DOSING REGIMEN AND THE FREQUENCY
`OF MACULAR HEMORRHAGES
`IN NEOVASCULAR AGE-RELATED
`MACULAR DEGENERATION TREATED
`WITH RANIBIZUMAB
`
`IRENE BARBAZETTO, MD,* NAMRATA SAROJ, OD,† HOWARD SHAPIRO, PHD,†
`PAMELA WONG, MPH,† K. BAILEY FREUND, MD*
`
`Purpose: The purpose of this study was to investigate if monthly intravitreal ranibizumab
`decreases risk of macular hemorrhages in patients with choroidal neovascularization
`secondary to age-related macular degeneration.
`Methods:
`Incidences of macular hemorrhages in the control and ranibizumab
`groups from three, multicenter, randomized, clinical trials (MARINA, ANCHOR, and
`PIER) were compared. Two time intervals (Months 0–3 and 5–17) were evaluated to
`account for transition from monthly to quarterly injections in PIER. Time interval after
`Month 17 was excluded because of crossover from control to active treatment in
`all trials.
`Results: Months 0–3: All trials showed higher incidence rates of hemorrhages in
`control compared with ranibizumab groups (ANCHOR: photodynamic therapy [27.3%],
`0.3 mg [8.0%], 0.5 mg [8.6%]; MARINA: sham [18.6%], 0.3 mg [8.8%], 0.5 mg [8.8%];
`and PIER: sham [16.1%], 0.3 mg [3.4%], 0.5 mg [3.3%]). In ANCHOR and MARINA, data
`of Months 5–17 showed higher incidence rates in control compared with monthly
`ranibizumab groups (ANCHOR: photodynamic therapy [47.8%], 0.3 mg [12.5%], 0.5 mg
`[12.3%]; and MARINA: sham [38.0%], 0.3 mg [13.2%], 0.5 mg [13.0%]), but this was not
`seen for quarterly ranibizumab groups in PIER (sham [22.4%], 0.3 mg [23.7%], 0.5 mg
`[28.3%]).
`Conclusion: Treatment with monthly intravitreal ranibizumab was associated with
`reduced risk of new macular hemorrhages when compared with photodynamic therapy
`(ANCHOR) or sham (MARINA and PIER). There was no difference between PIER quarterly
`ranibizumab-treated and sham patients.
`RETINA 30:1376–1385, 2010
`
`M acular hemorrhages are considered to be a hall-
`
`age-related macular
`mark of neovascular
`degeneration (AMD). Reading centers use the pres-
`ence of
`subretinal hemorrhages or hemorrhagic
`pigment epithelial detachments as a criteria for the
`choroidal neovascularization1 when
`presence of
`grading fundus photographs of patients with AMD
`in the absence of other imaging modalities such as
`fluorescein angiography or optical coherence tomog-
`raphy. Even intraretinal hemorrhages can be a sign of
`serious progression because they have been associated
`with the early stages of retinal angiomatous prolifer-
`ation/type 3 neovascularization.2 Overall, macular
`
`hemorrhages are considered to be a sign of disease
`activity and, when occupying larger areas or located in
`the subfoveal region, they are usually associated with
`a poor visual prognosis in a majority of cases.3–5
`Therefore, prevention or suppression of hemorrhagic
`incidences should help arrest vision loss.
`Intravitreal antivascular endothelial growth factor
`therapy has become the new standard of care for treating
`neovascular AMD. This therapy has not only changed
`the management of neovascular AMD but also, for the
`first time, improved visual function and limited disease
`activity in the majority of patients for at least two
`years.6,7 Thus, it seems reasonable to believe that
`
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`FREQUENCY OF MACULAR HEMORRHAGES  BARBAZETTO ET AL
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`
`frequent treatment could also potentially limit the
`occurrence of macular hemorrhages in these patients.
`The aim of this exploratory analysis of the data from
`three Phase 3 clinical trials was to investigate if monthly
`treatment with intravitreal
`ranibizumab (Lucentis;
`Genentech Inc., South San Francisco, CA) decreases
`the risk of new macular hemorrhages in patients with
`choroidal neovascularization secondary to AMD.
`
`Material and Methods
`
`An exploratory analysis was conducted using the
`2-year safety data from patients enrolled in three,
`Phase 3, randomized, controlled, multicenter, clinical
`trials: MARINA,6 ANCHOR,7,8 and PIER.9 Safety-
`evaluable population included all patients who re-
`ceived at least one study treatment.
`
`Treatment and Follow-up
`
`In MARINA, patients were randomized to sham
`control or monthly intravitreal ranibizumab injections
`of 0.3 mg or 0.5 mg. Patients in the ANCHOR study
`were assigned to verteporfin photodynamic therapy
`(PDT)
`(plus monthly sham injections) control or
`monthly intravitreal ranibizumab injections of 0.3 mg
`or 0.5 mg (plus sham PDT with saline infusion).
`In PIER, patients were randomized to sham control or
`intravitreal ranibizumab injections of 0.3 mg or 0.5 mg.
`Patients received 3 initial monthly treatments of their
`assigned dose followed by treatment every 3 months.
`In all 3 studies, patients were examined at
`screening and Day 0. In MARINA and ANCHOR,
`patients were seen at Day 7 and then monthly from
`Month 1 through Month 24. In PIER, patients were
`examined monthly through Month 3 and quarterly
`starting at Month 5 through Month 23 with additional
`visits at Months 12 and 24. There was no Month 4
`
`From the *Vitreous Retina Macula Consultants of New York,
`New York, New York; and †Genentech Inc., South San Francisco,
`California.
`This material was partially presented at the Retina Society
`Annual Meeting, Scottsdale, Arizona, September 2008.
`K.B. Freund is a consultant for Genentech. P. Wong, N. Saroj
`and H. Sahpiro are employees of Genentech.
`The study protocols of the ANCHOR, MARINA, and PIER trials
`(primary reports of safety and efficacy published previously6–9) were
`approved by the Institutional Review Board, National Competent
`Authority, or Ethics Committee at each participating clinical center
`before the start of the study. All US sites were compliant with the Health
`Insurance Portability and Accountability Act of 1996. The three studies
`are registered at ClinicalTrials.gov (ANCHOR ID No. = NCT0061594;
`MARINA ID No. = NCT00056836; PIER ID No. = NCT00090623).
`Before determination of their full eligibility for enrollment, all patients
`provided written informed consent for their study participation.
`Reprint requests: K. Bailey Freund, MD, Vitreous Retina Macula
`Consultants of New York, 460 Park Avenue, 5th Floor, New York,
`NY 10022; e-mail: kbfnyf@aol.com
`
`visit in the PIER study. At all study visits, patients
`were evaluated using Early Treatment Diabetic
`Retinopathy Study protocol–based best-corrected
`visual acuity,
`slit-lamp examination,
`intraocular
`pressure measurement, and dilated binocular indirect
`and high-magnification ophthalmoscopy. Adverse
`events were collected at every visit except at
`screening. Fluoroscein angiography and fundus
`photography were performed at screening and at
`Months 3, 6, 12, and 24 in MARINA, every 3 months
`starting at screening up to 24 months in ANCHOR,
`and at screening and at Months 3, 5, 8, 12, and 24 in
`PIER. In MARINA and ANCHOR, optical coherence
`tomography was done at select sites at Days 0 and 7
`as well as at Months 1 and 12. In PIER, optical
`coherence tomography was done at select sites at Day
`0 and at Months 1, 2, 3, 5, 8, and 12.
`
`Data Collection
`
`The incidences of new macular hemorrhages
`detected during these studies were identified based
`on verbatim reports by the study investigators. All
`verbatim adverse event descriptions coded to the
`MEDDRA (Medical Dictionary of Regulatory
`Activities) preferred term: ‘‘RETINAL HEMOR-
`RHAGE’’ in the databases were reviewed by the
`authors (I.B., K.B.F., and N.S.) and reclassified to
`three categories (‘‘Yes,’’ ‘‘Maybe,’’ and ‘‘No’’) on
`whether they were macular hemorrhages. Only events
`coded with ‘‘Yes’’ or ‘‘Maybe’’ were included in the
`final analysis (Table 1).
`To account
`for
`the transition from monthly
`injections to quarterly injections in the PIER trial
`after 3 months, the number of events in all studies was
`evaluated for 2 time intervals: 0 to 3 months (during
`monthly injections in MARINA, ANCHOR, and
`PIER) and 5 to 17 months (during monthly injections
`in MARINA and ANCHOR and quarterly injections in
`PIER). The 5- to 17-month time interval was further
`broken down into quarterly intervals: 5 to ,8 months,
`8 to ,11 months, 11 to ,14 months, and 14 to
`17 months. The time interval between 3 and 5 months
`
`Table 1. Included cases for ‘‘macular hemorrhage’’
`based on investigator verbatim report coded to the
`MedDRA (Medical Dictionary for Regulatory Activities)
`preferred term: ‘‘RETINAL HEMORRHAGE’’
`
`New subretinal hemorrhage
`Punctate hemorrhage – subretinal
`Hemorrhagic pigment epithelial detachment
`Peripapillary subretinal hemorrhage
`Recurrent subretinal hemorrhage
`Worsening of subretinal macular hemorrhage
`Macular dot-blot hemorrhage
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`1378 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2010  VOLUME 30  NUMBER 9
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`was excluded because there was no Month 4 study
`visit in the PIER trial. The time interval after Month 17
`was excluded because control patients remaining in
`the studies were allowed to ‘‘crossover’’ to receive
`ranibizumab in all 3 studies, and many patients switched
`to monthly 0.5 mg during this period in PIER.
`However, all adverse events occurring after
`the
`crossover were excluded from the analysis.
`
`Statistical Analysis
`
`Incidences of macular hemorrhages were compared
`using Pearson chi-square or Fisher exact test (when
`expected cell counts ,5) for treatment comparisons
`within each study as well as cross-study comparisons
`within each treatment group. These cross-study com-
`parison tests were performed not for formal comparison
`but for hypothesis generation only. Statistical signifi-
`cance was defined as P , 0.05; although in an
`exploratory analysis,
`it
`is particularly important
`to
`consider the risks of false conclusions due to multiple
`comparisons. All statistical analyses were carried out
`using SAS software v9.1 (SAS Inc, Cary, NC).
`
`Subgroup Analyses
`
`The influence of selected variables was explored in
`three separate subgroup analyses comparing the
`incidences of macular hemorrhages: 1) by baseline
`angiographic lesion composition, presence of classic
`(either predominantly classic or minimally classic)
`versus occult lesions in MARINA and PIER; 2) by
`baseline presence or absence of anticoagulation/
`platelet inhibitors; and 3) by baseline presence or
`absence of blood on fluorescein angiography.
`
`Results
`
`A total of 1,315 patients receiving at least 1 study
`treatment were analyzed from the 3, randomized,
`controlled, clinical
`trials: ANCHOR (n = 420),
`MARINA (n = 713), and PIER (n = 182). The sample
`size of each study for the evaluated treatment intervals
`and study arms is shown in Figure 1.
`
`Incidences of Macular Hemorrhages
`
`Months 0–3: monthly ranibizumab or sham injection.
`In all 3 trials, a higher percentage of patients developed
`macular hemorrhages in the control group compared
`with both the ranibizumab-treated groups during
`Months 0 to 3. In the ANCHOR trial (Figure 1A),
`new macular hemorrhages were seen in 27.3% of
`PDT-treated eyes compared with 8.0% in the 0.3-mg
`ranibizumab-treated group (P , 0.0001) and 8.6% in
`the 0.5-mg ranibizumab-treated group (P , 0.0001).
`
`The MARINA trial (Figure 1B) showed 18.6% in
`the sham group developing macular hemorrhages
`compared with 8.8% in the 0.3-mg ranibizumab-
`treated group (P = 0.0019) and 8.8% in the 0.5-mg
`ranibizumab-treated group (P = 0.0018).
`In the PIER trial (Figure 1C), 16.1% in the sham
`group and 3.4% in the 0.3-mg ranibizumab-treated group
`(P = 0.019) and 3.3% in the 0.5-mg ranibizumab-treated
`group (P = 0.016) developed macular hemorrhages.
`
`Months 5–17: monthly ranibizumab or sham injection
`(MARINA/ANCHOR); quarterly ranibizumab or sham
`injection (PIER). During Months 5 to 17, the incidence
`of macular hemorrhages was still higher in the control
`groups for ANCHOR and MARINA when compared
`with the ranibizumab-treated groups. The ANCHOR
`trial (Figure 1, Panel D) had 47.8% of PDT treated
`patients compared to 12.5% in the 0.3 mg ranibizumab-
`treated group (P , 0.0001) and 12.3% in the 0.5 mg
`ranibizumab-treated group (P , 0.0001) develop
`a macular hemorrhage. The MARINA trial (Figure
`1E) also showed a higher
`rate of new macular
`hemorrhages in the sham group with 38.0% compared
`with lower rates of 13.2% in the 0.3-mg ranibizumab-
`treated group (P , 0.0001) and 13.0% in the 0.5-mg
`ranibizumab-treated group (P , 0.0001).
`the
`However,
`in the PIER trial
`(Figure 1F),
`incidence rates were not lower in the ranibizumab-
`treated groups compared with the control group (in
`fact, they were slightly higher although the differences
`were not statistically significant). 22.4% of patients in
`the sham group developed new macular hemorrhages
`when compared with 23.7% in the 0.3-mg ranibizu-
`mab-treated group (P = 0.87) and 28.3% in the 0.5-mg
`ranibizumab-treated group (P = 0.46).
`For quarterly incidences of new macular hemor-
`rhages in the ANCHOR (Figure 2A) and MARINA
`(Figure 2B) studies after Month 5, the rate in the
`ranibizumab-treated groups appears stable between 1%
`and 7%, whereas the control groups (sham/PDT) range
`from 10% to 22%. In the PIER study (Figure 2C), the
`overall incidence of new macular hemorrhages ranged
`from 3% to 17% for the ranibizumab-treated eyes and
`from 4% to 10% for the control (sham) eyes.
`
`Cross-Study Comparison Between Studies
`
`Given the different patient populations; different
`control groups; and differences in sample size, follow-
`up, and crossover regimens, cross-study comparisons
`(Figure 1) are intended for hypothesis generation only
`and the data should be reviewed with caution. As
`a reference (not for formal comparisons), Pearson chi-
`square or Fisher exact test (when expected cell counts
`,5) yields the following P values for cross-study
`
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`
`Fig. 1. Summary of the in-
`cidences of new macular
`hemorrhages in the study eye
`in the ANCHOR (A & D),
`MARINA (B & E) and PIER
`(C & F) studies subdivided
`for
`the 2 study periods
`(months 0–3 and months
`5–17). *P , 0.0001, †P =
`0.0019, ‡P = 0.018 §P =
`0.019, **P = 0.016 vs. con-
`trol (sham or PDT). Error
`bars are 95% exact confi-
`dence intervals.
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`Fig. 2. Quarterly reported incidences of new
`macular hemorrhages in the ANCHOR (A),
`MARINA (B), and PIER (C) studies, Months 5 to
`17. *Months 14 to 17 for the PIER sham group
`were excluded from the summary because most
`patients in sham crossed over to receive 0.5-mg
`ranibizumab at Month 14. Error bars are 95%
`exact confidence intervals.
`
`comparison for the incidence of macular hemorrhages
`within each treatment group.
`For the Months 0 to 3 interval, little difference was
`found between the incidence rates in the PIER and
`
`MARINA trials (control [P = 0.65], 0.3 mg [P = 0.27],
`and 0.5 mg [P = 0.18]). Similarly, little difference was
`found between the incidence rates in PIER and
`ANCHOR trials (control [P = 0.09], 0.3 mg [P =
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`FREQUENCY OF MACULAR HEMORRHAGES  BARBAZETTO ET AL
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`
`0.35], and 0.5 mg [P = 0.24]). For the Months 0 to 3
`interval, the incidence of macular hemorrhages was 27%
`in the ANCHOR PDT arm and 19% in the MARINA
`sham arm (P = 0.049) although there was little difference
`between ANCHOR and MARINA in the ranibizumab
`arms (0.3 mg [P = 0.79] and 0.5 mg [P = 0.94]).
`However, at months 5 to 17 differences were
`observed between the rates in the PIER and MARINA
`trials for all the study arms including the control group
`(PIER vs MARINA: control [P = 0.026, rate in PIER
`less than MARINA], 0.3 mg [P = 0.046, rate in PIER
`greater than MARINA], and 0.5 mg [P = 0.0039, rate
`in PIER greater than MARINA]). The comparison of
`the PIER and the ANCHOR studies also showed
`similar results with differences between all groups
`(PIER versus ANCHOR: control [P = 0.0009, rate in
`
`PIER less than ANCHOR]), 0.3 mg (P = 0.049, rate in
`PIER greater than ANCHOR), and 0.5 mg (P = 0.0060,
`rate in PIER greater than ANCHOR). For the Months 5
`to 17 interval, the incidence of macular hemorrhages
`differed little between ANCHOR and MARINA among
`the treatment groups (control [P = 0.06], 0.3 mg
`[P = 0.84], and 0.5 mg [P = 0.84]).
`
`Lesion Composition at Baseline: Presence of Classic
`(Predominantly Classic or Minimally Classic) or
`Occult Without Classic
`
`Baseline angiographic lesion composition, as de-
`termined by the reading center (Figure 3), did not
`reveal any significant influence on the subsequent
`incidences of macular hemorrhages in the MARINA
`
`Fig. 3. Macular hemorrhages
`by baseline lesion type (clas-
`sic vs occult lesions) in the
`MARINA (A & C) and PIER
`(B & D) studies subdivided
`for
`the 2 study periods
`(months 0–3 and months
`5–17). There was only one
`safety-evaluable patient
`in
`ANCHOR with occult with-
`out classic lesion at baseline.
`Therefore,
`the
`subgroup
`analysis by lesion type was
`not done for ANCHOR. One
`PIER patient had a baseline
`lesion type that could not be
`classified and was excluded
`from the analysis. Error bars
`are 95% exact confidence
`intervals.
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`and PIER studies during the first 3 months, except for
`MARINA sham (P = 0.041, 26% classic versus 15%
`occult without classic). In the Months 5 to 17 interval,
`the MARINA study showed a trend toward lesions
`with a classic component to be more likely to develop
`hemorrhages than occult without classic lesions; the
`difference was statistically significant for the 0.3-mg
`group (P = 0.044, 19% classic versus 10% occult
`without classic). However, the PIER study showed
`a reversed indication during Months 5 to 17 (not
`statistically significant) where occult
`lesions were
`more likely to develop hemorrhages than classic
`lesions for the sham and the 0.3-mg ranibizumab–
`treated groups.
`The subgroup analysis stratified by lesion type was
`not done for ANCHOR because of the inclusion
`criterion that allowed only patients with at least 50%
`classic lesions in the trial. However, there was one
`safety-evaluable patient
`in ANCHOR with occult
`without classic lesion at baseline.
`
`Role of Anticoagulation/Platelet Inhibitors at Baseline
`
`The incidence of macular hemorrhages was ana-
`lyzed for patients taking anticoagulants (i.e., warfarin)
`or platelet aggregation inhibitors (i.e., acetylsalicylic
`acid [Aspirin], clopidogrel bisulfate [Plavix], etc.)
`versus patients taking none of these medications at
`baseline (Figure 4). No statistical differences between
`the groups were found in ANCHOR, MARINA, or
`PIER for each time interval.
`
`Presence or Absence of Blood at Baseline
`
`Blood at baseline was categorized as present, absent,
`questionable, or cannot be graded. For these analyses,
`present and questionable were combined as present at
`baseline and compared with absent at baseline (Figure 5).
`In ANCHOR, the incidence of macular hemorrhage
`was higher with blood present at baseline compared
`with blood absent at baseline except for the control
`group at Months 0 to 3 and the 0.5-mg group at
`Months 5 to 17. However, none of the comparisons
`were statistically significant.
`In MARINA, the incidence of macular hemorrhage
`was higher with blood present at baseline compared
`with blood absent at baseline in all instances although
`none were statistically significant.
`In PIER, the incidence of macular hemorrhage was
`higher with blood present at baseline compared with
`blood absent at baseline except for the control group at
`Months 5 to 17 and 0.3 mg at Months 0 to 3 where the
`reverse was found but was not statistically significant.
`One statistically significant comparison was found, for
`the sham group at Months 0 to 3 (P = 0.050, 22.2% for
`present versus 0% for absent).
`
`Discussion
`
`Macular hemorrhages of varying degrees and
`extensions are known to occur as part of the natural
`course of AMD3,4 and as complications after inter-
`ventions for neovascular disease.10 The outcome can
`be devastating for the patient and not only lead to
`visual
`impairment but also place a significant
`psychological burden on patients and families.5
`Controlling the neovascular process with reduction of
`exudative activity is a logical approach to reduce the risk
`of developing new hemorrhages secondary to AMD.
`Sustained inhibition of vascular endothelial growth
`factor with intravitreal ranibizumab is a promising
`strategy for such a therapeutic/preventive concept.6,11
`The analysis of the safety data of the three major
`controlled clinical trials (ANCHOR, MARINA, and
`PIER) presents the unique opportunity to evaluate large
`treated patient cohorts and controls for the incidence of
`macular hemorrhages
`in randomized double-blind
`studies with standardized treatment protocols. Patients
`on monthly ranibizumab in MARINA, ANCHOR, and
`PIER were significantly less likely to develop macular
`hemorrhages when compared with the control groups. In
`PIER, no benefit of ranibizumab over sham was observed
`after the patients were switched to the quarterly protocol.
`It should be noted that the evaluation of the PIER study
`data is complicated as a result of the study arms being
`significantly smaller and some patients of the sham group
`having crossed over (15 at Month 14 and another 17 at
`Month 17) to receive 0.5-mg ranibizumab. Baseline
`angiographic lesion composition as well as medications
`for anticoagulation and platelet aggregation inhibition did
`not influence the risk of developing macular hemorrhages
`in any of the study treatment groups. Baseline presence of
`blood was mostly consistent as to incidence of macular
`hemorrhages being higher in the group with blood
`present at baseline versus blood absent at baseline, but
`only 1 of the 18 comparisons among study treatment
`groups was statistically significant.
`This study is also limited by several factors, which
`include but are not limited to the retrospective nature of
`the data review as well as the differences in follow-up,
`treatment protocols, and control group composition of
`the individual studies. In the PIER study, the number of
`patients is significantly smaller when compared with the
`MARINA and ANCHOR studies. In addition,
`the
`follow-up intervals after the initial 3 months were only
`quarterly in PIER, which may result in missed events
`and lead to an underestimation of the number of events.
`Finally, because none of the studies required monthly
`fundus photographic documentation, identification of
`macular hemorrhages is dependent on verbatim reports
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`Fig. 4. Macular hemorrhages by base-
`line medication for anticoagulation/
`platelet
`inhibitors in the ANCHOR
`(A & D), MARINA (B & E) and PIER
`(C & F) studies subdivided for the 2
`study periods (months 0–3 and months
`5–17). Error bars are 95% exact
`confidence intervals.
`
`of adverse events by the individual investigators who
`may have varying definitions/methods of identification.
`However, in spite of its limitations, the results of this
`analysis may give the treating ophthalmologists
`additional information on how to manage their patients
`
`with AMD and to achieve best functional results and
`visual preservation.
`In conclusion, although none of the treatment arms
`in MARINA, ANCHOR, and PIER showed a complete
`absence of new macular hemorrhages during the study
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`period, monthly application of 0.3-mg or 0.5-mg
`ranibizumab significantly decreased the risk of de-
`veloping new macular hemorrhages when compared
`with the control groups (sham or PDT). As seen in
`
`PIER, switching from monthly to quarterly injection
`intervals may not have the same beneficial effect and
`could put the patient at an increased risk for vision-
`threatening complications.
`
`Fig. 5. Macular hemorrhages by baseline
`presence or absence of blood in the
`ANCHOR (A & D), MARINA (B & E) and
`PIER (C & F) studies subdivided for the
`2 study periods (months 0–3 and months
`5–17). Error bars are 95% exact confidence
`intervals.
`
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`
`Key words: age-related macular degeneration,
`choroidal neovascularization, ranibizumab, macular
`hemorrhage.
`
`Acknowledgments
`
`The ANCHOR, MARINA, and PIER studies were
`funded by Genentech, Inc., South San Francisco, CA,
`and Novartis Pharma, AG, Basel, Switzerland.
`Genentech designed and oversaw the conduct of the
`ANCHOR, MARINA, and PIER studies and managed
`and statistically analyzed the data.
`
`References
`
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`Disease Study severity scale for age-related macular de-
`generation: AREDS Report No. 17. Arch Ophthalmol 2005;
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`2. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous
`proliferation in age-related macular degeneration. Retina 2001;
`21:416–434.
`3. Scupola A, Coscas G, Soubrane G, Balestrazzi E.
`Natural history of macular
`subretinal hemorrhage in
`age-related macular degeneration. Ophthalmologica 1999;
`213:97–102.
`
`4. Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural history
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