Minimizing IOP variations an important consideration in glaucoma therapy

This aticle really freaked me out!  One thing is ophtalmologists have no clue of which eye drops should work for you.  It seems that they never read research reports like we do. 

-Agnes

Progressive visual field damage in eyes that seem to have adequately controlled intraocular pressure (IOP) may be due to fluctuations over the 24-hour period, particularly during the overnight hours, that are not seen by ophthalmologists when they check IOP only during regular clinic times.
Recent research underscores the importance of 24-hour IOP control to minimize pressure fluctuations.1 Nonetheless, practitioners may not be utilizing these important data when choosing IOP-reducing medications. They need to pay greater heed to the “sleeping giant” that rises at night.

The need to minimize IOP fluctuation

Research has shown that IOP fluctuation appears to be linked with glaucoma progression. Bergea and colleagues reported that visual field stability was better in newly diagnosed patients with small IOP variations who completed the two-year follow-up period.2 In particular, there was a greater correlation between visual field decay, IOP variation, and mean IOP, than baseline IOP or degree of IOP reduction. Asrani and colleagues also noted the risk associated with diurnal IOP variations in patients with open-angle glaucoma.1 (Figure 1) They found the diurnal range and range of IOP over several days were significant risk factors for progressive visual field deterioration.
Other investigators have noted similar findings. Nouri-Mahdavi et al. found that greater IOP fluctuation increases the odds of visual field progression by 30% (for each 5-year increment in age and 1 mm Hg increase in IOP fluctuation).3 The higher risk conferred by IOP fluctuation was consistently observed in eyes with and without a history of cataract extraction.
Hughes and colleagues noted that high IOP and wide diurnal IOP variation were major risk factors for glaucoma progression, and standard clinic follow-up evaluations failed to identify these phenomena.4
These trials all support the importance of clinicians selecting medical therapies that properly control IOP throughout the 24-hour period.

Prostaglandins: 24-hours and beyond

Topical prostaglandin analogues are the current mainstay of glaucoma therapy. They provide 24-hour control of IOP and are a clear treatment choice. Indeed, Orzalesi and colleagues recently reported that Xalatan (latanoprost 0.005%; Pfizer, New York, N.Y.), Travatan (travoprost 0.004%; Alcon, Fort Worth, Texas), and Lumigan (bimatoprost 0.03%; Allergan, Irvine, Calif.) all effectively lowered IOP compared to baseline values in patients with primary open angle glaucoma or ocular hypertension, both during the day and at night.5
Interestingly, travoprost has shown IOP efficacy beyond 24 hours.6-9 DuBiner and colleagues observed IOP to be significantly reduced in 21 patients treated out to 84 hours after the last dose.6 (Figure 2) In a follow-up study, there was a significant lowering of IOP at all time points during the 44 hours after the final dose.
Similarly, Sit and colleagues found this IOP-lowering effect was sustained from 41 to 63 hours after the last dose; notably during the nocturnal period.7 (Figure 3) Garcia-Feijoo et al. reported an IOP-lowering effect for 48 hours after last administration.8 Recently, Peace et al.9 showed Travatan, with and without BAK (Travatan Z, Alcon) effectively lowered IOP at all time points measured out to 60 hours after the last dose. A summary of these studies is depicted in Table 1.

Adjunctive therapy

Of course, one medication is often not enough to control IOP: almost 50% patients require more than one drug to achieve their target IOP.10,11 When a second hypotensive agent is required, it makes sense to choose one that complements the 24-hour control delivered by a prostaglandin.
Beta blockers have been the most common adjunct to prostaglandin therapy. While effective in controlling IOP during the daytime, their effect on IOP has been found to diminish at night.12,13 This makes sense as sympathetic tone has been observed to decrease during the nocturnal period.12 Clinically, Liu and colleagues did not observe any difference in IOP between timolol and nontreated patients during the nocturnal period in their sleep lab.13 (Figure 4) These observations raise some interesting questions regarding the role of these agents.
Akin to the beta-blockers, alpha-agonists do not appear to provide the steady 24-hour control that the prostaglandin analogs do. Alphagan P (brimonidine, Allergan, Irvine, Calif.) has been associated with significant peaks and troughs. Orzalesi et al. found Alphagan P was less effective in controlling IOP at midnight and 3 and 6 a.m. versus Xalatan and Cosopt (a fixed combination of timolol maleate and dorzolamide HCl, Merck, Whitehouse Station, N.J.).14 (Figure 5)
Carbonic anhydrase inhibitors (CAIs) are being reevaluated as a prostaglandin adjunct. Retrospective observations by O’Connor and colleagues suggested that Trusopt (dorzolamide; Merck) provided an additional reduction of 3.9 mm Hg, while eyes on beta blockers or alpha agonists showed a 2 mm Hg reduction when added to latanoprost.15 More recently, Feldman found in a prospective study of 163 glaucoma patients using travoprost that AZOPT (brinzolamide; Alcon Laboratories) lowered IOP greater than brimonidine by 1.2 mm Hg at 8 a.m., 1.1 mm Hg at 4 p.m., and 0.7 mm Hg in mean diurnal IOP (P=0.035).16
CAIs work by inhibiting carbonic anhydrase, produced throughout the day and night. Orzelazi found CAI therapy was more effective than timolol at midnight and 3 a.m. as monotherapy.17 (Figure 6)

Research shows that 24-hour control is critical to managing glaucoma progression

Figure 1: Diurnal IOP range and disease progression. Relative risk progression within 5 years.
Modified with Asrani S, et al. J Glaucoma 2000;9:134-142. (Permission pending)

Figure 2. Diurnal IOP control: travoprost and latanoprost With permission Dubiner, H.B., et. al, Clinical Therapeutics, 2004, Vol. 26, No. 1. (Permission pending)

Figure 3: Comparison of 24-hour patterns in IOP in patients treated with timolol and those receiving no treatment (baseline) Modified from Liu JHK, Kripke DF, Weinreb RN. Am J Ophthalmol. 2004;138:389-395. (permission pending)

Figure 4: Comparison of IOP control over a 24-hour period in patients treated with dorzolamide, a carbonic anhydrase inhibitor, versus the beta-blocker timolol. Modified from Orzalesi et al. Invest Ophthalmol Vis Sci. 2000;41:2566-2573. (Permission pending)

Figure 5: Comparison of Nocturnal supine and Diurnnal Sitting IOP patterns in health and glaucoma patients. Nocturnal and early morning pattern suggest differences in the glaucoma group.
Modified from Liu et al. Invest Ophthalmol Vis Sci. 2003;44:1586-1590.
Permission Pending