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The relationship between control of intraocular pressure and visual field deterioration, AGIS

The AGIS Investigators, Am J Ophthalmol 2000; 130:429-440

Paul Palmberg

The Advanced Glaucoma Intervention Study (AGIS) investigators have now published fundamentally important results from the study that bear upon the questions of (1) "How much of glaucoma damage is pressure dependent?" and (2) "How low must the pressure be to yield the maximum benefit?"

These were not the primary questions that the AGIS investigators set out to answer in 1988. AGIS, a National Eye Institute sponsored multicenter clinical trial, enrolled 789 eyes of 591 patients in 1988 to 1992 in order to compare the long-term outcomes of two randomized sequences of treatment in patients with open-angle glaucoma in whom medical therapy had failed: Argon laser trabeculoplasty (ALT) first or filtering surgery first, with cross-over when indicated. Intermediate reports from the study suggested roughly equal overall outcomes for the two sequences of treatment, but sub-group analysis suggested that surgery first yielded a better visual field outcome than ALT in whites, while surgery first yielded an equal visual field outcome and better visual acuity outcome in African-Americans (Ophthalmology 1998; 105:1146-64). The recommendation to skip ALT in whites has not been widely accepted.

The AGIS investigators have now looked at the relationship between IOP and visual field progression in the summed group of patients. In one analysis, the patients were divided into four groups, based upon the percentage of the time they achieved an IOP <18-mmHg. The four groups achieved the goal in either 100%, 75-99%, 50-74%, or less than 50% of visits, respectively. The corresponding mean IOP values during the first 6 years for the groups were 12.3, 14.7, 16.9 and 20.2 mmHg, respectively.

As can be seen in Figure 1, the lowest pressure group had a flat curve throughout follow up, meaning that on average glaucoma damage was halted. Each successively higher pressure group had a correspondingly greater mean progression of field loss. The visual field defect scores were measured in a scoring system particular to the study, AGIS units (see Ophthalmology 1994;101: 1445-1455). The mean baseline field defect was 8.4 AGIS units, which corresponded to a Mean Deviation of -10.5 dB in the more generally understood Humphrey Visual Field scoring.

The comparison of mean visual field defect scores for groups of patients in this analysis is far more powerful statistically than would be a comparison of the percent of patients found to progress by any specific criteria. Any "noise" (variability not due to true progression or true improvement) is cancelled. The AGIS investigators reported that in the lowest pressure group 15% of patients would have met their formal criterion for progression, but also 15% would have moved in the direction of improvement by the same degree. How much was due to noise and how much due to a true getting worse or getting better at these pressures? Perhaps a trend analysis, such as with the Progressor Program developed at Moorfields Eye Hospital, would identify progression in individual cases more reliably, or a random walk through the data in the low pressure group could estimate inherent noise in the testing procedure.

What are the limitations of these data? First, they are specific for patients with advanced open-angle glaucoma, and do not apply to persons with only ocular hypertension or to persons with normal tension glaucoma (NTG). Patients with milder glaucoma damage, as might be seen at diagnosis, might not be as sensitive to pressure as the AGIS patients. Such patients were randomized in the Comparison of Initial Glaucoma Treatments Study (CIGTS, NEI) to initial medical treatment or initial surgery, and are currently being studied. We should await results from that study before abandoning the usual practice of trying medical therapy and/or laser trabeculoplasty before surgery. The dose-response curve may be shifted to the right for such patients in comparison to the AGIS cohort.

Implications for practice

In patients with at least moderate visual field loss in whom medical therapy has failed, I believe a comparison of the AGIS results for surgery without antimetabolites to widely published results for surgery with either 5-FU or MMC favors antimetabolite use in most populations. One can achieve low normal pressures with the use of antimetabolites and is not likely to do so without them. Precautions should be taken, however, to reduce the potential complications of using antimetabolites.

When treating patients medically, the AGIS results suggest that in patients with moderate to severe glaucoma damage one should strive to achieve pressures in the low-normal range. This islikely to require the use of multiple medications, and to bring the use of combination therapies into favor. The days of placing a glaucoma patient with moderate glaucoma damage on a beta-blocker alone, and observing the patient at a pressure in the upper teens (just 25% lower than the initial pressure) have passed. Except in emergencies, one medication should be added at a time, with one-eye trials to prove effectiveness in pressure reduction, but one should proceed to add medications until a low normal pressure is achieved, if feasible, and to achieve at least a 30-50% lowering of IOP. Supplemental laser trabeculoplasty will often be needed to achieve such results.

While the AGIS results suggest that lower is better, we should keep in mind that about 70% of such patients would be stable at 15 mmHg, and that the risk-benefit rat