Correspondence patients do not manifest a reproducible diurnal IOP pattern over a 6-month interval. This statistical method was also previously used by others to evaluate the short-term repeatability of diurnal IOP patterns.2,3 The main comment of Nilforushan and Karimi is that the intraclass correlation coefficient calculation evaluates the strength of the association between quantitative measurements, but does not quantify in clinically useful terms the variability or differences between the repeated measurements. They suggested using as an alternative method the BlandeAltman plot and the associated 95% limits of agreement calculation. We agree that the intraclass correlation coefficient calculation alone is not sufficient to evaluate the reproducibility. In the online supplemental materials, we therefore also mentioned the variance components, the coefficient of variation, and the pooled within-subject testeretest standard deviation to account for this. These results can be found in Tables 3 through 9 online material (page 3 of the article, part Results, second paragraph, line 3).1 Online Table 3 contains all these data for all patients. Online Tables 4 through 9 contained all these data for patients with and without previous filtering surgeries, with and without medical hypotensive treatments, and with and without progression, respectively. These data allow evaluation of the dispersion of the IOP measurements over sessions in a clinically meaningful way, particularly the within-subject standard deviation, which is expressed in mmHg, and the within-subject coefficient of variation which is expressed in percentages. As mentioned by Nilforushan and Karimi, it could help the clinician to know whether a given IOP change between 2 IOP measurements performed months apart is within the normal, long-term variability of the IOP or could alternatively indicate a treatment effect or other change. Because we found that patients with primary open-angle glaucoma do not manifest reproducible diurnal IOP patterns from month to month, particularly patients naïve to filtering surgery, we concluded that a single diurnal IOP curve poorly characterizes IOP fluctuations and has limited value in clinical practice. We also pointed out that many clinical trials evaluating the effect of IOPlowering therapies typically include a single session of diurnal IOP measurements before initiation of treatment and a few sessions after initiation of treatment over a period of several months. It is assumed that time-of-day standardization reduces or eliminates spontaneous IOP variability from the calculation. Because we found that the variability of IOP at a given time of the day over a period of several months is substantial, we believe that this method may not distinguish the effect of treatment from spontaneous IOP variations. A more suitable method to estimate the effect of treatment in a clinical trial would probably be to perform several sessions of diurnal IOP measurements before the initiation of treatment, and an equal number of sessions after the initiation of treatment. In their letter, Nilforushan and Karimi suggested that it was not feasible. It is interesting to compare the within-subject coefficient of variation in filtering surgery-naïve patients (online Table 4) with the range of IOP decrease provided by some of the medications or laser therapy commonly used in patients with open-angle glaucoma.4,5 The decrease in IOP afforded by b-blockers, carbonic anhydrase inhibitors, a-agonists, or selective laser trabeculoplasty could be very close to the long-term IOP variability, suggesting that performing an equal number of sessions before and after the initiation of treatment could be a better methodology in clinical trials to evaluate the effect of a treatment or a therapeutic intervention.


Department of Ophthalmology, University Hospital, Grenoble, France; INSERM U1042, Hypoxia and Physiopathology Laboratory, Joseph Fourier University, Grenoble, France 2

Financial Disclosure(s): The authors have no proprietary or commercial interests in any materials discussed in this letter. Correspondence: Florent Aptel, MD, PhD, Department of Ophthalmology, University Hospital, Grenoble F-38043, France. E-mail: [email protected].

References 1. Aptel F, Lesoin A, Chiquet C, et al. Long-term reproducibility of diurnal intraocular pressure patterns in patients with glaucoma. Ophthalmology 2014;121:1998–2003. 2. Realini T, Weinreb RN, Wisniewski SR. Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals. Ophthalmology 2010;117:1700–4. 3. Realini T, Weinreb RN, Wisniewski S. Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals. Ophthalmology 2011;118:47–51. 4. Van der Valk R, Webers CA, Schouten JS, et al. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology 2005;112:1177–85. 5. Juzych MS, Chopra V, Banitt MR, et al. Comparison of longterm outcomes of selective laser trabeculoplasty versus argon laser trabeculoplasty in open-angle glaucoma. Ophthalmology 2004;111:1853–9.

Re: Korobelnik et al.: Intravitreal aflibercept for diabetic macular edema (Ophthalmology 2014;121:2247-54) Dear Editor: We read with interest the VIVID and VISTA publication by Korobelnik et al.1 We were surprised that the article seems to contain erroneous assertions and misleading partial interpretation of the published ranibizumab dataset, and neglects well-known, published, ranibizumab randomized controlled trials that contradict the authors’ conclusions. The authors claim that VIVIDDME and VISTADME were “the first phase 3 studies directly comparing [vascular endothelial growth factor] VEGF-blockade alone with laser alone in DME.” This is clearly untrue; the frequently cited, phase 3 RESTORE study first demonstrated the superiority of ranibizumab 0.5 mg as monotherapy or combined with laser over laser alone >3 years ago.2,3 Equally puzzling is the authors’ assertion that the inclusion of multiethnic populations in VIVID/VISTA rendered the studies “different from previous anti-VEGF DME trials.” Including different ethnicities is neither new nor groundbreaking. In 2011, the Diabetic Retinopathy Clinical Research Network ( study4 demonstrated the favorable safety and efficacy profiles of ranibizumab in 691 DME patients, 15% of whom were African American (VISTADME included around 12%). Another wellknown phase 3 ranibizumab study, REVEAL (NCT00989989;


Ophthalmology Volume 122, Number 6, June 2015 Ohji M et al. Invest Ophthalmol Vis Sci 2012;53:e-abstract 4664), included 396 Asian patients; VIVIDDME/VISTADME included 89. The authors’ concern that in RISE/RIDE5 “the 0.5 mg dose of ranibizumab had relatively higher rates of stroke and death than the 0.3 mg dose” is not supported by randomized, controlled published data, including those they reference themselves. The authors must have noted that, over the entire RIDE/RISE 2-year study period, there was only 1 more vascular death in the 0.5 mg ranibizumab group than in the 0.3 mg group (6 [2.4%] vs. 5 [2.0%]), and only 2 more nonvascular deaths (4 [1.6%] vs. 2 [0.8%]).5 Do the authors suggest a dose response based on a difference of just 1 vascular death? Or, do they suggest the additional 2 nonvascular events support this conclusion, despite these types of deaths resulting from adverse events such as cancer or infection? Regardless, the authors neglect to mention other, more relevant, randomized controlled trials that support the lack of such a difference. The RESTORE primary publication provides appropriate comparative 1-year follow-up data, similar to the period reported by the VIVID/VISTA investigators.2 In RESTORE, there was an equal distribution of deaths between the ranibizumab arms and sham (2 deaths in each of the ranibizumab 0.5 mg monotherapy, ranibizumab 0.5 mg þ laser, and laser monotherapy arms, with an incidence of 1.7%, 1.7%, and 1.8%, respectively).2 Furthermore, in the 2-year study,4 the comparative percentages of any APTC-defined vascular deaths were 6% (8 events), 4% (8), and only 3% (13) in the sham, triamcinolone, and pooled ranibizumab 0.5 mg groups, respectively. These numbers represent a greater difference in event rates than the authorcited RIDE/RISE study, and favor ranibizumab over sham. However, we naturally do not suggest that this constitutes a protective effect on mortality. Similarly, with respect to stroke, the same study showed that the comparative percentages of APTC-defined nonfatal cerebrovascular accidents were 6% (8 events), 2% (4), and 2% (7) in the sham, triamcinolone, and pooled ranibizumab 0.5 mg groups, respectively.4 Despite the 3-fold increase in cerebrovascular accident in the sham arm compared with the ranibizumab 0.5 mg arm, no credible commentator would claim that ranibizumab imparted a protective effect against stroke. Furthermore, over the 2-year RISE/RIDE study period, serious cerebrovascular adverse events (cerebrovascular accident, ischemic stroke, lacunar infarction, and transient ischemic attack) occurred in 3.6% (9 events) of patients in the sham group, 1.6% (4) in the ranibizumab 0.3 mg group, and 3.6% (9) in the ranibizumab 0.5 mg group.5 Would the authors consider these data as indicative of a protective effect of ranibizumab 0.3 mg against such events, simply because it compares favorably to sham? If not, with no evidence of a dose response (the 0.5 mg rate was numerically equal to sham), no difference between the doses should be suggested either. If the authors had considered all these data in detail, we believe they would agree with our conclusion that there is no evidence to suggest differences in the rates of death or stroke between either the 2 ranibizumab doses or ranibizumab vs. sham. In the interests of scientific balance and credibility, we would have fully expected these well-known data to have been included in the authors’ interpretations and were extremely surprised when they were not.

RON HASHMONAY, MD SOUMIL PARIKH, MD Novartis, Basel, Switzerland


Financial Disclosure(s): The authors have made the following disclosures: R.H.: Employee e Novartis. S.P.: Employee e Novartis. Correspondence: Ron Hashmonay, MD, Novartis, Basel, Switzerland. E-mail: ronny. [email protected].

References 1. Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014;121:2247–54. 2. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615–25. 3. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology 2014;121:1045–53. 4. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year followup of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609–14. 5. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema e results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801.

Author reply Dear Editor: Thank you for the opportunity to respond to the letter by Drs Hashmonay and Parikh. The VIVID and VISTA studies were pivotal, US Food and Drug Administration registration-supporting studies of patients with diabetic macular edema comparing an anti-vascular endothelial growth factor (VEGF) agent (intravitreal aflibercept injection) head-to-head against laser therapy. The focus of the discussion in our recent paper1 was to compare our studies with the comparably designed, registration-supporting, pivotal studies of ranibizumab, namely, the RISE and RIDE studies2; there was no intention to overlook other studies. In RESTORE,3 which provided a comparison of anti-VEGF with laser, ranibizumab patients improved by a mean of 5.3 letters over laser patients at 1 year. The unpublished REVEAL study (Ohji M, Ishibashi T, RESTORE Study Group, ARVO 2012 Annual Meeting Abstracts) reported similar outcomes of 4.8 letters gain with ranibizumab vs laser control. By comparison, a mean improvement of 9.3 to 12.3 letters was reported in the VIVID and VISTA studies. VISTA was a United States study, while VIVID was conducted in Europe, Japan, and Australia. While we are all aware that several related studies have reported results with multiethnic populations, the explicit point in our paper was that our pivotal studies had a larger population of Asian patients than the RISE and RIDE studies, thus allowing for relatively more compelling conclusions to be drawn from our studies about the efficacy of intravitreal aflibercept in diverse populations. Additionally, we noted accurately that in the RISE and RIDE studies, the 0.5 mg dose of ranibizumab had relatively higher rates of stroke and death compared to the 0.3 mg dose. More details, including rates of arterial thromboembolic events, are provided in the U.S. Prescribing Information for Lucentis,4 where it is noted that “although the rate of fatal events was low and included causes of death typical of patients with advanced diabetic complications, a potential relationship between these events and intravitreal use of

Re: Korobelnik et al.: Intravitreal aflibercept for diabetic macular edema (Ophthalmology 2014;121:2247-54).

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