CONTROVERSIES

SECTION EDITOR: NEIL M. BRESSLER, MD The Ocular Hypertension Treatment Study Lowering Prevents the Development of , but Does That Mean We Should Treat Before the Onset of Disease?

Editor’s Note physicians who must make ratio- nal decisions based on the data in these articles. We must consider the The following articles suggest that there will be fewer patients receiving ocular benefits and costs of therapy, ad- antihypertensive medications based, in part, on applying the results of the Ocu- verse effects of therapies, and qual- lar Hypertension Treatment Study to clinical practice. Readers are invited to review these articles to see if they concur with the authors. ity of life issues before a plan of ac- tion is made. Neil M. Bressler, MD Glaucoma is a serious, irrevers- ible but slowly progressive dis- ease.7,8 Because the disease affects the peripheral visual field first, it is usu- E WOULD LIKE years without treatment.1 Con- ally many years from the onset of dis- to congratu- versely, 64% of these relatively high- ease to functional visual loss unless late Kass et al1 risk patients will not develop dam- the IOP is higher than the range and Gordon age in a 5-year period. Kass et al then studied in the Ocular Hyperten- et al2 for their conclude that “clinicians should sion Treatment Study. Even using 2W well-written articles concerning a consider initiating treatment for in- standard achromatic automated well-designed and important study. dividuals with ocular hypertension static perimetry, the physician can They clearly demonstrate that medi- who are at moderate or high risk for detect visual-field defects below the cal therapy that lowers intraocular developing POAG [primary open- level of the defect from the physi- pressure (IOP) prevents or retards angle glaucoma].”1(p701) We believe ologic blind spot, which we all live the development of glaucoma in pa- that this recommendation requires with and have no symptoms. Given tients with ocular hypertension. This further consideration. the cost of treating all people with is noteworthy as it links the devel- Recent multicentered clinical ocular hypertension at moderate to opment of glaucoma to IOP lower- trials have only dealt with a smaller high risk of developing glaucoma, it ing for the first time in a conclusive proportion of the population that al- may still be reasonable to wait until manner. This helps us better under- ready has a disease. Intraocular pres- the earliest change in the stand the glaucomatous process sure lowering in these people has or visual field is detected. when combined with the results of been shown to retard glaucoma- Contrary to clinical percep- other multicentered studies3-5 that tous progression in those afflicted. tions, glaucoma progresses so slowly find IOP lowering can retard the pro- The Ocular Hypertension Treat- that most patients die before devel- gression of glaucoma at various ment Study results affect a large per- oping blindness, even in one eye. stages of the disease process. centage of the US population. The Quigley et al9 found that it takes 13 The critical question is how to number of patients with ocular hy- years for white individuals and 16 apply this information in clinical pertension is large, and most of those years for African American individu- practice and policy making. Kass et will not develop visual-field loss. So, als to go blind from glaucoma. It ap- al and Gordon et al find that medi- the issue is whether all these people pears to take 40 years for someone cal treatment halves the develop- should be treated. with visual-field loss at age 40 to be- ment of the earliest detectable glau- Almost 8% (7.4%) of eyes have come legally blind in one eye and de- coma damage given our current IOPs higher than 21 mm Hg on a velop visual-field loss in the fellow techniques. At 60 months, only 4.4% single eye examination but do not eye. In cross-sectional data using the of treated patients compared with have POAG as defined by optic nerve Baltimore Eye Study,10 the Beaver 9.5% of untreated patients develop damage consistent with POAG.6 If Dam Eye Study,11 and the Framing- glaucoma. If we look at one of the we consider an IOP higher than ham Eye Study,12 only 4% of white higher-risk groups, those patients 24 mm Hg, the proportion of the individuals and 8% of African Ameri- whose IOPs were higher than population without glaucoma is can individuals with glaucoma are 25.75 mm Hg and had corneal thick- 3.5%. The implications of these Ocu- legally blind from it. Also, there is nesses less than 555 µm had a 36% lar Hypertension Treatment Study little evidence of an effect on health- chance of developing glaucoma in 5 articles affect many patients and the related quality of life until the dis-

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©2004 American Medical Association. All rights reserved. Downloaded From: by a Washington University - St Louis User on 04/30/2018 ease progresses to moderate or quality of life loss, the loss would disease course. Or is the course of marked damage.13 Visual-field de- have to be at least 0.23 quality- the disease unaltered until later in terioration has also been shown to adjusted life-years for each year of the disease? This may be better an- be slow, and functional loss associ- blindness in order to make the in- swered by the Early Manifest Glau- ated with visual-field loss has been cremental cost-effectiveness ratio coma Trial, whose results will be shown to be minimal until central less than $100000 per quality- published shortly. vision is affected. In fact, Parrish et adjusted life-year. A gain of 0.23 on It may be that medical therapy al14 found that only central vision a health-related quality of life scale can prevent or retard the develop- correlated with health-related qual- ranging from 0 to 1 (where 0 is death ment of glaucomatous damage, but ity of life because peripheral visual- and 1 is perfect health) is a substan- we must now question whether it is field loss from glaucoma was not a tial gain, especially for older adults correct to treat these eyes. Ocular hy- significant predictor of either global who are unlikely to achieve a score pertension remains an extremely im- (Medical Outcomes Study 36-Item of 1 regardless of their vision. portant risk factor for disease but is Short-Form Health Survey) or vi- The assumption that a quality not itself a disease. Instead of rec- sion-specific (National Eye Insti- of life loss will occur immediately ommending treatment for moder- tute Visual Functioning Question- when blindness occurs and that no ate- to high-risk individuals, we sug- naire) quality of life measurements. quality of life loss occurs when tak- gest that these individuals be seen Glaucoma is not like cancer, ing a chronic medication is overly annually or semiannually, have ad- which often, if caught at an early generous to prevention. Jampel et equate high-quality baseline docu- stage, is easier and cheaper to treat al15 have found that medical therapy mentation of their optic nerves and more likely to yield a cure than can alter and potentially diminish and visual fields, and that both the if treated at a later stage when the one’s quality of life. Factors such as patient and the physician have an disease can be fatal. Let us consider compliance, allergy, long lashes, dis- obligation not to miss follow-up the consequences of treating pa- comfort, and tearing can signifi- evaluations. As this study has also tients with ocular hypertension. Let cantly affect daily life. This would shown us, we should remember that us assume that all who have no make the necessary gain from the one visual field with earliest detect- medical contraindications have tried avoidance of blindness in older able changes is not proof of the de- taking timolol maleate, the stan- adults even higher. velopment of glaucoma.18 At least 2 dard medication that the Food and However, if only high-risk in- visual fields are necessary to docu- Drug Administration, Rockville, Md, dividuals were considered, the abil- ment visual-field loss.19 Before ex- uses as a gold standard to compare ity to affect a larger proportion of the pensive and quality of life–limiting other IOP-lowering medications. population sooner would require a therapy is begun, we must ensure The annual cost per patient, includ- smaller gain to make prevention a that a disease actually exists and ing an extra office visit to evaluate cost-effective measure. One study that a glaucomatous process has IOP-control timolol maleate gel, pe- showed a decrement in utility asso- begun. rimetry, and scanning laser ophthal- ciated with binocular blindness of moscopy, is $504. This is ex- 0.477, but in reality only a fraction Alan L. Robin, MD tremely expensive if treating a of this effect would occur at 12 years Kevin D. Frick, PhD hypothetical population of 100000 after the onset of POAG and many Joanne Katz, PhD patients with ocular hypertension. patients will not suffer binocular Donald Budenz, MD Considering relevant mortality rates blindness before they die.16 James M. Tielsch, PhD (to age 85 years) and assuming that The costs of complications as- Baltimore, Md annual rates of progression to POAG sociated with the medications— observed during the 5 years of the arrhythmias, depression, or bron- The authors have no relevant finan- study continue for 35 years, that only choconstriction—include systemic cial interest in this article. those who are not blind are receiv- medical testing, more medications Corresponding author: Alan L. ing physician visits, that only those to treat these complications, and per- Robin, MD, 6115 Falls Rd, Suite 333, who have not had incident POAG haps even hospitalizations.17 These Baltimore, MD 21209-2226 (e-mail: are receiving pharmaceutical treat- costs would increase the necessary [email protected]). ment, and that blindness occurs 12 gain in health-related quality of life years after incident POAG, the pre- in order to achieve a potentially cost- REFERENCES sent value of the costs of treatment effective preventive measure. for the cohort would be more than We still do not know the best $900 million or an average of more time in the course of the glaucoma- 1. Kass MA, Heuer DK, Higginbotham EJ, et al. The than $20 million per year that would tous process to initiate therapy. Does Ocular Hypertension Treatment Study: a random- ized trial determines that topical ocular hypoten- be borne primarily by older adults the rate of perimetric loss diminish sive medication delays or prevents the onset of at present, given Medicare policy on if we treat glaucoma early in the dis- primary open-angle glaucoma. Arch Ophthal- prescription medications at this ease? We do not know if the dis- mol. 2002;120:701-713. point, and eventually, in part, by the ease progresses more rapidly if 2. Gordon MO, Beiser JA, Brandt JD, et al. The Ocu- lar Hypertension Treatment Study: baseline fac- federal government and taxpayers’ therapy is begun once reproduc- tors that predict the onset of primary open-angle legislation. Assuming that the blind- ible perimetric damage occurs so that glaucoma. Arch Ophthalmol. 2002;120:714- ness brings about an immediate earlier intervention assures a better 720.

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©2004 American Medical Association. All rights reserved. Downloaded From: by a Washington University - St Louis User on 04/30/2018 3. The AGIS Investigators. The Advanced Glau- glaucoma. Invest Ophthalmol Vis Sci. 1996;37: 14. Parrish RK II, Gedde SJ, Scott IU, et al. Visual func- coma Intervention Study (AGIS), 7: the relation- 1419-1428. tion and quality of life among patients with glau- ship between control of intraocular pressure and 9. Quigley HA, Tielsch JM, Katz J, Sommer A. The rate coma. Arch Ophthalmol. 1997;115:1447-1455. visual field deterioration. Am J Ophthalmol. 2000; of progression in open-angle glaucoma estimated 15. Jampel HD, Schwartz GF, Robin AL, Abrams D, 130:429-440. from cross-sectional prevalence of visual field dam- Johnson E, Miller RB. Patient preferences for eye- 4. Lichter PR, Musch DC, Gillespie BW, et al, and the age. Am J Ophthalmol. 1996;122:355-363. drop characteristics: a willingness-to-pay analy- CIGTS Study Group. Interim clinical outcomes in 10. Rahmani B, Tielsch JM, Katz J, et al. The cause- sis. Arch Ophthalmol. 2003;121:540-546. the collaborative initial glaucoma treatment study specific prevalence of in an ur- 16. Nease RF, Whitcup SM, Ellwein LB, Fox G, Lit- comparing initial treatment randomized to medi- ban population. . 1996;103:1721- tenberg B. Utility-based estimates of the relative cations or surgery. Ophthalmology. 2001;108: 1726. morbidity of visual impairment and angina. Oph- 1943-1953. 11. Klein BE, Klein R, Sponsel WE, et al. Prevalence thalmic Epidemiol. 2000;7:169-185. 5. Collaborative Normal-Tension Glaucoma Study of glaucoma: the Beaver Dam Eye Study. Oph- 17. Novack GD, O’Donnell MJ, Molloy DW. New glau- Group. The effectiveness of intraocular pressure thalmology. 1992;99:1499-1504. coma medications in the geriatric population: ef- reduction in the treatment of normal-tension glau- 12. Leibowitz HM, Krueger DE, Maunder LR, et al. The ficacy and safety. J Am Geriatr Soc. 2002;50:956- coma. Am J Ophthalmol. 1998;126:498-505. Framingham Eye Study monograph: an ophthal- 962. 6. Tielsch JM, Katz J, Singh K, et al. A population- mological and epidemiological study of , 18. Keltner JL, Johnson CA, Quigg JM, Cello KE, Kass based evaluation of glaucoma screening: the Bal- glaucoma, diabetic , macular degen- MA, Gordon MO, for the Ocular Hypertension timore Eye Survey. Am J Epidemiol. 1991;134: eration, and visual acuity in a population of 2631 Treatment Study Group. Confirmation of visual field 1102-1110. adults, 1973-1975. Surv Ophthalmol. 1980;24: abnormalities in the Ocular Hypertension Treat- 7. Katz J, Gilbert D, Quigley HA, Sommer A. Esti- 335-610. ment Study. Arch Ophthalmol. 2000;118:1187- mating progression of visual field loss in glau- 13. Gutierrez P, Wilson MR, Johnson C, et al. Influ- 1194. coma. Ophthalmology. 1997;104:1017-1025. ence of glaucomatous visual field loss on health- 19. Katz J, Quigley HA, Sommer A. Detection of inci- 8. Smith SD, Katz J, Quigley HA. Analysis of pro- related quality of life. Arch Ophthalmol. 1997;115: dent field loss using the Glaucoma Hemifield Test. gressive change in automated visual fields in 777-784. Ophthalmology. 1996;103:657-663.

We Should Treat Fewer Patients With Elevated Intraocular Pressure Now That We Know the Results of the Ocular Hypertension Treatment Study

HE OCULAR HYPER- conclude that to prevent glaucoma The relatively low risk of dam- tension Treatment damage in 1 person with ocular hy- age shown in the OHTS for eyes with Study (OHTS), a land- pertension, 20 persons need to be relatively low elevated IOP and the mark trial in glau- treated. influence of CCT on the risk pro- coma therapy, has de- If the OHTS investigators had file should lead to the treatment of finitivelyT answered the question supplied us with this information fewer patients with elevated IOP. Be- “Does lowering intraocular pres- only, we would be hard pressed to fore the OHTS, data on the rate of sure (IOP) in persons with elevated know how to apply it to our clinical conversion to glaucoma in patients IOP but no glaucoma damage re- practice. Fortunately, they have pro- with ocular hypertension were lim- duce the incidence of glaucoma?”, vided us with an analysis of risk fac- ited. Without firm data, many prac- confirming what most ophthalmolo- tors for the development of glau- titioners probably felt that it was bet- gists knew—that treatment works. coma that allows us to think more ter to treat all subjects with elevated However, even the most ar- critically about whom we decide to IOP because the risk of developing dent supporters of treatment to lower treat.5 Of greatest importance is the glaucoma damage might be very IOP would concede that the results role of central corneal thickness high (even in the absence of a proven of the study do not suggest that all (CCT) as a risk factor for the devel- treatment effect). With the OHTS persons with ocular hypertension opment of glaucoma. The investi- data, we can now find good reason should be treated.1,2 After all, only gators of the OHTS were able to not to treat many individuals with 9.5% of the subjects who were ob- stratify risk based on a combina- elevated IOP measurements only. served without therapy developed tion of IOP and CCT. They demon- Suppose that one’s practice pat- glaucoma during a mean follow-up strate that for untreated subjects in tern was to treat select individuals period of 6 years. As the authors of the OHTS with IOP ranging from 24 with an IOP lower than 21 mm Hg the study themselves conclude in to 32 mm Hg, the risk of incident but treat all patients with an IOP of their article, “The results of the damage varied 18-fold. Subjects with 21 mm Hg or higher (it would not OHTS do not imply that all indi- an IOP of 23.75 mm Hg or lower and surprise me if this were a common viduals with elevated IOP should be a CCT of 588 µm or less had a 2% practice among ophthalmologists). treated with ocular hypotensive incidence, whereas subjects with an Based on the OHTS, we now know medication.”3(p708) Others may look IOP of higher than 25.75 mm Hg and that some of these individuals with at the OHTS results with a “number a CCT of 555 µm or less had an in- an IOP of 21 mm Hg or higher have needed to treat” perspective4 and cidence of 36%. thick , suggesting that their

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©2004 American Medical Association. All rights reserved. Downloaded From: by a Washington University - St Louis User on 04/30/2018 to submitting the manuscript. If we agree that expe- nation. We believe that this best serves the ophthalmo- dited publication has merit, we will work with the au- logic community by providing the opportunity to fully thors to establish a timetable for the submission, re- evaluate the trial methods and results rather than giving view, and, if accepted, publication of the manuscript. We a snippet of the methods and results in a presentation or will identify reviewers who will agree to a 1-week turn- a press release. However, we recognize that there are ex- around time for the review. We will be willing to review ceptions, and there may be a trial result that is of such a near-final version of the manuscript with the under- importance for patient care that a delay of several months standing that minor updates to the data may be made in in disseminating the results is undesirable. conjunction with responses to reviewer comments. We Finally, an additional benefit to publication in the recognize that in multicenter trials, changes to a manu- ARCHIVES is the potential for dissemination of the re- script can be time-consuming owing to the number of sults in other AMA journals. When a clinical trial manu- individuals involved, possibly including a writing com- script is submitted to the ARCHIVES, it will also be con- mittee, a large number of investigators, a data and safety sidered for publication in JAMA. If accepted for publication monitoring committee, and the funding entity. For manu- in the ARCHIVES, the abstract will be considered for pub- scripts that are designated for expedited review, to fa- lication in JAMA. cilitate a rapid revision of the manuscript when we be- lieve a revision is warranted, we will indicate in a cover Roy W. Beck, MD, PhD letter accompanying the critiques which reviewer com- ments we believe are most important to address. Once Correspondence: Dr Beck, Jaeb Center for Health Re- the manuscript is accepted, the time to publication can search, 15310 Aberly Dr, Suite 350, Tampa, FL 33647 be as short as 8 weeks. Thus, if we are contacted prior to ([email protected]). submission so that reviewers can be contacted for expe- dited review, the time from submission to publication can be as short as 10 weeks. REFERENCES For major randomized trial reports, we recognize that publication of the manuscript is just one part of the process of disseminating the results. We will work with 1. Chalmers TC. Prophylactic treatment of Wilson’s disease. N Engl J Med. 1968; the authors to coordinate press releases timed to publi- 278:911-912. 2. Moher D, Schulz KF, Altman D; CONSORT Group. The CONSORT statement: re- cation and presentation of the results. In general, we have vised recommendations for improving the quality of reports of parallel-group ran- a strong preference that clinical trial results of public domized trials. JAMA. 2001;285:1987-91. Available at: http://www health importance be published prior to public dissemi- .consort-statement.org. Accessed February 25, 2004.

Correction

Error in the References. In the article titled “The Ocu- lar Hypertension Treatment Study: Intraocular Pres- sure Lowering Prevents the Development of Glaucoma, but Does That Mean We Should Treat Before the Onset of Disease?” published in the March issue of the ARCHIVES (2004;122:376-378), reference 9 should have read: Quig- ley HA, Vitale S. Models of open-angle glaucoma preva- lence and incidence in the United States. Invest Ophthal- mol Vis Sci. 1997;38:83-91.

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