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Regular Aspirin Use May Boost Risk of Eye Problem
 
 
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webmd.com

Dec. 18, 2012 -- Taking aspirin regularly appears to slightly raise the risk of the eye condition known as age-related macular degeneration or AMD, new research suggests.

The increased risk only occurred with people who had taken aspirin regularly 10 years before they were diagnosed with the potentially blinding eye disease. They had taken aspirin at least twice a week for more than three months, says researcher Barbara E.K. Klein, MD, MPH.

The risk was for the type of macular degeneration known as wet or neovascular AMD, says Klein, professor of ophthalmology and visual sciences at the University of Wisconsin School of Medicine, Madison.

Wet macular degeneration is generally more severe than another version, known as dry macular degeneration.

Although people taking aspirin regularly were two times more likely to get the condition, Klein says the absolute risk is still low because the condition is not common. About 1% of people aged mid-40s and older get wet macular degeneration, she says.

Klein studied nearly 5,000 men and women, ages 43 and older. She followed them for 20 years, although not all of them stayed in the study that long.

The research is published in the Journal of the American Medical Association.

Aspirin & Eye Problems: Study Details

Previous research findings about aspirin use and macular degeneration risk have been mixed.

As aspirin use and macular degeneration are increasing, Klein decided to follow men and women over many years to see if she could find a link.

Nearly 20% of adults, or 1 in 5, take aspirin regularly. Some use it for temporary relief of pain or fever. Others take it daily to prevent heart attacks.

The macula is a small area of the retina, the tissue lining the back of the eye, that is responsible for central vision.

Klein looked at wet (late) and dry (early) macular degeneration for the study. Both are potentially blinding conditions.

Over the course of the study, 512 people were diagnosed with early AMD and 117 with late AMD.

Although regular use of aspirin 10 years before the diagnosis was linked with late macular degeneration, aspirin use five years before the diagnosis was not linked with an increased risk of either form of AMD.

Klein can't explain the link and says it requires more study. "The absolute risk of this is small," she says. "There are so many folks who have been put on aspirin for [heart disease] prevention. ... The [heart] protective effect is still primo."

One co-author, Ronald Klein, MD, MPH, has served as a consultant for Pfizer, which makes AMD medicine. The study was funded by the National Institutes of Health and support from Research to Prevent Blindness.

Aspirin & Eye Problems: Perspective

"This study is suggestive that there may be a relationship but it is by no means definitive," says George Williams, MD, professor and chair of the department of ophthalmology at Oakland University's William Beaumont School of Medicine in Rochester, Mich.

Williams says a weakness in the study is that the men and women self-reported the aspirin use, so it may not have been totally accurate.

If a cardiologist has recommended aspirin for heart disease protection, Williams says, "I would not take anyone off it."

People who take aspirin regularly should consider their risk of macular degeneration and the benefits of taking aspirin, says Michael Tolentino, MD, medical director of the Macular Degeneration Association and an ophthalmologist in Lakeland, Fla.

People at higher risk for the disease include those with a family history, those with light eyes, and smokers.

"Everything is a risk-benefit ratio," he says.

He reports serving as consultant for Novartis, Genentech, Alarcon, and other companies involved in eye drugs.

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Long-term Use of Aspirin and Age-Related Macular Degeneration - pdf attached

JAMA. Dec 19 2012

Barbara E. K. Klein, MD, MPH; Kerri P. Howard, MS; Ronald E. Gangnon, PhD; Jennifer O. Dreyer, BS; Kristine E. Lee, MS; Ronald Klein, MD, MPH

"Our findings are consistent with a small but statistically significant association between regular aspirin use and incidence of neovascular AMD. Additional replication is required to confirm our observations. If confirmed, defining the causal mechanisms may be important in developing methods to block this effect to prevent or retard the development of neovascular AMD in persons who use aspirin, especially to prevent CVD......Among an adult cohort, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD."

ABSTRACT

Context
Aspirin is widely used for relief of pain and for cardioprotective effects. Its use is of concern to ophthalmologists when ocular surgery is being considered and also in the presence of age-related macular degeneration (AMD).

Objective To examine the association of regular aspirin use with incidence of AMD.

Design, Setting, and Participants The Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin. Examinations were performed every 5 years over a 20-year period (1988-1990 through 2008-2010). Study participants (N = 4926) were aged 43 to 86 years at the baseline examination. At subsequent examinations, participants were asked if they had regularly used aspirin at least twice a week for more than 3 months.

Main Outcome Measure Incidence of early AMD, late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy), assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System.

Results The median duration of follow-up was 14.8 years. There were 512 incident cases of early AMD (of 6243 person-visits at risk) and 117 incident cases of late AMD (of 8621 person-visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.01-2.63]; P = .05), with estimated incidence of 1.76% (95% CI, 1.17%-2.64%) in regular users and 1.03% (95% CI, 0.70%-1.51%) in nonusers. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (HR, 2.20 [95% CI, 1.20-4.15]; P = .01) but not pure geographic atrophy (HR, 0.66 [95% CI, 0.25-1.95]; P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.71-1.05]; P = .13) or 10 years (HR, 0.86 [95% CI, 0.65-1.13]; P = .28) prior to retinal examination was not associated with incident early AMD.

Conclusions Among an adult cohort, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.

Aspirin use in the United States is widespread, with an estimated 19.3% of adults reporting regular consumption, and reported use increases with age.1 Aspirin is used for temporary relief of pain and for arthritic or rheumatologic diseases2 and for its antipyretic effects. It is considered a nonsteroidal anti-inflammatory drug (NSAID), but it also suppresses thromboxanes by inactivation of cyclooxygenase, thus impairing the clot-enhancing action of platelets. This has made it attractive as a medical intervention for acute myocardial infarction; about half of persons who were told that they have heart disease reported taking aspirin every day or every other day.1

The results of cross-sectional studies of aspirin use and its relation to age-related macular degeneration (AMD) have been inconsistent.3- 5 AMD is a potentially blinding condition for which prevalence and incidence are increasing with the increased survival of the population, and regular use of aspirin is common and becoming more widespread in persons in the age range at highest risk for this disease. Therefore, it is imperative to further examine this potential association. The Beaver Dam Eye Study, a longitudinal study of age-related eye diseases, has assessed an adult population (aged 43 to 86 years at baseline) at 5-year intervals over a 20-year period. This study provided the unique opportunity to investigate the link between AMD and aspirin use in a population which, by virtue of its age distribution and low attrition, permitted examination of the associations of aspirin use 5 and 10 years before observed AMD incidence.

COMMENT

In our study, aspirin use 10 years prior was associated with incidence of neovascular AMD. Our exploratory analyses tend to support the findings of our primary analysis. Our hazard ratio estimate for neovascular AMD in participants who reported regular use of aspirin 10 years prior to observed AMD was 2.20 (95% CI, 1.20-4.15) (Table 3). This is based on our modeling of specific potential risk factors in a Midwestern, primarily white population. Although it is possible to estimate an attributable risk, the number of incident cases that our estimate is based on was small and requires corroboration before developing risk algorithms for clinical use.

Adjusting for age, age2, education level, and aspirin use 5 years prior to observed incidence, the adjusted attributable risk of late AMD for aspirin use 10 years prior to observed incidence was 0.77%, with an adjusted attributable risk fraction of 53.2%.16 This is in keeping with the finding of a small but significant cross-sectional association between aspirin use and AMD in the European Eye study and the inference that for a patient, aspirin use for cardioprevention does not imply a great increase in risk of AMD.17- 18 If our finding is borne out in other studies, it suggests that the effect of aspirin on mechanisms leading to AMD may be different, at least partially, from aspirin's immediate effects on clotting, which seem to be responsible for cardioprotection.19 Not all retinal lesions characterizing neovascular AMD involve bleeding that is detectable in photography. Aspirin, aside from its effects on clotting, may enhance choroidal neovascularization.20 Aspirin has been shown to increase vascular density in a laboratory model.21 Thus, it is possible that in the presence of injury, aspirin encourages the growth of aberrant new vessels.

Two studies by Christen and colleagues22- 23 describing the experience in 2 large randomized controlled trials for prevention of CVD, one with 7-year follow-up and the other with 10-year follow-up, found no evidence of a direct association between use of low-dose aspirin and late lesions of AMD. Those studies were performed among health professionals who are likely to be more health conscious than general populations. The number of AMD cases was small in both studies, and the definition and method of classification of the end point differed from the current study and the European Eye Study,17 which both used photographic documentation and systematic grading of lesions as opposed to self-reported AMD with decreased vision confirmed by medical record. Thus, there are likely to be important differences in exposures and outcomes and ascertainment between the studies that may have caused the disparate findings.

Several limitations may have affected our findings. First, there was a lack of detailed information on aspirin exposure at some visits. When the study began, questions on frequency of use and dosage were not initially included but were added into subsequent examinations to accommodate important clinical therapeutic trends in the community, especially the increasing use of aspirin for CVD. Second, leukocyte count was only measured at the baseline and second examinations; therefore, we could not evaluate potential associations for every study interval. Similar limitations apply to CRP measurements, which might have informed our analysis regarding possible effects of systemic inflammation and its potentially modifying effect on the association of AMD with aspirin use. Third, the study population is almost entirely white of European ancestry, so the extent to which our results may generalize to other races/ethnicities, particularly groups at elevated risk for CVD, is unknown.

Our findings are consistent with a small but statistically significant association between regular aspirin use and incidence of neovascular AMD. Additional replication is required to confirm our observations. If confirmed, defining the causal mechanisms may be important in developing methods to block this effect to prevent or retard the development of neovascular AMD in persons who use aspirin, especially to prevent CVD.

RESULTS

Of the 5924 eligible persons, 4926 aged 43 to 86 years (83%) participated in the baseline examination in 1988-1990. Ninety-nine percent of the population was white; 56% were women. The cohort was reexamined at 5-year (n = 3722), 10-year (n = 2962), 15-year (n = 2375), and 20-year (n = 1913) follow-up examinations. There was greater than 80% participation among survivors at each examination.13- 15 The mean duration of follow-up was 14.8 years, with a median duration of 15.9 years.

Participants included in these analyses tended to be younger and have fewer comorbid conditions at baseline than those excluded (Table 1). For incident early AMD, 2547 participants of the 4926 seen at baseline were excluded from analysis (1008 had prevalent early or late AMD at baseline, 84 were missing a covariate, 448 were missing AMD data at baseline, and 1007 did not have data at the first follow-up examination). Overall, there were 2379 participants at risk for early AMD, of which 512 developed incident disease, with a total of 6243 person-visits contributing to the analysis (Figure). For incidence of late AMD, 1794 participants of the 4926 seen at baseline were excluded from analysis (74 had prevalent late AMD at baseline, 104 were missing a covariate, 407 had missing AMD data at baseline, and 1209 had missing data at the first follow-up examination). There were 3132 participants at risk for developing late AMD, of which 117 developed incident disease, with a total of 8621 person-visits included in analyses (Figure). The unadjusted incidence rate per 10 person-years was 0.164 for early AMD and 0.027 for late AMD.

There was no significant association of self-reported aspirin use 5 years prior to observed incidence of early AMD accumulated over 20 years (HR, 0.86 [95% CI, 0.71-1.05]; P = .13; age- and sex-adjusted incidence, 9.6% [95% CI, 8.3%-11.0%] for aspirin users vs 10.5% [95% CI, 9.5%-11.6%] for nonusers) (Table 2). The incidence of late AMD was greater in participants using aspirin 5 years previously than in nonusers (age- and sex-adjusted incidence, 1.4% [95% CI, 1.0%-1.9%] vs 1.0% [95% CI, 0.7%-1.4%], respectively), although the association was not significant (HR, 1.21 [95% CI, 0.84-1.74]; P = .31), and there was no significant association for either late AMD subtype (HR, 1.07 [95% CI, 0.68-1.67]; P = .77 for neovascular AMD and HR, 1.65 [95% CI, 0.91-2.99]; P = .10 for pure geographic atrophy) for those who reported aspirin use 5 years prior (age- and sex-adjusted incidence, 0.8% [95% CI, 0.5%-1.3%] for neovascular AMD and 0.6% [95% CI, 0.4%-1.0%] for pure geographic atrophy) vs those who did not (age- and sex-adjusted incidence, 0.7% [0.5%-1.0%] for neovascular AMD and 0.4% [0.2%-0.6%] for pure geographic atrophy) (Table 2).

Because of the possibility of a lag in effect of first reported regular use of aspirin and AMD, we examined use at both 5 and 10 years prior to observed incidence. These data were combined and modeled as a 4-level nonordinal categorical variable (Table 3). Only incidence analysis over 15 years can be performed because of the lack of information regarding regular aspirin use prior to the baseline examination. The overall test for association was not significant for any category of aspirin use and incident early AMD (P = .43), late AMD (P = .20), neovascular AMD (P = .07), and pure geographic atrophy (P = .20) (Table 3).

We then tested the main effects of aspirin use 5 and 10 years prior to observed incidence in this model. The main effect of aspirin use 5 years prior showed no significant association with incident early AMD (HR, 0.93 [95% CI, 0.70-1.23]; P = .60; age- and sex-adjusted incidence, 9.0% [95% CI, 7.6%-10.7%] for aspirin users vs 9.0% [95% CI, 7.6%-10.6%] for nonusers), late AMD (HR, 0.91 [95% CI, 0.57-1.46]; P = .69; age- and sex-adjusted incidence, 1.3% [95% CI, 0.9%-1.9%] for users vs 1.4% [95% CI, 1.9%-2.1%] for nonusers), neovascular AMD (HR, 0.66 [95% CI, 0.37-1.19]; P = .17; age- and sex-adjusted incidence, 0.8% [95% CI, 0.5%-1.3%] for users vs 1.1% [95% CI, 0.7%-1.6%] for nonusers), or pure geographic atrophy (HR, 2.25 [95% CI, 0.75-6.72]; P = .15; age- and sex-adjusted incidence, 0.6% [95% CI, 0.4%-1.1%] for users vs 0.4% [95% CI, 0.2%-0.8%] for nonusers).

The main effect of aspirin use 10 years prior was significant for predicting the incidence of late AMD (HR, 1.63 [95% CI, 1.01-2.63]; P = .045; age- and sex-adjusted incidence, 1.8% [95% CI, 1.2%-2.6%] for users vs 1.0% [95% CI, 0.7%-1.5%] for nonusers). When examining the relationships by late AMD subtype, neovascular AMD was significantly associated with such use (HR, 2.20 [95% CI, 1.20-4.15]; P = .01; age- and sex-adjusted incidence, 1.4% [95% CI, 0.9%-2.1%] for users vs 0.6% [95% CI, 0.4%-1.0%] for nonusers), but pure geographic atrophy was not (HR, 0.66 [95% CI, 0.25-1.95]; P = .46; age- and sex-adjusted incidence, 0.5% [95% CI, 0.3%-1.0%] for users vs 0.5% [95% CI, 0.3%-0.9%] for nonusers). Similar analyses for the incidence of early AMD showed no significant associations with use of aspirin 10 years prior (HR, 0.86 [95% CI, 0.65-1.13]; P = .28; age- and sex-adjusted incidence, 8.5% [95% CI, 6.9%-10.5%] for users vs 9.5% [95% CI, 8.3%-10.9%] for nonusers).

History of arthritis and CVD, 2 common reasons for aspirin use, were analyzed to investigate the possibility of confounding by indication. For predicting incidence of early AMD, no significant interactions were found between arthritis or CVD and aspirin use 5 years prior to incidence (P = .16 for arthritis, P = .45 for CVD) or 5 and 10 years prior (P = .64 for arthritis, P = .33 for CVD). Similarly, for predicting incidence of any form of late AMD, no significant interactions were found between aspirin use 5 years prior and history of arthritis (P = .28) or CVD (P = .62) or between aspirin use 5 and 10 years prior and history of arthritis (P = .16) or CVD (P = .43).

Milligrams of aspirin taken per day were calculated for the third, fourth, and fifth examination phases. No significant relationship was found between milligrams of aspirin per day taken 5 years prior to observed early AMD (P = .53) or late AMD (P = .22). Similarly, no significant relationship was found between milligrams of aspirin reported taken 5 and 10 years prior and observed incidence of early AMD (P = .27) or late AMD (P = .37).

We examined whether the association between aspirin use and incidence of neovascular AMD was related to use of any NSAID and found no relationship between the use of any NSAID 10 years prior and incidence of neovascular AMD (P = .33). We also investigated whether warfarin was associated with incidence of late AMD or its subtypes and found no associations between AMD and warfarin use 5 years prior (P = .56 for late AMD; P = .88 for neovascular AMD; P = .52 for pure geographic atrophy) or 10 years prior (P = .15 for late AMD; P value nonestimable for neovascular AMD; P = .89 for pure geographic atrophy) to observed incidence.

To examine possible effects of systemic inflammation and the possible protective role of aspirin in the presence of systemic inflammation, we examined the associations of leukocyte count and CRP level with incidence of AMD and the effects of these inflammatory factors on the relationship between aspirin use reported 5 years prior and incident AMD. Neither were associated with incidence of early AMD (P = .13 for leukocyte count; P = .21 for CRP level) or late AMD (P = .56 for leukocyte count; P = .29 for CRP level), and neither showed a significant interaction with aspirin use (early AMD: P = .87 for leukocyte count and P = .29 for CRP level; late AMD: P = .25 for leukocyte count and P = .07 for CRP level). Adjusting for leukocyte count and CRP level did not alter the associations seen between aspirin use and incident late AMD.

To further explore the finding that time of first reported regular aspirin use was associated with AMD, we examined the data on aspirin use only in participants who had complete information on self-reported aspirin use at all study visits from the baseline visit through the fourth visit, who were free from AMD at the fourth visit, and who had complete outcome information from the most recent visit (Table 4). There was no apparent relationship between the visit since first regular use of aspirin and incidence of early AMD. Results are similar for those with consistent and inconsistent use.

For any late AMD, participants with no aspirin use and those with aspirin use only at the visit prior to the incidence of late AMD (use at the fourth visit) had a similar incidence (1.75% and 1.40%, respectively). Those who had reported regular aspirin use 10, 15, or 20 years prior to observed incidence showed a higher incidence than those with no aspirin use or only recent aspirin use (5 years prior to observed incidence). Incidence was similar for 10 years (4.67%), 15 years (4.21%), and 20 years (5.10%) since aspirin use was first consistently reported. The results are similar for participants with inconsistent use. It should be noted that for late AMD, several cells contain very low counts for incident cases (Table 4).

For pure geographic atrophy, there was no discernible pattern between incidence and years since first self-reported aspirin use. For neovascular AMD, the pattern was similar to what was seen for incidence of any late AMD (Table 4).

Methods

Participants


A private census of Beaver Dam, Wisconsin, was performed in 1987-1988 to identify all residents eligible for the study.6 Participants were examined at baseline (1988-1990) and every 5 years thereafter (1993-1995, 1998-2000, 2003-2005, 2008-2010) over a 20-year period. All data were collected with institutional review board approval from the University of Wisconsin-Madison in conformity with all federal and state laws; the work complied with the Health Insurance Portability and Accountability Act; and the study adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from every participant at each examination.

Participants were examined at the study site, a nursing home, or their home. By design, participants were requested to be seen on or near the anniversary date of their first examination. In this way, examinations occurred at regular 5-year intervals. For all person-visits included in analyses, 86% of visits occurred within 6 months of the target visit date. The same protocols for measurements relevant to this investigation were used at each examination.7 Participants were asked if they regularly used aspirin at least twice per week for more than 3 months. This self-report of regular aspirin use was the main exposure measure of interest in our primary analysis because it was asked at every examination. Additional information concerning frequency of aspirin use (<1 aspirin every other day, 1 every other day, 1 per day, 2 per day, 3 to 7 per day, or 8 or more per day) and dosage was obtained at the third, fourth, and fifth examinations. These data were used to calculate an estimated dose (in milligrams) per day and were used for auxiliary analyses to examine the potential dosing effect of aspirin on incidence of AMD.

Participants were asked to bring all currently used medications to the examinations. All medications, including NSAIDs and anticoagulants (eg, warfarin), were recorded. Hypertension was defined as systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, and/or history of blood pressure medication use. Heavy drinking was defined as consuming 4 or more servings of alcoholic beverages per day on a regular basis. A serving was defined as 12 oz (355 mL) of beer, 4 oz (118 mL) of wine, or 1.5 oz (44 mL) of liquor or distilled spirits. Blood samples were obtained and analyzed for levels of glycated hemoglobin (HbA1c) and for inflammatory factors, eg, leukocyte count and C-reactive protein (CRP) level. CRP level was measured only at the baseline examination, and leukocyte count was measured at the baseline and second examinations. Diabetes was defined as self-report confirmed by use of insulin or diet to control diabetes, self-report with HbA1c level greater than 6.5%, or no self-report with HbA1c level greater than 7%.8

Photographs of the retina7 were taken after pupillary dilation according to protocol9 and graded in masked fashion by experienced graders using the Wisconsin Age-Related Maculopathy Grading System to assess the presence and severity of lesions associated with AMD.9- 11 Grading procedures, lesion descriptions, and detailed definitions of presence and severity appear elsewhere (eMethods).9

The natural progression of AMD is described by the increase in level of severity. It is generally understood that an eye will have transitioned through each previous level (lower number in the scoring system) when it presents at a given severity level.

Statistical Analysis

We examined the relationship between self-reported regular aspirin use and incidence of early and late AMD in the presence of other known risk variables over 20 years of follow-up. Presence of early or late AMD was analyzed by person, combining the data from both eyes. Person-level variables were calculated at each visit for presence of early AMD, late AMD, neovascular AMD, and pure geographic atrophy. At a given visit, a person was considered free from a given type of AMD if both eyes were gradable and determined to be free of that AMD type. A person was considered to have a specific type of AMD at a given examination if at least 1 eye had gradable photographs and was determined to be prevalent of the given AMD type. If information from 1 eye was missing and the other eye was free from the given type of AMD, the person-level data were considered missing at that examination.

To be eligible for incidence of a specified type of AMD (early, late, neovascular, pure geographic atrophy), a participant must have been free of the given AMD outcome at the baseline examination and have complete AMD data from consecutive follow-up examinations, until incidence or censoring occurred. Further, to be included in analyses, a participant must have had complete data for self-reported aspirin use, age, sex, education, history of arthritis, and history of cardiovascular disease (CVD).

The 2 types of late AMD are not mutually exclusive, and both types may appear in the same eye sequentially or simultaneously. Incidence of late AMD was calculated as the first incidence of pure geographic atrophy or neovascular AMD. We followed the commonly accepted disease progression model that once a person develops neovascular AMD he or she cannot be further classified as having developed pure geographic atrophy (despite a change in the appearance of the fundus lesion); therefore, although a person who has prevalent or incident pure geographic atrophy is still at risk of developing neovascular AMD, the converse is not true. In this way, there were more persons at risk of developing neovascular AMD than any late AMD or pure geographic atrophy. Similarly, participants with early AMD were still at risk for developing late AMD; therefore, there were more participants in the risk set for late AMD than for early AMD.

For preliminary analyses, we calculated the overall percentage of participants incident for each combination of aspirin use 5 and 10 years prior to observed incidence (none at 5 years and none at 10 years, 5 years only, 10 years only, both 5 and 10 years). For each combination we then calculated the age- and sex-adjusted percentages for incidence. To explore the potential longitudinal association between aspirin use and AMD, we computed hazard ratios (HRs) for incidence of early and late AMD over 20 years, with time-varying covariates updated at each examination. Because the first incident cases were observed at the second examination and the main risk factor of interest was aspirin use at baseline, we refer to this as aspirin use "5 years prior." We also considered the hypothesis that the association between aspirin use and development of AMD may not be apparent with exposure at only 5 years prior to incidence. Therefore, for this analysis we accounted for aspirin use at the examination 5 years prior to incidence as well as for aspirin use reported at the previous examination, 10 years prior to observed incidence. When examining data that included aspirin use 10 years prior to incidence, those cases incident at the first interval were not included because aspirin use 5 years prior to the baseline examination was unknown. Because of this, the total interval for the longitudinal analysis of 10-year aspirin use is 15 years.

To establish the maximally adjusted statistical models, variables potentially associated with risk of AMD were first analyzed individually in age- and sex-adjusted models. These variables included body mass index, annual income, education, diabetes, systolic and diastolic blood pressure, hypertension, history of cancer, smoking (never, past, current), ever drinking, ever heavy drinking, history of arthritis, and history of CVD. All significant factors in the age- and sex-adjusted models were then included in a maximally adjusted model. The maximally adjusted model for early AMD included age, sex, education level, ever heavy drinking, smoking, and history of arthritis. The maximally adjusted model for late AMD and its subtypes included age, age2, sex, education, heavy drinking history, and smoking. Last, nonsignificant predictors from the maximally adjusted model were removed to establish the most parsimonious model; only these data are presented. This resulted in adjustment for age, arthritis history, and education level in models for early AMD and age, age2, and education level in models for late AMD. Interactions between potential reasons for aspirin use (arthritis and history of CVD) and aspirin use were tested.

To assess whether the timing of visits was driven by confounding factors, visits were divided into 3 groups: early (at least 6 months before the targeted visit date [the anniversary of the baseline visit]), late (more than 6 months after the targeted visit date), and on time (within 6 months of the targeted visit date). For the sensitivity analysis, observations from early or late visits were censored. The point estimates and confidence intervals in the 2 models were consistent; therefore, the full models are presented.

To explore whether frequency of aspirin use and amount of aspirin used was associated with AMD, we examined the association between self-reported daily dose of aspirin (in milligrams) and the incidence of early and late AMD with available data from the third, fourth, and fifth examinations. We also modeled the effect of inflammatory factors (leukocyte count, interleukin-6 level, and CRP level) on the association between aspirin use and incidence of AMD. We then examined the relationship between use of any NSAID and incidence of AMD and the relationship between warfarin use and incidence of AMD.

All models presented were fit using the discrete-time hazard model using the complementary log-log link function with time-varying predictors, with P values representing a 2-tailed test of significance with α = .05.12 In this way, risk variables (eg, use of aspirin 5 and 10 years previously) were updated throughout the course of the study; the model thus captures the change in risk for incidence of AMD, and censoring is accounted for appropriately. SAS version 9.3 (SAS Institute Inc) was used for all analyses.

We also conducted a secondary, exploratory analysis to examine whether the data supported the notion that time since first report of regular aspirin use was associated with incidence of late AMD. For these models, the outcome of interest was incidence of AMD between the fourth and fifth examinations. Our exposure variable was first self-reported aspirin use 5, 10, 15, or 20 years prior to observed incidence, which was examined in 2 ways. First, we included only participants who reported using aspirin consistently at each examination following their first self-reported use or who never reported using aspirin regularly. Next, we included participants who were inconsistent in reporting regular aspirin use following their first self-report of regular aspirin use. Participants with missing aspirin use data were excluded from both of these analyses. We used logistic regression for these models, with a 2-tailed test of significance with α = .05.

 
 
 
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