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The Collaborative Normal-Tension Glaucoma Study and some of its lessons

Stephen M. Drance

Ophthalmologists have had difficulty with managing patients who had all the hallmarks of chronic open-angle glaucoma but whose intraocular pressure (IOP) readings were consistently in the statistically normal range. It was not clear whether the normal pressure was involved in the pathogenesis of the disease and also whether the reduction of normal IOP was beneficial to these patients. This difficulty first arose shortly after the ophthalmoscope was introduced, when cupping of the optic nerve head was recognized as a feature of glaucomatous optic neuropathy by von Graefe.¹ He observed the existence of the optic nerve head abnormality associated with disturbance of vision in the presence of normal IOP, as estimated digitally. His colleagues strongly criticized this concept, which he later recanted; however, he continued to stress that different optic nerves might have different susceptibilities to IOP. Schnabel² stated that most ophthalmologists were aware of these cases, in spite of von Graefe's denial; furthermore, an understanding of the pathogenesis of glaucoma had to account for all diseased patients rather than deny the existence of patients in whom the IOP was not elevated. The introduction of Schiøtz impression tonometry confirmed the existence of low-tension glaucoma, but it was considered to be very rare.

The explanation for these "rare" cases was usually sought in the inadequacy of periodic pressure recordings to find the abnormally elevated IOP. It was also suggested that some patients might have damage from high pressure, but, with aging, decreased aqueous secretion might produce a decline in IOP, so that the patients really show a "burnt-out" phase of the disease. Damage to the optic nerve by sclerotic internal carotid arteries was also considered. The population studies in the United Kingdom,^3-5 Sweden,^{6, 7} the United States^8-12 and Japan^13-15 showed convincingly that normal-tension glaucoma was not rare.

In October 1998 the American Journal of Ophthalmology carried the first two papers from the multicentre Collaborative Normal-Tension Glaucoma Study,^16-17 which was started in 1984 to try to answer these basic questions. When the study was designed, some ophthalmologists suspected that lowering of the IOP was helpful, but others felt it was not. This presented the dilemma of how to design such a study, which had to include an untreated control group. To make the study ethically acceptable to the collaborating investigators and their institutions, only the better eye of each patient was studied, advanced disease was excluded, and eyes with threats to fixation were immediately randomized without waiting for them to demonstrate progression while being studied. The increments of visual field change constituting "progression" that were the basis for randomization into the untreated or treated arm of the study and that also determined "end points" for the study were chosen to be exceedingly small so that eyes assigned to no treatment could be released quickly from any constraints in their managements. These small visual field changes turned out to be nonspecific and had to be excluded from the study. The criteria subsequently required for "end point," although much more robust, were still small enough that the untreated control eyes were not endangered.

All the collaborators believed that filtering surgery would be needed to achieve the required pressure reduction of 30%, especially since all topically administered vasoactive medications that could affect the optic nerve, beneficially or adversely, were excluded because they would have confounded the interpretation of the effects of the IOP reduction, the main aim of the study. The scientific part of the study posed the question as to whether lowering of the IOP changed the course of the disease. The untreated patients were compared with treated patients after they attained a 30% reduction in IOP. The baseline values for the treated patients were obtained after the IOP reduction of 30% was achieved. The clinical trial, on the other hand, compared the "intent to treat." for which the baseline values for both arms of the study were obtained at the time of randomization.

The study showed unequivocally that once an IOP reduction of 30% was achieved, the disease subsequently showed a lower rate of progression of visual field defects than in eyes in which no effort was made to lower the IOP. We were pleasantly surprised that in nearly half of the patients the IOP reduction was achieved with topical drug therapy or laser trabeculoplasty, or both.¹⁸ A total of 140 eyes of 140 patients were studied. An overall survival analysis showed a 5-year survival rate of 80% in the treated arm and 33% in the untreated arm, a statistically significant difference (p < 0.0001), which confirmed recently reported findings.¹⁹ In the clinical trial, however, initial results showed that progression of visual field defects occurred at indistinguishable rates in the eyes with pressure reduction and the untreated control eyes. Of the 34 cataracts that developed during the study, 11 were in the control group and 23 were in the treated group (p = 0.0075), with the highest incidence in those whose treatment included filtration surgery. When the data were corrected for the development of cataracts, the overall survival analysis showed a 5-year survival rate of 80% in the treated arm and 40% in the control arm (p = 0.0018).

This study is the first to follow an untreated glaucoma population. The natural untreated history will be analysed and described in the next paper. It is also the first multicentre collaborative ophthalmologic clinical trial carried out with the support of a non-governmental foundation. One-third of the patients were recruited and followed in Canada. The results show convincingly that statistically normal IOP is involved in the pathophysiology of the disease. They also confirm that the progression of cataracts is more common in surgically treated patients. These cataracts mask the benefits of IOP reduction, but when they are accounted for in the analysis, the disease is favourably influenced by the 30% reduction in IOP. Given that the study started before the advent of many new powerful IOP-reducing agents and was done without the use of ß-blockers, it is likely that the proportion of patients with normal-tension glaucoma in whom an IOP reduction of 30% was obtained nonsurgically (50%) would be even greater if the study were done now. The risk of cataracts would therefore be further diminished. The great strides made in cataract surgery also reduce the price patients have to pay for the improved outcome of their glaucoma.

It should be pointed out that one in five patients with a 30% IOP reduction experienced progression of their visual field defects and that one in five untreated patients had no progression after fairly long periods of follow-up. It is possible that after even longer observation all patients may show some progression. However, it is more likely that there are other risk factors that either modify the IOP effects or even determine, in some patients, the course of the disease independently of the IOP. If there is a group of patients whose disease is not progressing or whose progression is so slow as to not produce the small increment of deterioration required for end points in the study, it is unlikely that they would have benefitted from a reduction in IOP. The variability of the natural history of normal-tension glaucoma will be analysed in the next paper, which will be followed by identification and analysis of the risk factors that determine which patients benefit from IOP reduction and which patients do not benefit and may even experience adverse effects.

The small amount of deterioration of the visual field used in this study to determine the end points does not necessarily tell us the quality of vision of an individual patient for the remainder of his or her life. This important relation will have to be determined by subsequent research for all forms of chronic open-angle glaucoma.

What have we learned from this study? A sizeable reduction in IOP favourably influences disease progression in patients with normal-tension glaucoma. The pressure reduction, particularly when surgically produced, accelerates cataract development. The disease is slowly progressive and in some patients may be almost nonprogressive, whereas in other patients even the 30% reduction in IOP does not prevent progression. It is probably appropriate in patients with normal-tension glaucoma, whose visual field defects are not imminently threatening the integrity of fixation, to establish whether the disease is progressing and preferably also the rate of progression before deciding on substantial pressure reduction, which is not without its price. When a decision is made to reduce the IOP, we at least know that this is likely to improve the course in most patients. There are many clinical factors that clinicians currently take into account when advising on these management steps. It is hoped that some of these factors will become clearer when the study is fully analysed and reported.

Reprinted with permission of the Canadian Journal of Ophthalmology

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