Glaucoma treatment: by the highest level of evidence.

1264 www.thelancet.com Vol 385 April 4, 2015 50 years ago, ophthalmologists thought glaucoma and increased intraocular pressure to be synonymous. In 1958, Wolfgang Leydhecker defi ned healthy limits for intraocular pressure and patients with intraocular pressure of 21 mm Hg or higher received a diagnosis of glaucoma, irrespective of whether there were any signs of glaucomatous damage. They were given intraocularpressure-lowering eye drops, and were told to use these drops three to four times a day or they would go blind. Patients with pressures of 20 mm Hg or lower were told that they did not have glaucoma. The problem was that increased intraocular pressure and glaucoma are not synonymous. The fi rst epidemiological study of glaucoma, done in Wales, UK in the 1960s, showed that many patients with glaucoma had intraocular pressure measurements within Leydhecker’s healthy range; these patients were said to have normaltension glaucoma. These fi ndings have been confi rmed in dozens of other epidemiological studies, and it is now accepted that about half of all patients with glaucoma have normal-tension glaucoma—a proportion as high as 90% in Japan. Equally confusingly, there were many Glaucoma treatment: by the highest level of evidence ageing of the population per se, that adds to pressure on health services and makes it harder to fi nd the time for doing anything other than following treatment guidelines and meeting performance targets. Yet feeling cared for is something that patients have always valued. In A Fortunate Man, an exploration of a general practitioner working in a deprived rural community in the 1960s, John Berger concluded that the physician was much valued by his patients not because of his clinical acumen, but because of his capacity to accompany people in their fear and anxiety. This brings us to the key issue of trust. To feel cared for is to trust. But trust is not just a quality of the relationship between a doctor and a patient. It is also a crucial dimension of a much broader set of relationships that citizens have with organisations, institutions, and government that is essential for societies to be able to function. The NHS is seen by many as a key national institution of value and trust, indeed, is emblematic of the sort of society we wish to live in. More attention needs to be given to the experience people have when they interact with it. Doing this cannot be achieved by endlessly pressing for greater effi ciencies, which assumes all things of importance can be monetised. A better defi nition is needed of the value people place in the services that are established to treat and support the sick and the frail. Developing this defi nition will require a rethink within the medical and caring professions about how the human dimension of care can become more central to training and practice, and deliberation of how far medical innovation should be defi ned purely in terms of technological and pharmacological advance. However, none of these changes will be facilitated if the UK Government continues in the misguided belief that improving the value and trustworthiness of the NHS will be achieved by promoting distrust in the foundations of the institution and those who work in it.


Glaucoma treatment -finally the highest level of evidence
Glaucoma is a disease in which optic nerve axons are damaged, leading to gradual loss of vision and, too frequently, to blindness.50 years ago, ophthalmologists considered glaucoma and elevated intraocular pressure (IOP) to be more or less synonymous. 1 In the 1950 Leydhecker defined normal limits for IOP, 1 and as a result patients with elevated IOP (≥ 21 mmHg) received a diagnosis of glaucoma, regardless of whether there were any signs of glaucomatous damage.They were given pressure-lowering eye drops, and were told to use these drops 3 to 4 times a day or they would go blind.On the other hand, patients having pressures of 20 mmHg or lower did not have glaucoma.
The problem was that it simply is not true that elevated IOP and glaucoma are synonymous.The first epidemiological study of glaucoma, in Wales in the 1960s, found that a considerable proportion of glaucoma patients had IOP values within Leydhecker's normal range, and these patients were said to have normal tension glaucoma. 2These findings have been confirmed in dozens of other epidemiological studies, and it is now well accepted that about half of all glaucoma patients have normal tension glaucomaand in Japan as much as 90%. 3 The other side of the coin was equally confusing: patients having pressures ≥ 21 mmHg without glaucomatous damage were in fact found to be very numerous, and if followed without treatment for up to 20 years, most of them developed no signs of glaucomatous damage. 4us, ophthalmologists realized that the relation between elevated IOP and glaucoma was not all that clear, which led to doubts regarding the efficacy of IOPlowering therapy.Because this uncertainty was an obstacle to clinical decisionmaking and to allocation of sufficient resources to glaucoma care, clinical studies were needed.The problem was first addressed in four randomized clinical trials in the 1980s to investigate whether reducing IOP in patients having elevated pressure in the absence of glaucomatous damageocular hypertensioncould reduce the incidence of glaucoma damage.Results were inconclusive, [5][6][7][8] and in 1989 a report ordered by the US Congress concluded that there was no proof that lowering pressure reduced glaucomatous damage.Soon two randomized studies with untreated control arms involving patients with manifest glaucoma were started.The Collaborative Normal Tension Glaucoma Study (CNTGS) enrolled only glaucoma with normal tension glaucoma , whereas the Early Manifest Glaucoma Trial (EMGT) studied glaucoma patients both with normal and elevated pressures.In 1998 the intent-to-treat analysis in CNGTS was negative, but after correction for the increased incidence of cataract in the treated arm, positive treatment effects were seen. 9In 2002 EMGT results showed that pressure lowering had clearly positive effects, regardless of patients' initial IOP. 9e United Kingdom Glaucoma Treatment Study (UKGTS) by Garway-Heath and co-workers 12 is the second randomized clinical trial to investigate the effects of IOPlowering therapy in glaucoma patients having elevated or normal pressures.In some ways, the UKGTS was modelled after the EMGT, e.g. the primary outcome criteria but the two studies also differ in a number of respects.First the UKGTS was placebocontrolled, while the EMGT was not.Second, the UKGTS used mono-therapy in the treatment arm, prostaglandin analog eye drops (latanoprost 0•005%), the most commonly used anti-glaucoma therapy today.The authors also sought a study design from which conclusions could be drawn in a relatively short amount of time, patients were followed for only 2 years.To achieve this, 11 visual field tests were obtained during this period, since it is well known that identifying visual field progression or measuring rate of progression requires multiple field tests, and that the time needed to identify progression strongly depends upon the frequency of testing.Also, UKGTS, was a multi-centre study involving ten centres in the UK in which a large number of subjects -516were randomized.
This study is important in many ways, perhaps most significantly, because it is the 2 nd study to demonstrate the positive treatment effects of IOP reduction in manifest glaucoma.the highest level of medical evidence, more than one study is usually required and this has been lacking until now.Since modern glaucoma treatment is based upon IOP reduction, and since glaucoma management uses about 25% of all ophthalmology resources, this is a fundamental issue in ophthalmic care.That the study was placebo controlled is a further strength.
The magnitude of treatment effects also is important.The IOP difference between the treated and the placebo arms after 24 months was a modest 2.9 mmHgdue to the fact that untreated pressure levels at study entry were quite low.IOP-reducing agents produce much smaller pressure reductions in eyes that start out with low pressures than in eyes where pressure is high.Still the risk of progression was 40% lower in the treated group than in eyes receiving placebo drops.This is a risk reduction of 13% per mmHg, confirming EMGT and Canadian Glaucoma Study results, demonstrating that IOP reduction is highly effective, and that "every mm of pressure counts ". 12,13 These results motivate careful clinical follow-up and monitoring of disease progression in glaucoma patients, and should also serve as a stimulus to the pharmaceutical industry to continue development of new and even more potent drugs.
It is also important that very significant treatment effects could be seen after only 24 months; in fact, the first differences were seen already after 12 months.Certainly, the UKGTS took a lot longer than 2 years to complete, but only because recruitment took several years.Measuring glaucomatous progression by following visual field status is the gold standard, and visual field sensitivity also is important to patients.Nevertheless, in recent years it has often been stated that studies using visual field endpoints take too long, and that it, therefore, is too difficult to assess the effects of new drugs or other treatment modalities.The authors clearly demonstrate that this view is too pessimistic, and that with frequent testing using widely available clinical tools, important studies can be completed within a very reasonable time.This is just the first of what I expect will be a series of papers reporting UKGTS results; I am convinced that additional intriguing findings will be reported in the future, notably comparing the results obtained with visual field testing with those of ophthalmic image analysis.