Epidemiolgy and Burden of Retina Disease

By Nancy M. Holekamp, MD

Age-related macular degeneration. The Eye Disease Prevalence Group has estimated that 1.75 million people in the United States have advanced age-related macular degeneration (AMD), including neovascular AMD or geographic atrophy, but not necessarily involving the foveal center, with the highest prevalence in adults older than 80 years of age.1 These numbers are estimated to increase substantially in the coming decades.

The numbers are huge, but what impact does AMD have on our patients? AMD is associated with an increased incidence of depression, mortality, and a greater need for assistance for daily tasks. In a quality-oflife study that was part of the Submacular Surgery Trials (SSTs), patients were asked to rate their current vision during phone interviews. Patient scores were converted to a preference value scale ranging from 1 (perfect health with perfect vision) to 0 (death). A mean preference value of 0.64 for subfoveal choroidal neovascularization (CNV) suggests a profound impact on quality of life. The impact is reported as greatest in those with the most severe loss of vision, but even patients with visual acuity of at least 20/40 in one eye had relatively low preference values.2 This is striking because it is right between having chronic renal failure and symptomatic HIV/AIDS (Figure 1). Clearly, AMD has a significant impact on the quality of life of individuals.

Diabetic retinopathy. It is well known that we are in the midst of an epidemic of obesity and diabetes in the United States. The rates of both have increased dramatically from 1990 to 2001, particularly in the southeast (Figure 2) and the increase in people with diabetes directly correlates to the rise in obesity.3 An estimated 18.2 million people had diabetes in the United States in 20023 and diabetes has been estimated to affect 151 million people worldwide, and is projected to increase to 324 million by 2025.4 It is also estimated that 35% of any diabetic population will have diabetic retinopathy.5 We know this from the Beaver Dam Eye Study. In terms of costs, the direct and indirect costs for diabetes were estimated at $132 billion in 2002.6 Almost $1 out of every $5 in the United States spent on healthcare is for patients with diabetes. Diabetes has an enormous impact on patients’ quality of life and represents a large economic issue.

Retinal vein occlusion. Retinal vein occlusion (RVO) is the second most common retinal disease after diabetic retinopathy. The Beaver Dam Study reported a prevalence of 0.6% in patients older than 43 years and the same study reported a 15-year cumulative incidence of BRVO of 1.8%.7 Although these numbers may sound low, the average age of these patients is 65 and this age group may have a host of comorbidities (eg, hypertension, vascular disease, diabetes). RVOs share risk factors with myocardial infarction (MI),8 stroke, and other arterial thrombotic events.9 In a study that is currently in press,10 we reviewed the records of 4,500 patients with RVO and compared them with 13,500 patients who were age-matched controls. We found that patients with RVO had significantly higher likelihood of having angina, cardiac arrhythmia, congestive heart failure, diabetes, heart disease, MI or stroke, hyperlipidemia, and hypertension (P=.001) The incidence of RVOs continues to increase as the incidence of diabetes increases and the population ages.

EVIDENCE-BASED MEDICINE
Evidence-based medicine is the practice of medicine based on the best scientific data available. The questions are, “How much evidence do you need?” and “How much science is behind it?”

These are the various levels of evidence. The weakest is the single-case report, which is level 5 evidence. The second weakest is the case series without a comparison group (level 4). Level 3 evidence consists of nonrandomized clinical trials that may compare two groups that are not concurrent or randomized. A level 2 clinical trial is similar to a phase 2 US Food and Drug Administration (FDA) clinical trial—it is randomized and controlled but it has a high type-1 error, where a trend is apparent and may be significant, but the number of patients is insufficient. A type-2 error is when a treatment difference likely exists but, again, there are not enough patients to isolate the difference.

Level 1 evidence is from randomized, prospective, controlled trials, with a low type-1 and type-2 errors. These are the phase 3 clinical trials that eventually lead to drug approval by the FDA. The key to level 1 evidence is a well-designed study and a large number of patients.

CLINICAL TRIAL DESIGN: WHY IS IT IMPORTANT?
In medicine we prefer level 1 trials because of random assignment to treatment or control; the concurrent enrollment that ensures patients are being treated in a similar manner; the large numbers of patients; and the masking of the investigators. The standardized follow up is also important to the significance of outcomes. By controlling these variables, we are able to clinically treat patients in the most scientific manner. My colleague Kuldev Singh, MD, who is a glaucoma specialist has said, “This term [randomized, controlled] allows the investigator to disarm the novice scientific critic, while impugning lesser prospective and all retrospective studies, not to mention case series and reports.” The randomized, controlled study is at the top of the food chain.

A case example of using low-level evidence-based medicine upon which to base treatment decisions is that of bevacizumab (Avastin, Genentech) for treating AMD. In August 2005, there was one case report (level 5 evidence) demonstrating improvement on optical coherence tomography (OCT) for a patient nonresponsive to pegaptanib sodium (Macugen, Eyetech/Pfizer) for AMD in the published literature.11 Simultaneously, Philip Rosenfeld, MD, PhD, one of the authors of the aforementioned case report, presented a paper (level 4 evidence) at the American Society of Retina Specialists in Montreal on a series of patients with exudative AMD who benefited from intravitreal bevacizumab. Clearly, the “bevacizumab for AMD” era was ushered in using the least convincing type of evidence.

Unlike bevacizumab, ranibizumab (Lucentis, Genentech) was subject to two phase 3 randomized, controlled clinical trials sponsored by industry (MARINA ANCHOR) that resulted in FDA approval. The extent to which the efficacy and safety of ranibizumab has been scrutinized is to the highest level.

But can you have a randomized, controlled trial for every disease and treatment? Paul Lichter, MD, said, “Authors of case reports, retrospective studies, and other manuscripts covering the gamut of imperfect clinical projects often conclude their papers by calling for a randomized, controlled, collaborative clinical trial. While I have no idea how many times such statements are made, there is no question that these pronouncements are abundantly more frequent then the clinical trials that result from them.”

CRITERIA FOR CONDUCTING A LEVEL 1 CLINICAL TRIAL
Clearly, a level 1 clinical trial cannot be conducted for every clinical situation. My four criteria for conducting a randomized, controlled clinical trial include the following:

* The disease must represent a significant health problem. An example of what can be called an questionable effort is in 1993 when the Canadian Ophthalmology Study Group conducted a multicenter randomized, controlled clinical trial to compare the argon green vs krypton red laser for choroidal neovascularization (CNV) in AMD.12 The comparison of these lasers was not a burning issue for the health care system.
* There must be scientific plausibility of benefit. In other words, there has to be some biologic basis for believing that a treatment works. An example from the AMD literature is subfoveal laser for CNV.13 There was no basis to suggest that applying laser to a patient’s fovea would be beneficial.
* A plausible, biologic benefit must exist. In other words, the early data on a new treatment should suggest the possibility of benefit. A good example of this is the Submacular Surgery Trials in AMD where early pilot data did not show any benefit to submacular surgery over laser photocoagulation.14 The eventual the long-term data supported this conclusion.
* Sufficient numbers of patients must be enrolled. If a study cannot recruit enough patients, it will not succeed. For example, it was almost impossible to recruit patients into the Macular Translocation clinical trial because they were randomized to either photodynamic therapy—a relatively painless 15-minute office-based laser procedure— or to macular translocation, which had a 25% complication rate at the time they were trying to enroll.15

The clinical trials’ registry, www.clinicaltrials.gov, currently lists 530 clinical trials for the treatment of AMD. Of those 200 trials are open and actively recruiting patients. Eighty-seven of these are randomized and controlled. Those of us in the field of ophthalmology and the subspecialty of retina are fortunate to be part of a profession that is committed to providing the best scientific evidence for its members. We have a long, proud history of practicing evidence-based medicine and performing randomized clinical trials in our field.

NON-INFERIOR CLINICAL TRIALS
There are basically three types of trial design: superiority, equivalence, and non-inferiority. The Comparisons of Age- Related Macular Degeneration Treatments Trials (CATT) is a non-inferiority trial comparing intravitreal ranibizumab to intravitreal bevacizumab. The margin of non-inferiority must be pre-specified in the design protocol to construct a two-sided, 95% confidence interval (CI) to determine the true difference between the agents. To be able to declare bevacizumab non-inferior, that interval must lay entirely on the positive side of the non-inferior margin.

Figure 3 helps illustrate how the results of a non-inferiority trial are interpreted. Applied to the CATT, if proved non-inferior, bevacizumab is either almost as good as, equivalent to, or better than ranibizumab. If bevacizumab fails non-inferiority then it is either equivalent, almost as good as, or inferior to ranibizumab. All of those possibilities exist.

The major criteria for non-inferiority clinical trials are:

1) historical evidence that the reference drug works (ie, MARINA and ANCHOR);

2) trial design must be the same as the reference trial (ie, the CATT has same design as MARINA and ANCHOR);

3) trial conduct must be the same (ie, many of the clinical sites from MARINA and ANCHOR are also sites for the CATT);

4) the non-inferior margin (minus delta) must be acceptable (ie, six letters for the CATT).

In addition to the CATT, there are two other non-inferiority trials in AMD: HARBOR (A Study of Ranibizumab Administered Monthly or on an As-Needed Basis in Patients With Subfoveal Neovascular Age-Related Macular Degeneration) and VIEW I (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD). These are both similar to MARINA and ANCHOR in historical evidence, trial design and trial conduct, and have an acceptable non-inferior margin.

SUMMARY
The best way to practice evidence-based medicine is with phase 3, randomized, and controlled trials. The requirements for level 1 clinical trials do not necessarily constitute a “cookbook” for successful trials; rather, they provide guidelines for those who are designing and participating in clinical trials.

Finally, evidence alone is never sufficient information to make a clinical decision—there are many factors to be taken under consideration. When treating our patients, we consider several factors including a patient’s values, socio-economic status, and age; however we should rely on three main components: our years of clinical experience, the patient’s particular circumstances, and what we have learned from evidence-based medicine.

1. Friedman DS, O’Colmain BJ, Muñoz B, et al; The Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Archives of Ophthalmology. 2004;122:564-572.
2. No authors listed. Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: II. Quality of life outcomes submacular surgery trials pilot study report number 2. Am J Ophthalmol. 2000;130(4):408-418.
3. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics Fact Sheet: General Information and National Estimates on Diabetes in the United States. Bethesda, MD, US Department of Health and Human Services, National Institutes of Health, 2003.
4. King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults: WHO Ad Hoc Diabetes Reporting Group. Diabetes Care. 1993;16:157–177.
5. Beaver Dam Eye Study.
6. Hogan P, Dall T, Nikolov P; American Diabetes Association. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003;26(3):917-932.
7. Klein R, Klein BE, Moss SE, Linton KL. Beaver Dam Eye Study. Retinopathy in adults with newly discovered and previously diagnosed diabetes mellitus. Ophthalmology. 1992;99(1):58-62.
8. National Heart Lung and Blood Institute. Heart attack. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/HeartAttack/HeartAttack_WhatIs.html.
9. Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Committee. Circulation. 2006;113:85-151.
10. Holekamp N. Arch Ophthalmol. In press.
11. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335.
12. The Canadian Ophthalmology Study Group. Argon green vs krypton red laser photocoagulation of extrafoveal choroidal neovascular lesions. One-year results in age-related macular degeneration. Arch Ophthalmol. 1993;111:181-185.
13. Macular Photocoagulation Study Group. Visual outcome after laser photo- coagulation for subfoveal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol. 1994;112:480–488.
14. Bressler NM, Bressler SB, Hawkins BS, Marsh MJ, Sternberg P Jr, Thomas MA; Submacular Surgery Trials Pilot Study Investigators. Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1. Am J Ophthalmol. 2000;130(4):387-407.
15. Hawkins BS, Bressler NM, Miskala PH, et al; Submacular Surgery Trials (SST) Research Group. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11. Ophthalmology. 2004;111(11):1967-1980.