Biomarkers associated with early onset of large submacular hemorrhage secondary to neovascular age-related macular degeneration after anti-VEGF intravitreal injection

doi:10.21203/rs.3.rs-2475941/v1

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Biomarkers associated with early onset of large submacular hemorrhage secondary to neovascular age-related macular degeneration after anti-VEGF intravitreal injection

https://doi.org/10.21203/rs.3.rs-2475941/v1

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Objectives: To identify clinical and morphological biomarkers associated with early onset of large submacular hemorrhage (SMH) secondary to neovascular age-related degeneration (nAMD) after anti-vascular endothelial endothelial growth factor (anti-VEGF) intravitreal injection (IVI).

Methods: We retrospectively included patients presenting large SMH secondary to treated nAMD, for which at least 2 examinations, including spectral-domain optical coherence tomography (SD-OCT), were available prior to the onset of the SMH. Clinical characteristics, cardiovascular risk factors and treatment, as well as SD-OCT qualitative and quantitative variables were extracted at the 2 last examinations before SMH onset. History of previous SMH on the fellow eye was also documented. Early SMH onset at defined as <45 days versus > 45 days since last IVI were compared.

Results: Forty-six eyes of 46 patients were included in this study, of which 93% were undergoing pro-re-nata regimen with a monthly follow-up. Onion sign, persistence of exudative signs and increasing height of PED between the two last SD-OCT were associated with early SMH onset following last IVI. SMH was bilateral for 41% patients (19/46). In case of history of SMH on the fellow eye, the pre-existence of a RPE-tear before second SMH was significantly higher (p=0.029) in comparison to unilateral SMH.

Conclusion: Persistence of exudative signs,, onion sign and increasing PED height despite anti-VEGF intravitreal injections between the two last examination, as well presence of RPE tear in case of history of an SMH on the fellow eye, should be considered as warning signs for SMH.

Health sciences/Biomarkers/Predictive markers

Health sciences/Diseases/Eye diseases/Retinal diseases

submacular hemorrhage

hematoma

age-related macular degeneration

imaging

Age-related macular degeneration (AMD) remains the main cause of vision loss in the developed countries¹. Despite the development of anti-vascular endothelial growth factor (VEGF) intravitreal injections (IVI), which considerably improved the visual prognosis of neovascular AMD (nAMD), submacular hemorrhage (SMH) remains a rare complication associated with a poor visual prognosis.² Therefore, identifying clinical and morphological factors for SMH could help preventing their occurrence. Several retrospective studies suspected the role of anticoagulants^3–6, antiplatelet agents^4,5, hypertension^3,5,7, photodynamic therapy^2,8 (PDT) or a seasonal effect in the onset of SMH in nAMD. Recently, Matsunaga et al.⁹ studied the timing of SMH from last anti-VEGF injection among patients treated on a treat-and-extend (T&E) regimen. The occurrence of SMH in the 30 days following last intravitreal injection suggested other mechanisms may be involved, such as loss of effective VEGF inhibition.

In 2009, Levine et al.¹⁰ reported 6 cases of SMH secondary to AMD with no exudative signs 1 month prior the onset of SMH : hence, the authors considered large SMH as an unpredictable complication of nAMD. Cho et al.² recently demonstrated that the occurrence of SMH in polypoidal choroidal vasculopathy (PCV) was significantly higher than in the neovascular AMD group (p < 0.007), highlighting the necessity to differentiate AMD and PCV to study the physiopathology of SMH. To our knowledge, to this date, no large study has been published on morphological biomarkers for SMH in treated nAMD prior their onset.

In this study, we aimed to investigate the clinical factors and morphological biomarkers associated with early onset of large SMH (defined as < 45 days following last antiVEGF IVI) in patients followed-up for neovascular AMD.

Population

We retrospectively reviewed the cases of patients treated for neovascular AMD at the Creteil University Eye Clinic between May 2020 and November 2020. We included consecutive cases of large SMH in neovascular AMD patients for which at least 2 examinations, including spectral-domain coherence tomography (SD-OCT, Spectralis Heidelberg Engineering Inc©, Germany), were available prior to the onset of the SMH. The two last examinations prior to the onset of SMH are respectively termed T-2 and T-1.Exclusion criteria included age inferior to 50 years old, high myopia, a history of PDT or any other vascular retinopathy (e.g. macroaneurysm, diabetic retinopathy, retinal vascular occlusion), PCV, history of vitreoretinal surgery or an absence of at least 2 visits prior to the onset of SMH.

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Federation France Macula. Patients consent was waived due to the retrospective nature of this study.

Clinical and Morphological variables

Baseline clinical characteristics included age, gender, use of antiplatelet agents or anticoagulant, cardiovascular risk factors (hypertension, smoking, ischemic cardiomyopathy, obliterative arteritis of the lower limbs [OALI]) were reviewed.

Clinical characteristics included the timing from last anti-VEGF IVI (aflibercept or ranibizumab), the total amount of IVIs performed, the treatment regimen (pro re nata [PRN] or T&E),, the best-corrected visual acuity (BCVA) before SMH and at last visit. For patients followed up in a PRN regimen, patients were injected only if exudative signs were present on SD-OCT at the discretion of the ophthalmologist, whereas in the T&E regimen, in absence of exudative signs, the interval of injection was extended by two weeks or, conversely, if exudative signs were present, the interval of injection reduced by 2 weeks.

On SD-OCT, qualitative biomarkers were analyzed as follows: type of macular neovascularization [MNV], presence/absence of exudative signs at T-2, T-1, presence of retinal pigment epithelium [RPE] tear, presence/absence of onion sign, presence/absence of choroidal cleft, presence/absence of fibrosis and the localization of the SMH. Past history of a SMH on the fellow eye was also documented.

Quantitative variables were also extracted from SD-OCT as follows: size of the hemorrhage (surface in mm²), height of the pigment epithelial detachment (PED) at T-2 and T-1 using the follow-up mode of Spectralis Heidelberg. All qualitative variables and quantitative measures have been performed independently by two retina specialists (SZ and DC). In case of disagreement, a third reader (AM) adjudicated discordances.

Statistical analysis

All statistical analyses were performed by STAT 16.1/IC (Statacorp©, USA). Visual acuity was converted to logarithm of the minimal angle of resolution (logMAR) for analysis. Qualitative variables were compared using the Fischer test or Chi-square test, whereas quantitative variables were compared using the Mann-Whitney test. The significance threshold for all statistic tests was p < 0.05. Comparison between prior morphological parameters on SD-OCT between early SMH (defined as less than 45 days following last anti-VEGF IVI) and > 45 days was performed. Given the “real life” follow-up of the patients included in this study, a threshold of 45 days since the last injection was decided to take into account variability of injection appointments even for patients treated with a 4 weeks interval. Biomarkers associated with bilateral SMH were also investigated : for eyes presenting a history of SMH on the fellow eye, only the last SMH in date was included in the analysis.

Demographics, clinical and morphological characteristics

Among 2500 patients followed up for AMD between May 2020 and November 2020, 75 cases of SMH secondary to AMD were identified. Among the 75 cases, only 46 eyes of 46 patients had undergone at least 2 monthly examinations prior to the SMH onset and where therefore included. The mean age was 87.51 ± 6.48 years with a sex ratio (men/women) of 12: 34. Ten patients (21.70%) reported a use of anticoagulant drugs and 12 (26.00%) of antiplatelet agents. Among the 46 eyes treated by antiVEGF IVI, 41 (89.13%) were followed up in a PRN regimen, whereas only 3 patients (6.52%) in a T&E regimen and 2 (4.34%) in their monthly induction phase. The median total number of anti-VEGF IVI performed in included eyes was 19 injections (mean 21 ± 16). The median delay from last anti-VEGF IVI to SMH onset was 56 days [32 ;156], Clinical characteristics of the study population are reported in Table 1.

Table 1

Clinical characteristics of 46 eyes from 46 patients presenting submacular hemorrhage in the context of treated neovascular age-related macular degeneration (nAMD)
Clinical characteristics	Values Mean ± SD (Percentage % ou Median)
Age (years)	87.51 ± 6.48
Sex ratio (Men : Women)	12 (26%) : 34 (74%)
Type 2 diabetes	2 (4.34%)
Hypertension	29 (63.04%)
Smoking	2 (4.34%)
Ischemic heart disease and/or Arteritis obliterans of the lower limbs	12 (26.08%)
Atrial fibrillation	8 (13.04%)
Dyslipidemia	6 (21.73%)
Anticoagulant use (anti-vitamine K or anti-factor Xa)	10 (21.73%)
Antiplatelet agent	12 (26.08%)
Cardiovascular risk factors not available	6 (13.04%)
Best-corrected visual acuity (BCVA)
BCVA at last clinical control preceding the occurrence of SMH (logMAR)	0.50 ± 0.42
BCVA at last clinical control to date (logMAR)	0.83 ± 0.56
AntiVEGF intravitreal injections (IVI)
Previously treated Pro-re-nata (PRN) Treat-and-extend (T&E) Monthly loading dose	41 (89.13%) 3 (6.52%) 2 (43.47%)
Total number of anti-VEGF IVI performed before the onset of SMH	21 ± 16 (19)
Time between first anti-VEGF IVI and onset of SMH (months)	44 ± 37 (35)
Time between last anti-VEGF IVI and onset of SMH (median in days, interquartile range)	56 [32 ;156],
Evolution of the interval of injection decided at T-1 Stable Shortened Extended	19 (41.30%) 6 (13.04%) 21 (45.65%)
Treatment of macular hematoma
Anti-VEGF injections	37 (80.43%)
rt-PA* IVI + anti-VEGF IVI + SF6**	5 (10.86%)
Pars plana vitrectromy + subretinal injection of rtPA* + anti-VEGF IVI + SF6** (20% dilution)	7 (15.21%)
*rt-PA : recombinant tissue plasminogen activator
** SF6 : sulphur hexafluoride gas

At baseline, included eyes presented type 1 MNV in 69.56% of eyes (32/46), type 2 MNV in 2.17% of eyes (1/46), type 3 MNV 19.56% of eyes (9/46) and mixte type 1–2 for 8.69% of the cohort (4/46).. RPE tear was present for 16 eyes (34.13%). Of 46 patients, 19 (41.30%) had a history of SMH on the fellow eye. Table 2 reports morphological parameters revealed on SD-OCT prior the onset of SMH.

Table 2

Morphological biomarkers on SD-OCT present at T-1 and T-2 prior to the onset of submacular hemorrhage.
Morphological parameters on SD-OCT	Values Or Mean ± SD (Percentage % or Median)
Type of macular neovascularization (MNV) Type 1 Type 2 Type 3 Mixte 1–2	32 (69.56%) 1 (2.17%) 9 (19.56%) 4 (8.69%)
Exudative signs at T-1 Onion sign Subretinal fluid (SRF) Intraretinalfluid (IRF) Subretinal hyperreflective material (SHRM)	34 (73.91%) 11 (23.91%) 19 (41.30%) 27 (58.69%) 27 (58.69%)
Retinal pigmented epithelium (RPE) tear at T-1	16 (34.78%)
Choroidal cleft	8 (17.39%)
Vitreomacular traction	2 (4.34%)
Fibrosis	7 (15.21%)
Pigment epithelial detachment (PED) Height at T-1 (µm) Height at T-2 (µm)	257 ± 188 246 ± 158
Macular central thickness (MCT, µm) MCT at T-1, µm MCT at T-2, µm	350 ± 123 348 ± 110
Fellow eye Intermediate AMD Geographic atrophy (GA) Neovascular AMD Exudative signs at last visit Recurrence of exudative signs at last visit Quiescent neovascular AMD SMH scar (46 eyes of 46 patients)	9 (19.56%) 4 (8.69%) 36 (78.26%) 11 (23.91%) 3 (6.52%) 9 (19.56%) 19 (41.30%)
Submacular hemorrhage characteristics
Surface of the SMH (mm²)	20.07 ± 9.29 (18,01)
Macular central thickness (µm)	560 ± 206 (505)
Foveolar localization	37 (75%)

Biomarkers on SD-OCT for early SMH

The comparison of the clinical and morphological characteristics of SMH occurring in less and more, respectively, than 45 days following anti-VEGF IVI is presented in Table 3. The biomarkers significantly associated with early SMH after last anti-VEGF IVI were persistence of exudative signs at T-1 (p < 0.01), onion sign (p = 0.039) and an increase in height of the PED between T-2 and T-1 (p = 0.031) despite anti-VEGF therapy and a non-significative tendency for type 3 MNV (p = 0.059). Moreover, MNV type 1 tends to bleed longer after last antiVEGF IVI (p = 0.047). Figure 1 illustrates 3 cases of SMH occurring in the 15 days following anti-VEGF IVI.

Table 3

Comparison of the clinical and morphological characteristics of eyes presenting a large SMH in the 45 days or more following anti-VEGF intravitreal injection (IVI).
Parameters	Late SMH after last anti-VEGF IVI (> 45 days) N = 25 (54%)	Early SMH after last antiVEGF IVI (< 45 days) N = 21 (46%)	P
Age (median, IC)	88.0 [86.0 ; 92.0]	86.0 [82.0 ; 90.0]	0,22*
Hypertension (n, %)	16 (67%)	12 (67%)	1 ^Γ
Antiplatelet agent (n,%)	6 (25%)	6 (33%)	0.85 ^Γ
Anticoagulant use (n, %)	5 (21%)	3 (17%)	1 ^Γ
Treatment and Follow up
Timing between the two last IVI (days)	64.0 [36.5 ; 136]	32.5 [28.2 ; 42.0]	0.036 *
Protocol of injection PRN T&E Induction	24 (96%) 1 (4%) 0 (0%)	17 (81%) 2 (9.5%) 2 (9.5%)	0.23 ^Γ
Morphological parameters
Fibrosis	6 (24%)	1 (5%)	0.11 ^Γ
Onion sign	3 (12%)	8 (38%)	0.039 **
Retinal pigmented epithelium (RPE) tear	10 (42%)	6 (29%)	0.42 **
Exudative signs at last control	14 (56%)	20 (100%)	< 0.01**
Choroidal cleft	5 (20%)	3 (14%)	0.71 ^Γ
Serous retinal detachment (SRD)	9 (36%)	10 (48%)	0.43 **
Subretinal hyperreflective material (SHRM)	13 (52%)	13 (62%)	0.50 **
Type of MNV MNV type 1 MNV type 2 MNV type 3 MNV mixte 1–2	21 (84%) 1 (4%) 2 (8%) 2 (8%)	11 (52.40%) 0 (0%) 7 (33.33%) 2 (9.5%)	0.047 1 ^Γ 0.059 ^Γ 1
Scar of SMH on the fellow eye	9 (36%)	10 (48%)	0.43 **
Size of the SMH
Surface (mm²)	17.5 [14.5; 25.5]	18.8 [13.8; 23.8]	0.97 *
Central macular thickness (CMT, µm)
CMT at T-1	298 [259; 383]	314 [274; 399]	0.43 *
CMT at T-2	321 [270; 368]	325 [301; 360]	0.70 *
∆CMT T1-T2, median	1.00 [-14.0; 23.0]	1.00 [-6.00; 56.0]	0.84 *
Pigmentary Epithelial detachment (PED, µm)
PED Height T1(µm)	162 [110; 240]	251 [166; 314]	0.032 *
PED Height T2 (µm)	163 [130; 255]	234 [146; 354]	0.26 *
∆ PED Height T1-T2 (µm)	-9.00 [-41.0; 10.0]	31.0 [-21.0; 85.0]	0.031 *
* Mann-Whitney test
** Chi-2 test
Γ Fisher exact test

For the 3 patients treated according to an T&E protocol, the median interval of injection was 23 days (interquartile range [18.5;35.5]) and the interval of injection was stable for the 3 of them (6 weeks). All eyes considered, 46% had a recent increase of the injection interval: 52% explained by a loss of follow up, 23% due to a disappearance of the exudative signs and 23% of exudative signs not treated par the ophthalmologist.

Morphological biomarkers associated with of SMH on the fellow eye

Table 4 reports results of the comparison of clinical and morphological biomarkers between patients presenting bilateral SMH and those with unilateral SMH. Among 19 patients (41.30%) having a history of SMH on the fellow eye, the morphological factors associated with a second SMH were a pre-existent RPE-tear prior to SMH onset (p < 0.029).

Table 4

Comparison of clinical and morphological characteristics between patients presenting an unilateral submacular hemorrhage (SMH) complicating neovascular AMD and those with a previous history of SMH on the fellow eye
Parameters	Unilateral SMH N = 27 (59%)	Bilateral SMH N = 19 (41%)	P
Age (mean)	87.0 [81.5; 91.5]	91.0 [86.0; 92.5]	0.11 *
Antiplatelet agent (n, %)	5 (20%)	6 (38%)	0.46 ^Γ
Anticoagulant use (n, %)	5 (20%)	4 (25%)	1 ^Γ
Hypertension (n, %)	7 (28%)	6 (38%)	0.84 ^Γ
Morphological parameters
PED Height at V1 (µm)	172 [131; 281]	187 [138; 294]	0.86 *
PED Height at V2 (µm)	165 [136; 264]	220 [124; 391]	0.95 *
∆PED Height V1-V2	-4.50 [-22.5; 23.5]	15.0 [-12.0; 85.0]	0.15 *
Fibrosis (n, %)	4 (15%)	4 (21%)	0.70 ^Γ
Retinal pigmented epithelium (RPE) tear (n, %)	7 (26%)	11 (58%)	0.029
Choroidal Cleft (n, %)	3 (11%)	6 (32%)	0.13 ^Γ
Serous retinal detachment (SRD) (n, %)	8 (30%)	9 (47%)	0.22 **
Subretinal hyperreflective material (SHRM) (n, %)	15 (56%)	10 (53%)	0.84 **
Onion Sign (n, %)	6 (22%)	5 (26%)	1 ^Γ
Exudative signs at last visit (n, %)	19 (70%)	14 (74%)	0.81 **
Follow up and Treatment
Timing from last antiVEGF injection (days)	57.5 [38.0 ; 98.5]	47.0 [28.0 ; 172]	0.72 *
Follow up (months)	83.0 [64.0; 108]	99.0 [49.5; 121]	0.41 *
Monthly follow up (n, %)	14 (52%)	8 (42%)	0.51 **
Size of the SMH
Surface (mm²)	17.1 [13.1; 22.9]	19.2 [15.9; 26.6]	0.35 *
* Mann-Whitney test
** Chi-2 test
Γ Fisher exact test

To our knowledge, this study reports for the first time morphological biomarkers on SD-OCT associated with early SMH occurrence despite recent anti-VEGEF injections on a large cohort of 49 eyes. In accordance with recent study results^11,12, anticoagulant or antiplatlet use or hypertension have not been associated with early SMH after anti-VEGF injection or bilateral SMH. Moreover, given their demonstrated effects on vital prognosis in cardiovascular disease, their interruption in patients affected by neovascular AMD does not appear justified.

All patients benefited from a monthly follow-up before SMH onset : given the burden and the cost of such a follow-up for elderly patients and the suspension of injections in absence of exudative signs, this protocol should be questioned. The occurrence of SMH despite the absence of exudative signs at last visit for 29 eyes out of 46 should also make us reconsider the protective effect of PRN against SMH. Finally, the recent extension of the interval of injection for 50% (22 out of 44 eyes) may be incriminated in the mechanism of the hemorrhage. As previously supported by SUSTAIN¹³ and CATT¹⁴ studies, monthly injections were significantly associated with better results than a PRN regimen, with equivalent results between T&E and monthly injections in LUCAS¹⁵ and TREND¹⁶ studies. This is consistent with the small percentage of eyes treated on a T&E protocol (3 eyes) in our cohort that developed SMH, highlighting the potential protective effect of such a regimen by sustaining an inhibitor pressure on VEGF secretion : the short and stable interval of injection (6 weeks) allows us to not incriminate the extension of the interval in the occurrence of the SMH.

As reported by Matsunaga et al⁹, the occurrence of 46% of SMH in the 45 days following an anti-VEGF IVI in our study suggests a possible loss of inhibition of the VEGF pathway. Moreover, for these eyes, the median interval since the two last IVI was 32 days [32–42], therefore contradicting the hypothesis that the last anti-VEGF IVI would be responsible of the SMH after a long period without treatment.

Interestingly,, onion sign and persistence of exudative signs, as well as an increase in PED height at T1 and increasing between T2 and T1 were significantly associated with a risk of early SMH. The increasing height of the PED despite anti-VEGF IVI could be another argument for loss of VEGF inhibition in these eyes compatible with the increase of the underlying macular neovessel and its exudation. Despite the absence of a significant association between SMH and type 3 MNV in our study, type 3 MNV have been associated with an early risk of recurrent hemorrhage by Kim et al.¹⁷. Recently, Miere et al.¹⁸ demonstrated the association between type 3 MNV ans sub-RPE multilaminar hyperreflectivity, associated with a worse visual prognosis at one year follow-up.

In contrast to Hwang et al¹⁹ retrospective study on SMH recurrence despite antiVEGF IVI, our study carefully excluded PCV from nAMD given their specific hemorrhagic tendency already reported².

Interestingly, this is the first study documenting a 41% rate of bilateral occurrence of SMH in AMD, suggesting intrinsic risk factors for bleeding could be present in these patients. The pre-existence of an RPE-tear on the second eye has significantly been associated with a risk of bilateral SMH (p < 0.029) supporting the hypothesis of a weakened external hematoretinal barrier in these patients.

This study presents several limitations : its retrospective design explained by the rare incidence of SMH, the manual measurements of the quantitative biomarkers on SD-OCT and the heterogeneity of follow-up and treatment between patients in the same cohort. However, further prospective studies are needed with multivariate analysis to support these promising results.

In conclusion, the persistence of exudative signs despite intravitreal injections,, onion sign and an increase in PED height at two consecutive visits, should be considered by ophthalmologists as warning signs for imminent SMH in nAMD.

ACKNOWLEDGMENTS/DISCLOSURE:

a. Funding/Support: No funding was received.

b. Financial Disclosures: Samira Zegrari, Donato Colantuono, Camille Jung: none.

Salomon Yves Cohen is a board member and consultant for Bayer Shering-Pharma (Berlin, Germany) and Novartis (Basel, Switzerland). Eric H. Souied is a board member and consultant for: Allergan Inc (Irvine, California, USA), Bausch + Lomb (Rochester, New York, USA), Bayer Shering-Pharma (Berlin, Germany), Novartis (Basel, Switzerland). All authors attest that they meet the current ICMJE requirements to qualify as authors. Alexandra Miere is a consultant for: Novartis (Basel, Switzerland).

The authors have no competing interests to declare.

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Biomarkers associated with early onset of large submacular hemorrhage secondary to neovascular age-related macular degeneration after anti-VEGF intravitreal injection

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Abstract

Figures

Introduction

Materials And Methods

Population

Clinical and Morphological variables

Statistical analysis

Results

Demographics, clinical and morphological characteristics

Biomarkers on SD-OCT for early SMH

Morphological biomarkers associated with of SMH on the fellow eye

Discussion

Declarations

References

Additional Declarations

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