CRVE as an outcome. The opposite effects were found for those using beta blockers. These exposures should be considered in studies examining RVDs.
The associations of retinal vessel diameters with phosphodiesterase 5 inhibitors are not addressed in the primary analyses in this paper because there were few users in this older population (N=25). These medications were associated with wider retinal arterioles (β=3.39, P=0.05) and were suggestive of an association with retinal venules (β=3.88, P=0.11) in the maximally adjusted models, not adjusting for multiple comparisons. These medications may have strong vasodilating effects and this should be pursued in populations in which their usage is more widespread than has been in Beaver Dam during the intervals under study.
There are many limitations to our investigation. First, we limited our study to those medications for which a vasodilating effect had been reported in the literature and to medications and supplements for which such effects were hypothesized. Thus, we may have excluded other medications that may be associated with retinal vessel diameters. To the extent that participants failed to report medication use, our analyses may be underestimating usage and the effects of unreported medications on the retinal vessel diameters. However, under-reporting of the medications included in this analysis was minimized, as the examination contained questions specifically regarding use of glaucoma drops, products containing aspirin, and antihypertensive and diuretic agents. Second, we examined the associations between RVD and given classes of medications rather than analyzing the effects of specific medications within a class (e.g., beta blockers such as propranolol and carvedilol may have different effects on retinal vessel diameters). Third, we examined relationships of each class of medication independently of other medications which may be taken in combination by the same individual. To the extent that there are synergistic or antagonistic effects on the outcome, we may be under- or overestimating associations of any given class of medications/supplements. Fourth, the dose, frequency, and history of medication use were not recorded. For participants who reported use of eye drops, the eye in which medication was used was not recorded. To this end, we cannot evaluate time trends or dose response from our data. Also, the effect of eye-specific medications may be over- or underestimated.
The Bonferroni corrections made for multiple comparisons are somewhat conservative and may have underestimated the relationships between some medications and RVDs. This may lead to discarding observed findings that may be meaningful;31 thus, we give both P-values so that interested readers might evaluate the results of our analyses from the observed data. In addition, our investigation is an observational, prospective one. As such, we report the temporal finding of exposures to an endpoint. While an association in this context may be causal, we cannot be certain of it. Confirmation of these findings needs corroboration or replication and, if possible, further support from bench research to be more certain of causality. Finally, our analysis has excluded persons with cataract severe enough to affect the ability to obtain and/or grade the retinal photographs, as well as persons who have undergone cataract surgery.
In summary, the role of RVDs as risk factors or as important confounders of the relationships of other exposures to disease is still uncertain. If the associations of specific medications to RVDs are confirmed, then consideration of effect and possible adjustment for such use will be important in evaluating the relationship of the vessel diameters to the medical conditions in question.
ACKNOWLEDGEMENT
This research was supported by the National Institutes of Health grant EY06594 (R Klein, BEK Klein), the Retina Research Foundation, Houston, TX, and an unrestricted grant from Research to Prevent Blindness, New York, NY. The organizations that provided funding were in no way involved in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Footnotes
DATA ACCESS STATEMENT
Ms. Howard had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Eye Institute or the National Institutes of Health.
DISCLOSURE
Dr. B. E. K. Klein has served as a member of a Scientific Advisory Committee to Pfizer in the past.
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