Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Ophthalmology University Program 2006

Dresden, Germany / September 17-18, 2006

Researchers have long been aware that elevated intraocular pressure (IOP) is associated with the development and progression of glaucoma. In the Ocular Hypertension Treatment Study (OHTS), individuals between 40 and 80 years of age with normal visual fields and optic discs and IOP ³24 mm Hg in at least one eye were randomized to receive treatment or no intervention. Participants were then monitored for signs of glaucomatous visual field loss and/or optic disc damage. The patients in the treated group achieved a mean reduction in IOP of 22.5% compared to 4.0% in the control group.

At 60 months, the cumulative probability of developing primary open-angle glaucoma (POAG) was 4.4% in the treated group and 9.5% in the observation group. Thus, according to Dr. Lutz E. Pillunat, Director, University Eye Clinic of Dresden, Germany, “Lowering IOP is the only proven treatment for glaucoma and we know that a significant reduction in IOP is beneficial in reducing the rate of progression in POAG.”

This dedicated session was held at the University of Dresden and was chaired and hosted by Dr. Pillunat.

The Link Between Elevated IOP and Optic Nerve Damage

The sclera is a fibrous elastic tissue that buffers pressure changes in the eye; with age, the sclera becomes stiffer. In the presence of chronic increases in IOP, the sclera may also become stiffer through strengthening the extracellular matrix. When this occurs, the sclera is less able to carry out its buffer function. Myopic eyes, which have a longer axial length, may be particularly vulnerable to such processes because the sclera is stretched thinner.

The non-myelinated axons of the ganglions in the lamina cribrosa are particularly susceptible to damage once the buffering mechanism for reducing stress is compromised. Additionally, the increased rigidity of the lamina cribrosa may lead to activation of astrocytes and a remodelling of the extracellular matrix. Dr. Pillunat suggested that activated astrocytes could in turn lead to damage of the axons of retinal ganglion cells through accumulation of toxic substances such as NO and TNFa.

Reviewing 24-hour Monitoring

Although studies such as the OHTS and the CIGTS (Collaborative Initial Glaucoma Treatment Study) established the benefit of lowering IOP, Dr. Anastasios Konstas, Associate Professor in Ophthalmology and Head, Glaucoma Unit, University Department of Ophthalmology, AHEPA Hospital, Thessaloniki, Greece, pointed out that they were mainly based on single IOP readings. Like blood pressure (BP), IOP can fluctuate throughout the day. In the most extensive study of the 24-hour IOP profile, applanation tonometry was used to measure IOP in 1072 eyes of 547 Caucasian glaucoma patients or those with suspected glaucoma at 7 a.m., noon, 5 p.m., 9 p.m. and midnight (Jonas et al. Am J Ophthalmol 2005;139(6):1136-7). Peak IOP values tended to occur early in the morning, although the authors concluded that more than three-quarters of any single IOP measurement taken between 7 a.m. and 9 p.m. would miss the peak IOP.

Other smaller studies of other types of glaucoma generally coincide in that peak pressures will occur early in the morning, but Dr. Konstas explained that there are certain “difficult” groups such as young glaucoma patients and patients with secondary glaucoma who have irregular fluctuations. In such cases, IOP readings can be misleading and patients may progress even though a single IOP reading suggests that control is good. On a practical point, not all ophthalmologists will have the resources to do a 24-hour profile, but by scheduling visits at three different times, for example, it is possible to build up a diurnal profile that is fairly representative of the 24-hour one.

Intraocular Pressure Profiles

Ambulatory monitoring of BP in hypertensive patients can accurately predict organ damage. Such measurements have long been used in the development of antihypertensive therapies to better identify trough and peak effects and confirm if efficacy is maintained throughout the 24-hour period (Zanchetti A. Am J Hypertens 1997;10(9 Pt 1): 1069-80). By analogy, 24-hour monitoring of IOP could help improve therapies and help in the development of combinations that minimize circadian fluctuation as far as possible.

A number of recent studies have compared the efficacy of IOP-lowering treatments by measuring profiles rather than taking single IOP measurements. For example, comparison of latanoprost with another prostaglandin analogue, bimatoprost, suggested that the latter agent works slightly better during the day. Studies with 24-hour profiles can also help determine the optimal time to administer therapy. Thus, a study comparing morning vs. evening administration of travoprost found that evening administration yielded smaller fluctuations in IOP. Given that not all patients have peak IOP at the same time, knowledge of when a given compound is most effective can help tailor the medication and thereby improve outcome.

Dr. Konstas discussed a study conducted in Greece that compared latanoprost 0.005% given every evening vs. a fixed combination of timolol 0.5% and dorzolamide 2% given twice daily in 34 patients with POAG or ocular hypertension (Konstas et al. Ophthalmology 2003; 110(7):1357-60). The study was single (investigator) masked with a crossover design (six-week treatment periods), with IOP measured at four-hour intervals throughout the day. Thirty-three participants completed the study. Differences in IOP between the two groups were not statistically significant except at 10 p.m., when mean IOP for the fixed combination was 15.3±2.0 mm Hg compared to 15.9±2.0 mm Hg for latanoprost (P=0.05).

Evidence-based Decisions in Glaucoma Patients

According to Dr. Neeru Gupta, Director, Glaucoma and Nerve Protection Unit, and Associate Professor of Ophthalmology and Vision Sciences, Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, the increasing medical literature impacting clinical practice is something she characterized as “a paradigm shift, whereby physicians are using evidence based on the literature to help guide decisions.” At the heart of this paradigm shift is the concept of evidence-based medicine. According to the methodology of evidence-based medicine, reports in the medical literature are assigned levels of evidence according to rules that give an indication of the reliability of the findings of a study. The underlying assumption is that “clinical practice based on an understanding of the evidence will help provide better patient care,” noted Dr. Gupta. “There are some ‘rules of evidence’ that may help each of us to assess independently the credibility of published information. The design of the study from the highest to lowest level of evidence are randomized controlled trials, cohort studies, case-control designs, case series, case reports and opinions,” she commented. The results from randomized controlled trials are considered the most robust because randomization ensures comparison of like with like, whereas non-randomized studies are considered less robust because of selection leading to potential bias.

For the findings of a study to be valid, it is also important that a study be well conducted. Dr. Gupta, using several articles, highlighted some general considerations when judging whether this is the case. For example, are the aims of the study clearly stated and was the study design appropriate for addressing those aims? Are the statistical methods clearly documented? Were the patients properly accounted for and how were patients who dropped out of the study treated in the analysis? Was follow-up long enough and complete enough? Studies of glaucoma present their own particular challenges with IOP considerations, including the measurement of corneal thickness. For a valid assessment of safety, adverse events also need to be properly documented.

“In summary, when assessing articles appearing in peer-reviewed journals, it is helpful to keep in mind several important questions: Is the design appropriate to the aims? Is the aim clear? These questions will help to quickly determine whether the article is worth studying further and how likely it is to provide meaningful information. Only then can we ask, ‘Can these results be applied to my clinical practice.’ Critical appraisal of the literature is not an academic exercise, but rather central to optimal patient care,” Dr. Gupta concluded.

Normal-tension Glaucoma

Elevated IOP is the most important predictor of glaucomatous visual field loss and/or optic disc damage and that lowering IOP should be the most important goal of any glaucoma treatment. However, according to Dr. Colm O’Brien, Professor of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland, “A number of recent studies suggest that almost 35% of newly-diagnosed glaucoma patients had normal IOP when they were first seen.”

The CNTGS (Collaborative Normal-Tension Glaucoma Study) randomized patients with normal-tension glaucoma to IOP-lowering treatment. The treatment goal was attaining at least a 30% reduction in IOP (Drance et al. Am J Ophthamol 2001;131(6):699-708). Dr. O’Brien pointed out that neither prostaglandin inhibitors nor carbonic anhydrase inhibitors were available when the study started in the early 1990s. Consequently, treatment was limited to pilocarpine, laser trabeculoplasty or surgery. Progression was observed in 12% (7/61) of treated patients and 35% (28/79) of control patients (P=0.001).

Role of Ocular Blood Flow in Glaucoma

Some glaucoma patients show progression with low IOP, whereas others with high IOP do not progress. Clearly other factors are involved. Dr. Andreas Böhm, University Eye Clinic of Dresden, identified vascular risk factors such as hypotension, vasospasms and disc hemorrhages which could “lead to a reduction of optic nerve head perfusion and therefore to optic nerve head damage.” Reduced systemic pressure can be particularly harmful. The present trend is for internists to aggressively lower BP, but this can lead to nocturnal hypotension due to overtreatment. A detailed medical history, paying particular attention to cold hands/feet, migraine and Raynaud symptoms can also help identify patients at risk of progression due to poor ocular blood flow.

A major problem with any study that tries to definitively establish a link between poor blood supply to the optic nerve head and glaucomatous damage is that ocular perfusion is hard to measure reliably: “There is no gold standard,” as Dr. Böhm observed. Many techniques measure blood velocity with Doppler methods and higher velocity is generally taken to correlate with higher perfusion. However, this is not necessarily the case—velocity could be high in a partially occluded vessel even though the actual perfusion is low. Nevertheless, Dr. Böhm concluded that the techniques available could give an overall picture of ocular blood perfusion.

Dr. Leopold Schmetterer, Extraordinary Professor and Section Head, Department of Clinical Pharmacology, Medical University of Vienna, Austria, pointed out that the CNTGS also identified two vascular factors as predictive of progression, namely, migraine sufferers and patients with optic disc hemorrhage. The EMGT (Early Manifest Glaucoma Trial) in patients with POAG identified the same risk factors for progression. Subsequent studies have shown impaired ocular blood flow to be predictive of progression as well. According to Dr. Schmetterer, the Egna-Neumarkt study showed that “the prevalence of glaucoma is four times higher at a diastolic perfusion pressure of 50 mm Hg than at 80 mm Hg” (Bonomi et al. Ophthalmology 2000; 107(7):1287-93). Interestingly, this study also showed systemic hypertension to be associated with a higher prevalence of glaucoma. Dr. Schmetterer speculated that this could be because hypertension is treated aggressively by internists. Another possibility is that increased BP is also linked to increased IOP. This is supported by the observation that systemic hypertension is associated with a higher prevalence of POAG but not normal-tension glaucoma.

The perfusion pressure in healthy eyes may fluctuate throughout the day for a number of reasons. These changes in BP do not, however, cause glaucomatous damage because autoregulation mechanisms ensure a constant supply of oxygen to the optic nerve head. According to Dr. Schmetterer, the current line of thinking is that these autoregulation mechanisms are impaired in glaucoma patients, mainly through endothelial dysregulation. Given that impaired ocular blood flow seems to play a part in glaucoma, interventions that improve ocular blood flow would be desirable.

After a review of the options, Dr. Schmetterer concluded, “Dorzolamide is the only available topical antiglaucoma drug for which a positive effect on ocular blood flow is evidenced in a larger study population.”

Summary

During the course of this University Program, delegates learned of the importance of building up a profile of IOP. The ideal situation of 24-hour monitoring might not be practicable in many cases, but forethought in the timing of visits can help give a better overall indication of IOP. A more detailed picture of IOP can make measurement of the efficacy of IOP-lowering agents in clinical studies more robust. In clinical practice, patient management can be improved by ensuring the use of a treatment that provides 24-hour IOP control. The tendency to base clinical decisions on evidence-based medicine makes critical reading of the biomedical literature important. Delegates were shown how to spot weak studies, for example, those with mismatches between the stated aims and the final analysis and those conducted according to vague protocols.

While IOP is undoubtedly important in glaucoma management, an understanding of vascular factors should help further identify patients at risk of progression. This knowledge will help ensure appropriate management with agents that have demonstrated efficacy in controlling blood flow and IOP.