Risk factors of blindness due to primary open angle glaucoma versus doubtful benefits of identifying patients at risk of glaucoma
Main risk factors for going blind due to primary open angle glaucoma are late detection, elevated initial intraocular pressure, poor control of IOP , progression of the disease detected in follow-up visits, lack of compliance to prescribed treatment and social risk factors that includes patients that come from lower socioeconomic groups and often live in developing countries.
Risk factors for developing POAG are, among others, statistically high IOP, family history of POAG, old age and race. Risk factors for the development of glaucoma put millions of healthy patients in the label of glaucoma suspects. Nevertheless, having the diagnosis of early POAG or being a glaucoma suspect carries a very low risk of going blind due to POAG.
We discuss the paradox of medical practice directed to prevention and early detection of diseases versus medical decision based on disease outcomes, taking POAG as an example.
Ambiguity and paradox characterize the two main roads of modern medicine: medical decision based on disease outcomes versus medical practice directed to the prevention and early detection of diseases.
The focus of scientific knowledge has shifted from care to risk assessment, making virtually all human beings run the risk of being labeled as sick when approaching doctors. Health expenditure grows driven mostly by over treatment and defensive medicine 1.
Discussion on this subject is frequently seen in medical literature but has received little attention in ophthalmology. Primary open angle glaucoma (POAG) is a good example of the mentioned paradox because the main risk factors that may lead to blindness are well known yet most efforts in clinical and epidemiologic research are directed to early diagnosis and treatment or to the identification of patients vulnerable to be labeled as glaucoma suspects. The fact that these patients are at a very low risk of visual loss is purposely bypassed. It should also be mentioned that most researches on glaucoma are based on surrogates.
The statement that glaucoma is a blinding disease and that it is one of the leading causes of blindness in the world is generally used as a first sentence in many papers on glaucoma. Degeneration of the macula comes first among the main recorded causes of certifications for blindness (around 60%), followed by glaucoma (10%) and diabetic retinopathy (6%)2 . Despite being so widely used, both words, glaucoma and blindness, are ill defined.
Glaucoma gathers several different diseases that may cause visual loss but have different physiopathology, treatment and prognosis. POAG and primary angle-closure glaucoma are the two most important types of glaucoma and differ widely in incidence in different regions of the world, as do their relevance as a cause of blindness. Most efforts in screening research, detection of early disease, identification of risk factors, new technologies to detect progression and development of new drugs are directed to POAG.
The word blindness, so often used in medical literature, may have different meanings 3. Bilateral visual acuity worse or equal to 0.1 is frequently used. It is also defined as visual field of less than 20 degrees, even with a 20/20 visual acuity 4, 5 . In the mind of those who hear the word, doctors of layman alike, it is immediately understood as complete darkness or no light perception in both eyes. Registered bilateral blindness in glaucoma patients often does not have glaucoma as the only or the main cause of blindness. Other associated diseases like cataract or macular disease being the reason of low visual acuity 4.
We discuss the importance of distinguishing risk factors for progression to blindness due to POAG from risk factors of developing glaucoma.
Risk factors of blindness due to POAG
Despite the improvement of diagnostic and treatment methods, glaucoma still remains an important cause of blindness worldwide. Despite this truth, the risk of going blind from POAG in treated patients is relatively small, unless one or more of the risk factors for progression to blindness are present 6, 7, 8 . These risk factors for going blind are most critical in those patients with POAG diagnosed with high IOP and are:
- Advanced stage of glaucoma at diagnosis or late detection, i.e., severe field loss in at least one eye in newly diagnosed patients 6, 8, 9;
- Elevated initial IOP 5, 8;
- Poor control of IOP or fluctuation of IOP detected in follow-up visits 8 ;
- Progression of visual field loss, increase in optic disc cup, disc haemorrhages in follow-up visits, which may allow doctors to classify patients as slow and fast progressors; fast progressors are at increased risk of going blind 10;
- Lack of compliance to prescribed treatment 6. Many cases of no compliance have in its root the fact that medical therapy for glaucoma involves potentially lifelong adherence to therapies that may be expensive, difficult to obtain in poor or rural areas, and often have annoying collateral effects 11.
- Social risk factors, which includes being born and living in developing countries; patients from lower socioeconomic groups and patients less educated are more likely to have late presentation of glaucoma and to be non-compliers 6, 9.
The identification of patients that run an increased risk of progressing to visual loss is very important so that a more aggressive approach on clinical or surgical treatment may be taken.
Risk factors for the development of glaucoma, such as elevated IOP with normal optic disc and normal visual fields, family history of glaucoma, race, corneal thickness and myopia were not found to be significant on visual outcome of glaucoma patients 5, 8.
Risk factors for the development of glaucoma
The idea that the early treatment of patients with glaucoma decreases the probability of going blind is usually accepted as true 12. This unproven idea prompted the design of hundreds of researches and the publication of a huge number of peer reviewed scientific papers. Several characteristics that are more common in patients that eventually develop POAG were identified and are considered risk factors for the development of glaucoma. These risk factors put millions of healthy patients in the medical label of “glaucoma suspects” or “ocular hypertension”. Industry is constantly introducing new technologies to be used in those glaucoma suspects 11. The plethora of exams validates the prescription of medication to patients that probably could postpone it or never need it and that are at a very low risk of suffering any kind of visual loss related to POAG.
Some of the main accepted risk factors for the development of glaucoma are: statistically high IOP (generally 20 to 24 mmHg), family history of glaucoma, large optic disc, large cup, thin central corneal thickness, race, high myopia and old age. Despite being one of the most important risk factors for development of glaucoma, ocular hypertension per se should not be considered a clinical entity 13.
The decision to treat any patient lies upon his doctor. It is generally accepted that patients found to have anatomic and functional loss of POAG should be treated. One may consider postponing treatment in those patients with early disease and low life expectancy 14. It should always be kept in mind that POAG is a slow progressing disease and that the risk of visual loss is low unless those risk factors of progressing to blindness are present.
There is some controversy on management and prescription of drugs to those patients that do not have anatomic and function loss of POAG but carry one or more of those risk factors for the development of glaucoma. The cost, inconvenience and side effects of using eye drops, not to say the psychological burden of using those drugs and being labeled as glaucomatous, is often underweighted. So, do the cost and inconvenience of performing and repeating periodically those countless exams, some of them of unproven benefits 11. The development of early POAG damage in non-treated suspect patients carries a low risk of blindness or interference in the quality of life, although this risk tends to be overestimated.
Use of surrogates in glaucoma research
Clinical trials are designed to measure disease outcomes. Endpoint outcomes correspond to main features or consequences of the disease and may be classified as primary and secondary. Taking POAG as an example, primary endpoint outcomes would be blindness or severe visual loss in one or both eyes and poor quality of life due to visual impairment. Secondary endpoint outcomes could be, for example, worsening of visual field defects or widening of optic disc cup.
Surrogate endpoints can be described as some outcome of a therapeutic intervention that are not themselves any direct measure of either benefit or harm. They are used because they may be easily and cheaply measured and may reduce the duration of clinical trials, further reducing costs. They must have been objectively validated and must be linked to the development and progression of the disease 15.
The use of IOP as a surrogate variable endpoint in glaucoma research has been long accepted by United States Food and Drug Administration (FDA) 16, due to its importance as a risk factor, both for the development of glaucoma and to progression of the disease. It is non-invasive, cheap and easy to measure. It is so embedded in ophthalmic publications that usually it is not even mentioned that a surrogate variable is being used to test different modalities of treatment for glaucoma 17. There is a shortage of papers that rely on the efficacy of prevention or of different treatments on the meaningful outcome, i.e., visual loss and poor quality of life. Treating IOP is generally confused with the concept of treating the disease, even in those healthy patients whose prescription was based on the label of glaucoma and the supposed risk of developing the disease. Most ophthalmologists do not grasp the concept that reducing IOP is a surrogate endpoint in glaucoma treatment, but not itself a measure of structural or functional optic neuropathy 10. The fact that high IOP is both a risk factor for developing POAG and a risk factor for visual loss and that it is also a surrogate and not a primary or secondary outcome of the disease is confusing to many ophthalmologists.
Although the level of IOP is one of the most consistent risk factors for the presence of POAG, the concept that statistically raised IOP is a defining characteristic for glaucoma has been almost universally discarded. POAG is an optic neuropathy associated with characteristic structural damage to the optic disc and associated visual dysfunction 18. The term glaucoma should be reserved for people with established, visually significant, end organ damage. Stabilization or control of POAG can’t be measured just by reduction of IOP, but must be evaluated by other means like visual fields and optic disc examinations.
FDA is waiting for the establishment of definition of glaucoma progression and consensus about structural-functional relationships that characterize early, moderate and late stages of disease 10, in order to accept the use of new technologies as surrogates in POAG clinical researches.
Screening for POAG
No randomized, controlled trials of population screening for POAG have been reported. The US preventive service task force concluded that the benefit of delaying progression of visual field loss on vision-related function in patients with early POAG is unclear and that there is no proof that screening and early recognition and treatment of glaucoma in asymptomatic patients are effective in improving vision specific outcomes and health-related quality of life 19.
Screening to detect all individuals with glaucomatous optic nerve damage, either by structural or functional testing, remains an unsolved challenge. One approach would be to concentrate on the detection of more advanced cases or on opportunistic screening of people at risk, like older Africans 20. The cost-benefit effectiveness for glaucoma screening in the general population is not favorable because too many normal individual are referred for evaluation and over 50% of glaucomatous patients are missed. Even new methods, like evaluation of optic disc head or retinal nerve fiber layer do not satisfy many of the proposed criteria for an effective screening test 21, 22.
There is a paradox related to the proven inefficacy of different methods of testing structural and functional parameters for POAG screening in the general population and the acceptance of routinely performing these very same tests for screening in office patients. The reasoning is that every effort should be done to identify early glaucomatous damage, even with the unproven benefit of doing so. General acceptance of this clinical practice has been shaped along years and years of undue influence of conflicting interests on researches, consensus panels, congresses and so on. It is a good example of indiscriminate use of technologies that might provide high value for carefully selected patients, to a much larger cohort of patients 23.
Most glaucoma in the world remains undiagnosed, screening paradigms are neither useful nor practical, and access to therapy is severely limited 11. POAG is a serious and irreversible disease and may cause severe visual loss, yet it is a slowly progressive disease. Contrary to clinical perceptions, glaucoma frequently progresses so slowly that most patients die before developing blindness, even in one eye 24. Life expectancy should be taken in consideration before prescribing a lifelong treatment 14. Careful education concerning the risk of loss of visual function and shared medical-patient decision might be a more effective approach to treating patients with high IOP and other risk factors of developing POAG 14.
Special attention should be given to the presence of risk factors for progression to blindness in glaucoma patients and to medical decision based on disease outcomes. Every effort should be made to avoid the waste of resources, the use of technologies of unproven value, the undue labeling of healthy patients as “glaucoma suspects” and unnecessary prescription of eye drops to patients at low risk of visual loss 24.
Guideline panels often include conflicted experts and care should be taken on the adoption of the recommendations. Main reasons to be cautious with guidelines are the difficulty of finding experts that do not have financial ties with pharmaceutical or equipment industry and the even more difficult task of finding authorities that are free from reputational conflicts of interest. Reputational conflicts of interest refers to researchers that have already declared view on a question been considered or may be interested in validating their own clinical conducts 25, 26, 27.
Industry takes profit from medical practice based on the idea that treating healthy patients supposedly at risk of POAG is cost-effective in preventing blindness. Doctors often carry conflicts of interests, even when they believe they are acting in the best interest of patients, and feel free to recommend a bunch of unnecessary exams at frequent intervals, not to say to recommend frequent visits to office. Those healthy patients that receive the label of glaucoma suspects stand the burden of being labeled as sick, of living frightened by the ghost of blindness and of using for their lifetime drugs that may be expensive and have significant side effects.
Resources may come from private health insurance companies or from public health system. Even then, it is more appropriate to say that the burden of costs lies on the society. Resources that are wrongly spent could have been used in a more effective way, like medical assistance, education, fighting poverty or elsewhere. Prosperity in some parts of the world, especially in the last few decades, has blinded doctors, patients and politicians alike. It seems that everyone has forgotten that resources are scarce on earth, both in developed or underdeveloped societies. It is time to make a better use of them. For sure more cases of blindness and other disabilities would be prevented.
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Foto – Bruegel – Louvre – The cripples (1568)