AS62 - Prevention of age-related maculopathy in the WHI HRT CT: WHISE

Investigator Names and Contact Information

Mary Haan (mary.haan@ucsf.edu)

Introduction/Intent

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1. INTRODUCTION AND BACKGROUND

The purpose of this research study was to evaluate whether hormone replacement therapy in women would prevent or slow the progression of age-related maculopathy (ARM). ARM is a leading cause of permanent visual impairment among Americans aged 65 and older.¹ It is gradually progressive, often over a period of more than five years. Estimates of prevalence range widely across studies, depending on the age of the population, geographical location and method of ascertainment. Table 1 summarizes the studies that have reported prevalence and their estimates. Studies for this estimate were selected from population-based studies with relatively large sample sizes. Methods of ascertaining ARM were based on widely accepted standardized approaches such as the Wisconsin ARM Grading System. Studies that were based on convenience samples or nursing home populations were not included.

Table 1. Summary of ARM prevalence in population-based studies

Only two studies have reported gender differences: the Beaver Dam study reported that women 75 years of age and older have a higher prevalence of exudative macular degeneration than men (7% versus 3%).² Delcourt reported an approximately equal prevalence of late ARM in men (1.7%) and women (1.5%) aged 70-79³. Risk factors associated with ARM include hereditary factors; cardiovascular disease (CVD) and CVD risk factors; diabetes and glycemic status; smoking; chronic exposure to light; dietary and blood levels of zinc or antioxidant vitamins; and the use of post-menopausal estrogens. At this time, there was neither a preventive approach nor cure for ARM. Currently, treatment is limited to laser photocoagulation, which has a statistically significant, though quantitatively very limited, effect in reducing the progression of visual loss in highly selected cases of neovascular ARM⁴. Some forms of ARM may respond to treatment with high dose vitamin therapy or other dietary interventions⁵. There may be ethnic differences in ARM: one report describe a lower occurrence of ARM in blacks⁶. However, others report no ethnic differences after age adjustment⁷. Dietary antioxidants have been examined in relation to the risk of ARM: several observational studies have reported that vitamins C, E and carotenoids are associated with reduced risks of ARM ^8,9. The Blue Mountains Eye Disease Study did not find an association between alpha tocopherol or beta carotene and ARM¹⁰.

Estrogen Replacement Therapy. Several studies have reported a higher occurrence of ARM in women compared to men. Vingerling reported that early menopause (< age 45) was associated with a 90% increase in risk of ARM. This was highest in those with surgical menopause involving an oophorectomy (RR, 3.8)¹¹. Two published observational studies have addressed the association between ARM and estrogen replacement therapy (HRT). The Eye Disease Case Control Study found the risk of neovascular ARM was reduced by 70% in women who were current users of HRT and by 40% in women who were former users¹². Adjustment for covariates did not affect these associations. A report from the Beaver Dam Study¹³ based on cross-sectional data also suggested a protective effect of HRT on ARM. Another study found a protective association for early ARM with increased years from menarche to menopause, suggesting a protective effect with longer exposure to endogenous estrogen.¹⁴ To date, there have been no clinical trials conducted to examine this protective association between estrogenic hormones and ARM. Possible mechanisms by which estrogen may influence the risk of ARM include its effects on vascular factors which have been variously linked to ARM.^15,16,17 The presence of estrogen receptors¹⁸ in the retina and retinal pigment epithelium has suggested that estrogen could play a role in ocular diseases. Vingerling has reported a 2.5-4.7 fold increased risk of ARM associated with atherosclerosis in several cardiovascular beds. Estrogen affects microvascular circulation through its influence on endothelial function¹⁹, vascular reactivity, and a range of hemostatic and coagulation factors²⁰. If ARM is linked to or influenced by vascular factors²¹, estrogen could play a role in preventing this disease. Genetic factors also play an important role in maculopathy²² and could potentially modify any effects of estrogen on the risk of maculopathy. The association between apoE lipoprotein E and ARM was examined in the Rotterdam study which reported a 57% reduced risk of ARM in those with ApoE4. Work by Souied found a lower frequency of E4 in those with the exudative form of ARM. Estrogen is widely recognized as an antioxidant: the antioxidant activity of estrogens^23,24 may be another mechanism by which this compound could reduce the risk of ARM in women. Since the effects of estrogen may be modulated by ApoE, genetic factors may also modify the relationship between HRT and ARM.

2. OBJECTIVES

The primary goal was to evaluate the efficacy of Premarin® (conjugated equine estrogen (CEE)) and Prempro™ (conjugated equine estrogen plus medroxyprogesterone (CEE + P)) versus placebo in slowing the progression of ARM as measured by a systematic grading of stereoscopic retinal fundus photographs.

3. STUDY DESIGN

The Women's Health Initiative Sight Exam study (WHI-SE) was an ancillary study to the Women's Health Initiative Hormone Replacement Therapy Clinical Trial (WHI HRT CT), and enrolled 4,347 women who were in the HRT of the study. Data collection was completed. The Women's Health Initiative (WHI) was launched in 1991 by the National Institute of Health (NIH). WHI consisted of several clinical trials and an observational study and included generally healthy postmenopausal women. WHI HRT CT was one of the WHI clinical trials and was a randomized, multi-center (21 sites), double-blinded clinical trial of conjugated equine estrogen, 0.625 mg per day (CEE) for women without a uterus or conjugated equine estrogen, 0.625 mg per day plus medroxyprogesterone, 2.5 mg per day (CEE+P) for women with a uterus, versus placebo. CEE or CEE+P was assigned in a 1:1 ratio to placebo.

WHI HRT CT participants from 21 centers were recruited to participate in WHI-SE between April 2000 and June 2002, an average of 5.1 (median, 5.0; range, 1-10) years after randomization. Data on risk factors for eye disease or on eye disease diagnoses were not generally collected as part of the main study, nor were relevant biochemical or genetic measures available to the WHI-SE. The WHI-SE study added fundus photography for assessment of age-related maculopathy to the main study. In addition, data about visual acuity and self-reported visual functioning, eye disease history, risk factor exposures were collected. Blood for biochemical analysis and assessment of genetic factors were collected and banked for future analysis when additional funding becomes available. None of these data were collected as part of the main WHI study. WHI-SE participants underwent an eye exam and fundus photography session, completed at a brief questionnaire on eye disease and treatments, and a one-time venipuncture for blood/serum was collected. Study participants were contacted by mail or telephone annually at the anniversary of their original eye exam to respond to questions about new diagnoses of maculopathy and other eye diseases and surgeries, such as cataract surgery. When a new diagnosis of maculopathy was reported, the WHI-SE Coordinating Center obtained verification by mail from the diagnosing physician. Thus, there were two complete sets of fundus photography obtained by the WHI local clinical center and four annual contacts by telephone conducted by the WHI-SE Coordinating Center. Determination of incidence was based on the fundus photographs and verified ARM diagnoses in interim years. Data collection during interim years is necessary to obtain data on diagnoses of ARM that might occur in women who die or drop out of the study and are not seen at the second evaluation. The total duration of the study was 7 years and participants were followed for 4 years, on average. After close out of the main WHI study, HRT information was obtained and added to the study data to evaluate the association of HRT with age-related maculopathy (ARM).

WHI-SE was originally designed to include both a cross-sectional eye examination and a second eye examination to capture ARM incidence, but the sponsor canceled the study in the wake of the WHI HRT CT results so the second examination could not be done. Thus, WHI-SE was a cross-sectional study.

4. SELECTION OF PATIENTS

Since the study population was drawn from the WHI HRT Clinical Trial, patients were already included or excluded based on those criteria. Refer to the WHI HRT Clinical Trial Study protocol for more detail.

4.1. Inclusion Criteria

1. Women aged 65 years or older currently enrolled in the WHI HRT Clinical Trial.

2. Speak and read English or Spanish, agree to complete study questionnaires and two eye examinations with fundus photography, and sign the informed consent document

3. Patient has at least one eye that can be dilated for the purpose of retinal fundus photography

4.2. Exclusion Criteria

1. Allergies to dilating eye drops

2. Other known contraindications for the administration of dilating eye drops

3. Any reason that the participant cannot be subjected to retinal fundus photography

5. STUDY METHODS

5.1. Schedule of Visits

5.1.1. Screening and Baseline Evaluation (Visit 1 and 2, Weeks –12 to 0)*

Visit 1. Review of protocol with subject, screen for contraindications (allergies to dilating drops or neither eye able to be dilated) and consent to participate obtained prior to study entry. Patient completed a questionnaire on visual function, history of light exposure, vitamin, and medication usage. Questionnaire was returned to WHI-SE Coordinating Center after review by WHI CC staff. Patient had a blood draw of 32 ml of blood.

Visit 2. Patient was scheduled for an eye exam and fundus photography session. The eye exam included a check of visual acuity with pinhole refraction, if required. The anterior chamber of the eye was examined for contraindications to dilation or other abnormalities, and the intraocular pressure was measured. Dilating drops was administered (barring any contraindications), and a set of stereoscopic fundus photographs was taken for each eye. Patient completed brief questionnaire on history of eye disease and associated treatments at time of eye examination.

5.1.2. Visits 3-5 Annual followup questionnaire.

Questionnaire on eye disease or visual problems identified since the eye exam and photography in Visit 1 or 2 were administered by telephone or mail by WHI-SE staff on the first, second and third anniversary of the baseline eye examination through 3/30/05.

5.2. Eye Exam and Fundus Photography

Fundus photography was done using a 30 degree Zeiss FF series fundus camera. To avoid photographic artifacts, frequent inspection and cleaning of the front surface of the objective lens was essential to remove dust and debris. Professional Ektachrome Daylight film with a speed of 100 or slower was recommended by The Reading Center. It was also strongly recommended that Ektachrome films be processed by a certified "Q-Lab" to ensure consistent film processing quality. It was important that the processor correctly number the slide mounts to make slide sorting easier and more accurate.

5.2.1. Photographer Certification

All photographers taking photographs for this study were certified by the Reading Center for the seven standard fields protocol, before submitting actual patient photographs. Each clinical center was required to have at least one certified photographer, with preferably one or two additional photographers in order to participate.

5.2.2. Pupillary Dilation

Adequate dilation of the pupil was important to permit good quality stereo photography. Sufficient time was allowed for dilation to at least 6 mm, repeating drops if necessary, to achieve and maintain a pupil of at least this size during photography. Only if repeated instillation of drops and passage of at least 30 minutes after the last drops failed to produce dilation of 6 mm were photographs taken through a smaller pupil.

5.2.3. Required Color Photographs: The Standard Fields

Participants With Diabetes

The seven standard fields of the fundus, taken in stereo, of each eye were required for diabetic participants in the study. The following description assumes that there were two cross hairs in the camera ocular, one vertical and the other horizontal.

Field 1 - Disc: Centered the optic disc at the intersection of the cross hairs in the ocular.

Field 2 - Macula: Centered the macula at the intersection of the cross hairs in the ocular. In practice, to keep the central gray artifact created by some cameras from obscuring the center of the macula, the intersection of the cross hairs were placed about 1/8 - 1/4 DD nasal of the center of the macula.

Field 3 - Temporal to Macula: Positioned the macula at the nasal edge of the field.

Field 4 - Superior Temporal: The lower edge of the field was tangent to a horizontal line passing through upper edge of optic nerve and the nasal edge of the field was tangent to a vertical line passing through the center of the disc.

Field 5 - Inferior Temporal: The upper edge of the field was tangent to a horizontal line passing through the lower edge of the optic disc and the nasal edge of the field was tangent to a vertical line passing through the center of the disc.

Field 6 - Superior Nasal: The lower edge of the field was tangent to a horizontal line passing through the upper edge of optic disc and the temporal edge of the field was tangent to a vertical line passing through the center of the disc.

Field 7 - Inferior Nasal: The upper edge of the field was tangent to a horizontal line passing through the lower edge of the optic disc and the temporal edge of the field was tangent to a vertical line passing through the center of the disc.

Field 8 - An Optional Field: Outside the seven standard fields taken to document new vessels and/or preretinal or vitreous hemorrhage.

Participants Without Diabetes

A modified version of three standard fields of the fundus was required for the study, (two photos of the modified Field 1M and two photos of Field 2, both in stereo, and one modified photo of Field 3M were taken.) The modified three standard fields of the fundus specified by this protocol differ from the traditional Fields 1, 2, and 3, that were part of the seven standard field protocol, in the position of two fields. Field 1M and Field 3M were both modified to include the center of the macula; in Field 1M, near the edge of the field and in Field 3M, approximately midway between the edge and center of the field.

Field 1M was centered on the temporal edge of the optic disc, rather than on the center of the disc as in the traditional Field 1. Field 2 remained unchanged and was centered slightly above the center of the macula. Field 3M was centered about 3/4 to 1.0 disc diameter (DD) temporal to the center of the macula, so that the center of the macula was approximately midway between the center of the photograph and its nasal edge, rather than at its nasal edge (as in the traditional Field 3.) The modified three fields were illustrated in Figures 2a and 2b for the right and left eyes.

The following descriptions of the standard fields assume that there were two cross hairs in the camera ocular, one vertical and the other horizontal intersecting in the center of the ocular.

Field 1M - Disc: Centered the temporal edge of the optic disc at the intersection of the cross hairs in the ocular.

Field 2 - Macula: Centered the macula near the intersection of the cross hairs in the ocular. To keep the central gray artifact created by some cameras from obscuring the center of the macula, the intersection of the cross hairs were placed about 1/8 – 1/4 DD above the center of the macula. A suitable position could often be obtained by rotating the camera temporally from the Field 1M position, without vertical adjustment.

Field 3M - Temporal to Macula: Positioned the intersection of the cross hairs in the ocular 3/4 to 1.0 DD temporal to the center of the macula. If Field 2 was centered above the center of the macula, as suggested above, Field 3M may be centered 3/4 to 1.0 DD temporal to Field 2, a position easily achieved by rotating the camera without making any vertical adjustment or movement of the fixation device.

5.2.4. Fundus Reflex ("Lens") Photograph

A stereo fundus reflex photograph was taken in addition to those required of the seven standard fields (diabetic), and three modified standard fields (non-diabetic). As well as documenting the condition of the lens, the fundus reflex photograph allowed the Reading Center's graders to take opacities of the media into consideration when reviewing photographic quality. If fundus photography was not possible because of opacities in the media, a bound-down pupil, previous enucleation, or for any other reason, a fundus reflex photograph was taken to document the reason.

In order to take the fundus reflex photograph, it was necessary to use the +16/+33 diopter setting on the auxiliary lens system of the Zeiss camera. The small white knob on the right side of the fundus camera was turned until the correct number (+20/+40 on some Zeiss cameras, perhaps similar high plus diopter readings on others) appeared at the dot. In order to standardize the magnification of these photographs (the object being to obtain a red reflex photograph magnified until the corneal diameter measures approximately 13 mm measured on the film), the following procedure was used:

1. The film-to-lens distance of the camera was increased to its maximum, by turning the large focusing knob so that its upper aspect moved toward the subject. The knob was turned in this direction as far as it would go. This adjustment determined the magnification.

2. The subject's headrest was moved away from the camera until the iris was in crisp focus (approximately one and a half inches further away than when adjusted for taking photographs of the fundus.) It was acceptable to move the subject slightly further away, so that the joystick could be used for fine adjustment of focus if the photographer wished. Focus was on lens opacities when present, otherwise on the pupillary margin.

3. The subject was asked to open his/her eyes very wide, or the lids were gently retracted if necessary, so that the entire cornea was visible.

4. The stereo photograph was taken.

After processing of film as slides, they were labeled and mounted into plastic slide sheets and sent to the UW Reading Center. The clinics sent fundus photographs to the University of Wisconsin labeled with the WHI ID number and a name code (the first three letters of the last name, followed by the first three letters of the first name).

5.2.5. Pathology Alert

All slides underwent a preliminary grading and detailed grading. During the preliminary grading, photographs were scanned for lesions which threaten vision or life and require immediate evaluation by the participant's private physician or ophthalmologist.

Lesions that prompted a pathology alert were as follows—

1. Treatable age-related macular degeneration

2. Preproliferative/proliferative diabetic retinopathy

3. Clinically significant macular edema

4. Large cup to disc ratios suggestive of glaucoma

5. Large elevated nevus

6. Hollenhorst plaque (cholesterol emboli)

7. Macular hole

8. Retinal vascular occlusions

9. Miscellaneous lesions that may need evaluation for treatment

5.3. Grading Procedure at UW

The following describes the grading protocol used in the Women's Health Initiative Sight Exam (WHI-SE). It was adapted from Beaver Dam Eye Study and represented a modification of the Wisconsin Age-related Maculopathy Grading System. It was divided into sections on the materials needed in grading, photographic processing procedures, identification information, evaluating photo quality, and grading of specific lesions for diabetic retinopathy, retinal arteriolar focal narrowing, arterio-venous nicking, age-related maculopathy, and other fundus lesions. The specific protocols used to take fundus photographs and to mail alerts regarding abnormal fundus pathology that required immediate feedback were described elsewhere. This section was limited to procedures involving photograph grading.

The grading involved a preliminary and detailed grading followed by a photograph edit and adjudication if necessary. Each set of photos was graded on the items detailed below using custom designed computer software with built in completeness and consistency checks. (An example paper grading form was included at the end of this protocol that mimics the direct entry grading system. Item numbers from the paper form were referenced throughout with right eye (OD) first followed by the left eye (OS) item number.) Upon completion of this detailed grading, a comparison was made between the preliminary grading and the detailed grading. If there was a disagreement in the levels assigned for specific lesions, the eye was sent to a third grader for an edited grade of those lesions. If the edited grade still did not agree with either the preliminary or detailed score, then the eye was sent to the consulting ophthalmologist for adjudication. The specific rules for edits/adjudications were under development.

The grader entered the ID# of the participant, the namecode, and photo date, the grader's ID code and the date graded.

5.3.1. Preliminary Grading

5.3.1.1. Zeiss Photo quality

Overall Photo quality was graded as good (0), fair (1), borderline (2), poor-ungradable (3), or not applicable-no picture (9). Wisconsin Age-Related Maculopathy Grading System standards were used to characterize photo quality. This was an evaluation of overall photo quality that was assigned based on focus, field definition, stereopsis, photographic artifacts, and absence/presence of fields.

In grading photographic quality, a three-step scale was used. The steps, "good", "fair" and "poor", were defined below as they apply to a single photographic field.

A photographic field was considered "good" if all three characteristics listed above were graded "good"; "fair" if one of the conditions listed as "fair" was present and the other two were "fair" or "good"; and "poor" if one or more of the conditions listed as "poor" was present. Photo quality was also marked down when photographic artifacts were present in a field which affect the ability to evaluate retinopathy, or when the seven standard fields should have been provided but were incomplete.

A set of photographs was graded "good" (code "0"), "fair" (code "1"), "borderline" (code "2"), or "poor-ungradable" (code "3") according to the following criteria:

• Good: Field 1 and 2 were of "good" quality, and four of the remaining five fields were of at least "fair" quality. (In patients where only three fields were taken Field 3 should be of "fair" quality.)

• Fair: Field 2 was of "good" or "fair" quality, and Field 1 and four of the remaining five fields were of at least "fair" quality. (In patients where only three fields were taken, Field 3 could be any quality.)

• Borderline: The photo set was judged acceptable for grading. Quality was poor, but proliferative lesions or significant non-proliferative lesions were evident. Large soft distinct drusen should also be gradable. Fields 1 and 2 should not be "poor".

• Poor Ungradable: Quality was too poor to evaluate retinopathy and/or ARM status.

If the photographs were graded as fair, borderline, or poor-ungradable, then reasons for decreased quality were assessed. Focus, field, stereo, and other were considered. If something was judged to be borderline/ poor, but explainable due to severe lens opacities or other conditions, code 2 was chosen. If the assessment was borderline/poor but the reason for the poor quality was unexplainable, the grade was code 3. If any of these factors could not be assessed, the grade was code 8 (cannot grade [CG]). The "other" category was used for camera artifacts. If either of the borderline/poor codes were chosen, the grader details in the Comment section specifically what the artifact is, such as dust, haze, or arc.

Next, a decision was made whether retakes should be requested. This decision was based on whether the grader feels that there was no obvious reason that the photographs were borderline or poor-ungradable. Retakes were requested if it was thought that gradable photographs would result. If the WHI coordinators believe that retakes would not offer any better photographs, the OERC was notified and the original photographs submitted were graded according to protocol.

5.3.1.2. ARM Exclusions

While evaluating the photographs, the grader determined if there was a retinal condition that confounded the ability to grade the macula for age-related macular degeneration. If a confounding retinal condition existed the grader selected the most appropriate code for that condition. All of the ARM lesions were then coded "cannot grade" (code 8) and the grader continued grading the remaining items. In some cases a comment was included at the end of grading detailing the specifics of the exclusion condition.

Codes for ARM Exclusiousion