Management of glaucoma progression

Purpose: To define the features of glaucoma progression, considering the analysis of treatment approaches (regimens) in patients with primary open-angle glaucoma.

Methods: The multicenter clinical cohort study was performed during Nov 2015 - Jan 2018 in 30 clinical bases of 6 countries. Data of 155 primary open-angle glaucoma patients (247 eyes) was included. Anamnesis, intraocular pressure (IOP) by the moment of the first treatment regimen as well as the administered treatment were analyzed retrospectively. IOP (baseline and 5 more measurements each 6 months) was analyzed prospectively. During the automated perimetry analysis, mean deviation of light sensitivity (MD) and its pattern standard deviation (PSD) were analyzed. IOP, MD, PSD data dynamics in the prospective part was described by y=kx+b equation, where b was a constant, an average parameter rate, and k - the coefficient of line slope, describing the trend of parameter increase/ decrease during the 2.5 year follow-up.

Results: No statistically significant difference in age and anamnesis between men and women was found. Mild glaucoma stage was found in 192 eyes (77.73%), moderate -in 40 (16.19%), advanced - in 15 (6.08%). Glaucoma duration in patients with different disease stages by the moment of study beginning was comparable and averaged 5.7 (3.9; 8.6) years.

Throughout the average follow-up period of 8 years mild stage did not progress in 135 (70.31%) of 192 eyes, turned into moderate stage in 45 eyes (23.44%), into advanced -in 8 eyes (4.17%) and into terminal - in 4 eyes (2.08%). During the average follow-up period of 8.45 years moderate

glaucoma stage remained stable in 17 of 40 eyes (42.50%), turned into advanced in 19 eyes (47.50%), into terminal -in 4 eyes (10.00%). In turn, existing advanced glaucoma remained stable in 11 eyes (73.33%) and progressed into terminal in 4 eyes (26.67%) during 7.6 years of follow-up.

Generally, the only manageable criteria of glaucoma treatment and lack of optic neuropathy progression is adhering to the recommended IOP level its and timely correction according to disease stage.

IOP difference in dependence of glaucoma stage by the moment of disease diagnostics was statistically significant (p<0.001; H=43.965): the higher the glaucoma stage, the higher IOP level by the time of diagnosis verification. However, no statistically significant IOP difference in dependence of glaucoma stage was found after prescribing the first treatment regimen (р=0.238; H=2.875).

Target IOP was reached only in patients with mild glaucoma, in 75% of moderate stage patients IOP was >19.5 mmHg, and in 75% of advanced stage patients on the first treatment regimen IOP was >20 mmHg. By the moment of prospective part start, no statistically significant IOP difference depending on glaucoma stage were found (р=0.924; H=0.479).

By the final visit a statistically significant IOP difference in dependence of glaucoma stage was found (p=0.050; H=7.807). The more advanced glaucoma stage the patient had, the lower IOP was achieved. Since the start of the prospective part, a more aggressive treatment was observed in order to reach the lowest individually possible IOP, using accessible treatment options.

A slow disease progression tendency was revealed during 2.5 years of study by static automated perimetry in each glaucoma stage group and on the whole: MD changed from -3.27 (-7.98; -1.37) to -4.08 (-10.33; -1.95), PSD from 3.14 (2; 5.79) to 3.56 (2.14; 6.31) dB.

Patients with mild stage remained stable during the 2.5              years follow-up with negative MD trend of 6 months -0.09 (-0.27; 0.08) dB, in case of MD decrease of -0.86 (-1.24; -0.44) dB per 6 months the transition to the following stage occured. Moderate stage patients showed a positive tendency with the stage being stable for 2.5 years. Progression to the following stage occurred in cases of a -1.42 (-1.58; -0.82) dB dynamics per 6 months. Advanced stage remained stable if the dynamics measurements did not exceed -0.25 (-0.61; -0.09) dB per 6 months, and progressed to terminal if it reached -0.85 (-1.79; -0.73) dB per 6 months. Retinal light sensitivity loss accelerates with stage progression, however, there is no trend of PSD acceleration with the stage increase.

By the time of glaucoma diagnosis verification 90.3% patients fell into one of 5 following regimens: beta-blockers (BB - 43.7%), prostaglandin analogues (PA - 27.1%), carbonic anhydrase inhibitors (CAI - 3.2%), beta-blockers and prostaglandin analogues combination (BB+PA - 12.1%), beta-blockers and carbonic anhydrase inhibitors combination (BB+CAI - 4%). Laser and surgical treatment amounted to 5.2%. The use of these “top-5" hypotensive regimens lead to IOP level decrease to 20.5 (18; 23) - 23.5 (22; 25) mm Hg irrespective of the disease stage.

By the moment of prospective study start, the amount of treatment regimens combinations increased to 31; the most popular being beta-blockers (BB)+prostaglandin analogues (PG), PG, BB+PG+carbonic anhydrase inhibitors (CAI), BB, BB+ICA (72.3%). Laser and surgery treatment amounted to 24.3%.

By the end of the study 40 different variants of treatment were used. The most popular regimens didn't change (BB+PG+CAI, BB+PG, PG, BB+CAI), BB was replaced by surgical intervention at the top of the list.

PG and BB were used during mild stage glaucoma, and PG use caused the slightest light sensitivity loss among there hypotensive drugs. CAIs were added in more advanced stages, enforcing the PG and BB therapy. BB use showed the most prominent negative trend. Combined BB+PG therapy was followed by a 2.85-times slower disease progression than BB monotherapy.

The higher was the baseline IOP, the more changes of treatment regimens were tried. PSD trend does not show the dependence of treatment regimens amount.

Conclusion: Starting treatment helped reach target IOP only in patients with mild glaucoma, in 75% of moderate stage patients IOP exceeded 19.5 mm Hg, in 75% patients with advanced stage IOP exceeded 20 mm Hg. The progressing negative MD trend increased with the disease stage (-0.14; -0.26; -0.46).

By the moment of glaucoma diagnosis verification 90.3% prescriptions consisted of five main regimens (BB, PG, BB+PG, BB+CAI, CAI). BB monotherapy caused the most prominent MD negative trend during 2.5 years of follow-up (-0.4). The best trends were showed by PG (-0.07), PG+BB (-0.14), BB+CAI (-0.14).

Regimen change provided extra IOP decrease (IOP trend change from 0 to -2.5), however the disease progression still occurs (trend change from -0.18 to -0.81), which may bear witness both to the starting therapy inefficacy and 'programmed' disease progress.

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