fOriginal Article
Complications of Different Intravitreal
Anti VEGF Injections at Multiple Centers Observing Different Protocols
Hussain Ahmad Khaqan, Tariq
Khan, Haroon Tayyab, Tariq Khan Marwat, Muhammad Qasim Lateef, Muhammad Tayyab
Pak J Ophthalmol 2019, Vol. 35, No. 1
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Intra-vitreal injections of anti-vascular
endothelial growth factors (VEGF) have become the mainstay of treatment for
various diseases of the posterior pole including proliferative diabetic
retinopathy (PDR)1, choroidal neovascularization (CNV)2, diabetic macular edema (DME)3, retinal vein occlusion (RVO)4 and exudative age-related macular degeneration (Ex-AMD)5. VEGF plays a cardinal role in regularizing the angiogenesis6. Overproduction of VEGF is associated with diseases like PDR7, CNV8 and RVO9. This anti-angiogenic therapy inhibits VEGF production thus
resulting in reversal and prevention of further neovascularization10.
Currently three most popular anti-VEGF being
administered including Bevacizumab (Avastin®, Genentech, San
Francisco, CA), Ranibizumab (Lucentis®, Genentech, San Francisco,
CA) and Aflibercept (Eylea®, Regeneron, Tarrytown, New York,
USA). Bevacizumab is a fully-humanized monoclonal antibody against
VEGF-A, which was primarily approved as an adjuvant to the treatment of
metastatic colorectal carcinoma11. It is currently being used as an off-label drug for the
treatment of retinal diseases11. As it is not available in individual doses by the manufacturer,
it is being compounded by the pharmacies into ready to use syringes. Ranibizumab
is a humanized monoclonal antibody fragment against VEGF-A12. United States Food and Drug Administration approved it for the
treatment of retinal diseases. It is commercially available as single dose vial,
packaged specifically for use as intravitreal injection. Aflibercept
(previously known as VEGF-Trap) is a recombinant fusion protein, which acts
against VEGF-A, VEGF-B and Placental Growth Factor13. It has longer duration of action and higher binding affinity
thus theoretically making it superior to both Ranibizumab and Bevacizumab13. It is also commercially available as a single dose vial,
packaged specifically for use as intravitreal injection.
Despite widespread global use of intra-vitreal injection
technique, there are no standard guidelines for the technique. There is no
consensus on the use of sterile drapes, speculum, masks and pre-operative or
post-operative antibiotics. Avery et al
proposed some guidelines in 2014 after a consensus of panel of experts14. The major ocular complications of intra-vitreal injections
include endophthalmitis12, sterile inflammation10, retinal detachment, and vitreous hemorrhage11. Albeit rare but intra-vitreal injection of anti-VEGF drugs can
also cause serious systemic side effects. These include acute hypertension,
cerebrovascular accidents and myocardial infarction15.
In this study we are presenting a
multicenter audit of intra-vitreal injections of anti-VEGF, so that we can
compare different techniques of different surgeons and their outcomes and
complications.
MATERIAL AND METHODS
This is an open label, prospective, multicenter study. Data
was collected from 5 different hospitals. 10 different surgeons performed the
procedures. Patients of both gender, suffering from a retinal disease that
required intra-vitreal anti-VEGF were included in the study.
Patients younger than 18 years of age and patients older
than 18 years of age suffering from other ocular diseases along with retinal
disease were excluded from the study. The study followed the tenets of the
Declaration of Helsinki. Before administration of the injection, an informed
consent was obtained from all the patients. All the patients receiving
Bevacizumab injections were made aware of the fact that this injection is used
as an off-label drug. Possible ocular and systemic complications of all the
anti-VEGF were explained. The total
number of intravitreal injections of Bevacizumab, Ranibizumab and Aflibercept
given from September 2016 to March 2018 were tabulated irrespective of the
context of the injections. These injections were given for different retinal
pathologies including proliferative diabetic retinopathy, retinal vein
occlusions, exudative age related macular degeneration and macular edema due to
various other entities.
A proforma was devised to obtain information about the hospital
protocol following the procedure. Questions were asked in the proforma
regarding use of povidone iodine, sterile drapes, Opsite, speculum, sterilized
instruments, pre-operative and post-operative antibiotics. Data was also
collected about scrubbing before the procedure, use of cap and mask during the
procedure and whether injection was given in the operation theater or in an
office based setup. Type of anti-VEGF drug used was also mentioned in the
proforma. Complications, whether systemic or ocular, were enumerated and their
management was also noted down. In the case of Bevacizumab injection attention
was paid to the compounding pharmacies and maintenance of cold chain.
All patients underwent complete ocular
and systemic examination. Ocular examination included Best Corrected Visual
Acuity (BCVA), applanation tonometry, Slit lamp examination and indirect ophthalmoscopy
at baseline and then monthly at each follow-up. Systemic examination included
recording of blood pressure, random blood sugar levels and a consultation with
an internist.
RESULTS
A total of 2,854 injections were given
to 2,289 patients from September 2016 to March 2018. A total of 10 different
surgeons performed the procedures in 5 different institutes. 1,724 patients
received unilateral injections while 565 patients received bilateral
injections. Out of 2,289 patients, 1,236 were male and 1,053 patients were
female.
Table 1: Distribution of
differentAnti-VEGF injections.
|
Type of Intravitreal Injection |
Number (n) (%) |
|
Bevacizumab |
2,321 (81.32%) |
|
Ranibizumab |
513 (17.97%) |
|
Aflibercept |
20 (0.70%) |
|
Total |
2,854 |
Table 2: Indications for treatment.
|
Disease |
Number (n) (%) |
|
PDR |
953 (33.4%) |
|
DME |
832 (29.1%) |
|
Ex AMD |
785 (27.5%) |
|
RVO |
211 (7.4%) |
|
Others |
73 (2.5%) |
Out of total 2,854 injections, 2,321
were Bevacizumab, 513 were Ranibizumab and 20 were Aflibercept (Table 1).
Indications for the injections are summarized in Table 2. Regarding
perioperative procedure details, slight variations were noted among the
surgeons. Most common variable condition was the use of pre-operative
antibiotics. There were 6 surgeons who did not prescribe pre-operative
antibiotics. 4 surgeons reported that they did not use cap and mask during the
procedure, while 2 surgeons reported that they did not use Opsite during the
procedure. Office based injections were given by 1 surgeon while all the others
administered injection in an operation theater. Every surgeon followed all the
other steps in same manner. Table 3 provides an insight about the number of
cases for each step and its correlation with endophthalmitis if any.
Table 3: Distribution of injection
protocol.
|
Protocol |
Yes (n) |
No (n) |
|
Povidone Iodine |
2,854 (100%) |
0 |
|
Opsite |
2,282 (80%) |
572 (20%) |
|
Sterile Drape |
2,854 (100%) |
0 |
|
Sterilized Instruments |
2,854 (100%) |
0 |
|
Cap |
2,001 (70.1%) |
853 (29.9%) |
|
Mask |
2,093 (73.3%) |
761 (26.7%) |
|
Scrub |
2,854 (100%) |
0 |
|
Operation Theater based |
2,560 (89.7%) |
294 (10.3%) |
|
Office Based |
294 (10.3%) |
2,560 (89.7%) |
|
Pre-Op Antibiotics |
932 (32.7%) |
1,922 (67.3%) |
|
Post-Op Antibiotics |
2,854 (100%) |
0 |
Most
common ocular complication reported was subconjunctival hemorrhage, which was
observed in 184 cases. Sterile inflammation was noted in 78 cases, which was
managed by topical steroid eye drops. Transient raised IOP was noted in 53 eyes
and was managed by topical anti-glaucoma medication. 1 case each of
endophthalmitis, lens damage and retinal detachment were reported. 6 patients
suffered from acute hypertension, 2 patients had cerebrovascular accidents
while 1 patient had myocardial infarction. All of these patients survived the
incidents. Complications with regard to injection type are tabulated in table
4.
Table 4: Complications.
|
Name |
Bevacizumab |
Ranibizumab |
Aflibercept |
|
Ocular |
|
|
|
|
Subconjunctival Hemorrhage |
117 (5%) |
63 (12.3%) |
4 (20%) |
|
Raised IOP |
40 (1.72%) |
12 (2.34%) |
1 (5%) |
|
Lens Touch |
1 (0.04%) |
0 |
0 |
|
Sterile Inflammation |
45 (1.94%) |
32 (6.23%) |
1 (5%) |
|
Endophthalmitis |
1 (0.04%) |
0 |
0 |
|
Retinal Detachment |
0 |
1 (0.2%) |
0 |
|
Systemic |
|
|
|
|
Acute Hypertension |
3 (0.13%) |
2 (0.4%) |
1 (5%) |
|
Myocardial Infarction |
1 (0.04%) |
0 |
0 |
|
Cerebrovascular Accidents |
1 (0.04%) |
0 |
1 (5%) |
DISCUSSION
This study aims to give an insight about different protocols
for intra-vitreal injections being followed in different hospitals and their
outcome. Since there are scarce specific guidelines for the procedure, there
are variations in the pre and peri-procedural steps among different surgeons.
Avery et al14 published guidelines after consensus of a panel of experts. Some
of the points on which there was a consensus were, 1) use of povidone iodine
(5-10%) at the injection site was recommended, 2) pre, peri and post-injection
antibiotics were considered unnecessary, 3) use of sterile or non-sterile
gloves was recommended, 4) no evidence for the support of use of sterile drape
was found and 5) use of surgical mask and monitoring of pre and post injection
IOP was also recommended. The points on which there was no consensus were 1)
application of povidone iodine to eyelids and eyelashes, 2) use of speculum and
3) need for pupillary dilation14.
In our study application of 5% povidone iodine to eyeball as
well as eyelashes, use of speculum, sterile drapes, sterile gloves, scrub, and
prescription of post-op antibiotics was done in all cases. Although use of cap
and mask, application of Opsite and administration of pre-operative antibiotics
were variable, but these variables had no statistical significance in terms of
outcomes of the injections.
Although uncommon, endophthalmitis is the most feared
complication of intravitreal injections. Sigford et al did a literature review
and out of 445,503 injections administered they found out that risk for
endophthalmitis after Ranibizumab injection was 0.029% and that after
Bevacizumab was 0.058%12. In comparison of AMD treatment trial (CATT) the rates reported
for post injection endophthalmitis were 0.7% for Ranibizumab and 1.4% for
Bevacizumab5. The higher reported incidences of endophthalmitis in Bevacizumab
group indicate there may be a problem in the compounding procedures. In our
study rate of endophthalmitis for Bevacizumab, Ranibizumab and Aflibercept were
0.04%, 0% and 0% respectively which are in line with the results of the other
studies. One case, which had endophthalmitis, underwent pars-plana vitrectomy
with final visual outcome of 6/18 in that eye.
Other reported ocular side effects include Subconjunctival
hemorrhage16, sterile inflammation10, retinal detachment and tears11, lens damage, raised IOP17 and intraocular hemorrhage. Frequency of uveitis was found out to
be 0.09%15 and 0.4%16 in two large retrospective studies. One study reported TRD in 11
eyes following 211 injections (5.2%)18. Several studies have also reported occasional cases of raised
IOP after intra-vitreal injection of anti-VEGF requiring the use of anti ocular
hypertensive agents17,19. We observed 184 cases of subconjunctival hemorrhage, 78 cases of
sterile inflammation and 53 cases of transiently raised IOP. All the cases were
managed with topical medications. Our findings were consistent with other
published literature.
Cerebrovascular accidents, Myocardial infarction and acute
hypertension are the major side effects reported in the literature15. Systemic absorption of
anti-VEGF can give rise to these complications. In one study 22.4% of the
patients showed hypertension20. In our study raised blood pressure was noted from few hours
after injection to 2 weeks after injection. Fung et al did an internet-based
survey to assess the systemic adverse effects of intravitreal injection. Out of
7,113 injections for 5,228 patients, they reported 2 deaths, 5 cerbrovascular
accidents and 15 cases of hypertension21. Several other clinical trials comparing different anti-VEGF have
reported mortality rate of 2-4% in both experimental and control group. In our
study we experienced 6 cases of hypertension, 2 cases of cerebrovascular
accidents and 1 case of myocardial infarction but no mortality was noted.
The limitations of this study are low
cohort and lack of longer follow-up. To assess the long-term complications,
much longer follow-up is needed.
CONCLUSION
The ocular and systemic complications number is low and comparative to
the available literature after injecting different intra-vitreal anti-VEGF and
observing different pre-operative, per-operative and post-operative protocols
by ten different surgeons at five different centers.
Author’s Affiliation
Dr. Hussain Ahmad Khaqan
Associate Professor of Ophthalmology
Department of Ophthalmology
Lahore General Hospital/ Ameer ud Din Medical College/ Postgraduate
Medical Institute, Lahore
Dr. Muhammad Tariq Khan
Associate Professor of Ophthalmology
Department of Ophthalmology
Akhtar Saeed Medical and Dental College, Lahore
Dr. Haroon Tayyab
Assistant Professor of Ophthalmology
Department of Ophthalmology
King Edward Medical University/ Mayo Hospital, Lahore
Dr. Muhammad Tariq Khan
Marwat
Associate Professor of Ophthalmology
Department of Ophthalmology
Khyber Girls Medical College, Peshawar
Dr. Muhammad Qasim Lateef
Associate Professor of Ophthalmology
Department of Ophthalmology
Jinnah Hospital, Lahore
Dr. Muhammad Tayyab
Doctors Hospital, Lahore
Author’s contribution
Dr. Hussain Ahmad Khaqan
Study Design, Manuscript
Writing, Critical Review, Injecting Surgeon
Dr Muhammad Tariq Khan
Study Design, Literature
Search, Data Collection, Injecting Surgeon
Dr. Haroon Tayyab
Literature Search,
Manuscript Writing, Manuscript Editing, Injecting Surgeon
Dr. Muhammad Tariq Khan
Marwat
Data Collection,
Manuscript Editing, Statistical Analysis, Injecting Surgeon
Dr. Muhammad Qasim Lateef
Literature Search,
Statistical Analysis, Critical Review, Injecting Surgeon
Dr. Muhammad Tayyab
Data Collection,
Literature Search, Critical Review, Injecting Surgeon
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