Here is my discussion in the January 2010 issue of Retinal Physician:

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The biggest risk we need to be prepared for in retina practices is anaphylaxis from fluorescein angiography. A publication this past summer showed the incidence of anaphylaxis is one per 350 fluoresceins.² Because anaphylaxis can be life threatening, and because it is treatable, we must train our staff to recognize it — and our retina practices must be prepared to deal with it.

Anaphylaxis is a multisystem allergic reaction. The severity of the reaction is difficult to predict at its outset, and the internal medicine literature advocates treating it early with subcutaneous or intramuscular epinephrine (1:1000). Anaphylaxis can involve four major organ systems: respiratory, cardiovascular, gastrointestinal and cutaneous. Involvement of any two of these organ systems meets the definition of anaphylaxis. So if a patient has itching and shortness of breath, the internal medicine literature advocates treating with epinephrine. I think many of us are hesitant to give epinephrine in our practices because of the potential risks in our patients with diabetes and cardiac disease. But it’s certainly worth having epinephrine on hand. It’s also important to have a protocol in place.

In developing protocols for our practice, I consulted with other retina specialists to see what protocols they had in place. At hospital-based practices, the most common protocol was “call the code blue team.” Most private practices I spoke to don’t have written protocols. In developing ours, I sought the advice of my colleagues in internal medicine, emergency medicine and anesthesia. Among these specialties, they advocated a wide range of reasonable approaches. If you have easy access to a 911 team, then your protocol can be minimal — administer diphenhydramine, maybe epinephrine, and monitor blood pressure. If, however, you want to be more complete, because of a slower anticipated response time, your protocol could include administering oxygen or IV fluids, monitoring oxygen saturation and a cardiac tracing, and having available an airway, bag and an automatic external defibrillator.

Our protocol is primarily a checklist that includes several sections: preparation, which includes checking the blood pressure and pulse, reviewing drug allergies, pregnancy, and any history of prior cardiac or respiratory problems. Most of these data are already on the chart, so this portion of the checklist is a sort of a “time out” to review things before injecting the fluorescein.

The second portion of the checklist addresses things that must be available prior to injecting: Personnel —which is an MD in the office; Equipment — which, in our case, is a cardiac monitor, and bag and mask; Supplies — such as IV fluid, needle, tape and gauze; Drugs — we stock oral and IV diphenhydramine, and IM/SQ epinephrine (1:1000); and Paperwork — the consent form, the symptoms checklist, and treatment flowsheets.

The protocol in our practice is symptom-based. For example, if there is nausea or vomiting, the protocol directs staff to provide an emesis basin, support, and monitor the patient for 30 minutes. In the event of mild hives or itching, the protocol calls for notification of the MD, the administration of oral diphenhydramine 25-50 mg, and monitoring until symptoms improve. For more severe hives or itching, we administer the drug IV.

In the event of the onset of respiratory symptoms, our protocol calls for us to record oxygen saturation and blood pressure, to call 911, to prepare the epinephrine for possible administration, and to get the doctor in the emergency room on the phone for guidance while awaiting arrival of the emergency team. Our entire protocol is available online at TheRetinaBlog.com.

The truth is that severe symptoms are rare, and fortunately, death from fluorescein angiography is reported to be only 1/220,000. But it is prudent to be prepared to deal with the more severe symptoms in the unlikely event they arise.

In terms of training, I think we physicians have to periodically review the management of anaphylaxis, and an excellent review is available in the article, “Office Approach to Anaphylaxis: Sooner Better than Later” by Stephen F. Kemp, which appeared in the Amercian Journal of Medicine (2007) 120, 664-668.

I do think it’s reasonable for nonphysicians to administer fluorescein, under the supervision of a physician.* In our case, it means that they have shown their ability to administer FA successfully 10 times under direct physician observation. After that, a physician must be present in the office and available to deal with any emergencies during administration. In our office, all staff (including doctors) maintain current CPR certification.

* OMIC warns that allowing unlicensed staff to inject may be illegal. See their risk management recommendations on FAs.

Intravitreal injections, which have become standard of care for treatment of AMD are fairly innocuous in terms of surgical insult. The “wound” is a 31 gauge needle entry site. Nevertheless, endophthalmitis may develop. For example, in the VISION study of intravitreal pegaptanib, the incidence of endophthalmitis was 0.16%. In the MARINA study of intravitreal ranibizumab, it was 0.05%. And in the ANCHOR study of ranibizumab, it was 0.05% (3 cases our of 5,921 injections). A study by Pilli et all reported an incidence of 0.029% (3 cases in 10,254 injections). These incidences were for unilateral injections.

So, is there an increased risk for bilateral same-day injections? Lima et al (Yannuzzi’s group) out of New York published their retrospective analysis of bilateral same-day intravitreal injections of VEGF inhibitors in the October 2009 issue of Retina. They report that of 1,534 bilateral injections (3,068 injections total), the incidence of culture-proven endophthalmitis was 0.065%, and the incidence of acute intraocular inflmaation was 0.033%. None of those cases were bilateral. There were no cases of retinal breaks. They conclude that it appears that there is no increased risk for same-day bilateral injections of VEGF inhibitors, as the complication rates are similar.

It’s noteworthy that all patients in their study were done in the office, and received surface disinfection with 5% providone-iodine solution, followed by 2 days of either polytrim or ofloxacin qid.

The study is very useful and gives comfort to those of us considering bilateral same-day injections. In any disease process where the incidence of an occurence is very low, large numbers of patients are needed to determine whether or not there is a difference in incidence between groups, and so, it is fair to say that there is no obvious increase in the risk of complications from bilateral VEGF inhibitor injections, while recognizing the limitation of the comparison.

We get some indirect answers in a study published in the November/December issue of Retina.  The study (Comparison of two doses of intravitereal bevacizumab as primary treatment for macular edema secondary to branch retinal vein occlusion:  results of the pan american collaborative retina study group at 24 months) by Wu et al and the Pan-American Collaborative Retina Study Group was a retrtospective multicenter study looking at results from 63 eyes treated with two different doses of bevacizumab:  1.25 mg and 2.5 mg.  Other studies had shown benefit in visual acuity and central macular thickness (CMT) with bevacizumab in BRVO, and the authors wondered if an increased dose may improve the visual outcome or decrease the frequency of injections.  Patients with macular edema were given bevacizumab at one of the two doses (depending on the center they visited) and were examined on a monthly basis.  OCT’s were performed at months 1, 3, 6, 12 and 24.  If at any time the OCT measured CMT > 250 microns, they were classified as “recurrent” or “persistent” macular edema, and were re-injected.  Re-injections were also given if visual acuity decreased by more than 5 letters (1 line).

Their study found that there was no additional benefit from the higher dose, and that both groups experienced improved vision and decreased CMT.  The results showed that on average, CMT improved from about 450 mic at the first visit, to 250 mic at 3 months, and ended up at the 240 mic range at 24 months.  Furthermore, the mean time for repeat injections was in the 10-13 week range.

But is this better than laser?  Well, the study doesn’t directly look at this question, but it does state that among its small sample size of 63 eyes, of those receiving 1.25 mg, 68% experienced improvement in vision by 3 or more lines of vision (72% in the 2.5 mg group).  That’s pretty significant percentage of improved vision.  You’ll recall that the SCORE Study patients had improved vision in the 26-29% range for IVTA and laser.  So bevacizumab seems to give better results than laser for BRVO.  I realize I’m mixing studies — not really a meta-analysis (maybe a “mini”-analysis), and clearly this needs to be studied further.  But the authors seem to lay out a reasonable approach for treating BRVO with bevacizumab, and their results seem to be significantly better than best results we have available with laser or IVTA.  Check vision monthly, and if worse by 5 letters, treat with bevacizumab;  check OCT at 3, 6 12 and 24 mo, and if CMT > 250 treat with bevacizumab.  Expect about 70% to improve 3 or more lines of vision.

The CRYO-ROP trial had given us the “threshold” of treatment for ROP.  Threshold was defined by the CRYO-ROP as at least five clock hours of contiguous, or eight cumulative clock hours of stage 3 ROP in zone I or II in the presence of plus disease.  When I was a resident, a quick trick we were taught was to look at the posterior pole for plus disease.  If there was no plus disease, no matter how extensive the ROP might be, you weren’t at threshold.  And I still do this now, looking first at the posterior pole for plus disease, before heading off into the periphery to determine zones and stages.

The ETROP study came about because of a sense that treating some patients sooner than these threshold definitions could be beneficial, and in fact the ETROP proved it to be so, effectively changing the threshold for treatment.  The most important change is that treatment can now be considered sooner without regard to the number of clock hours involved.  The new criteria defined by ETROP are:

1.  Zone I ROP with plus disease (doesn’t matter what stage)

2.  Zone I ROP with stage 3 disease (don’t need plus disease)

3.  Zone II ROP, stage 2 or 3, with plus disease.

These three criteria are defined as “Type I” ROP.

Treating these eyes instead of waiting for CRYO-ROP threshold criteria resulted in reduction in unfavorable visual acuity outcomes from 19.8% to 14.3%, and a reduction in unfavorable structural outcomes from 15.6% to 9.0% (both at 9 months).  Bear in mind that these results are not comparing “treated” to “untreated”, but are comparing “treating earlier” to “waiting for CRYO-ROP threshold”.  Treating these Type I eyes resulted in treatment on average 2 weeks earlier than waiting for CRYO-ROP threshold.

Looking at these numbers, there is a definite clinical benefit to treating earlier, but you can spin the numbers in a couple of ways.  You can say that unfavorable visual acuity outcomes were reduced by 25% (from 19.8 down to 14.3%), but I think it’s more meaningful to look at the absolute percentage reduction, which is about 5%.  A 5% decrease means that for every 20 eyes you treat early, you see a benefit in one of them.  Not great, but given that you’re only changing the timing of the treatment in most cases, (66% of control eyes went on to need treatment by CRYO-ROP criteria anyway), it’s pretty good.  The question though is, what risk was involved in treating these infants two weeks earlier?  The study showed that there was a definite increase in morbidity in the early treatment group (but not mortality) — bradycardia, re-intubation, etc.  How often did this occur?  If you treat two patients early, one had a potentially serious systemic side effect.  So, the decision regarding the timing of treatment is not so cut and dried as the study numbers might suggest.  On the other hand, it does support treating ROP at “pre-threshold” levels, and that should be taken into account.  Furthermore it points to the need to follow pre-threshold eyes more closely, and to be prepared to treat within 48 hours of reaching threshold.

One of the things that the study did not do, was differentiate the patients with CSME into those with cystic edema and those with non-cystic edema.  My hunch is that we would find that in the group with cystic edema, the difference between the effectiveness in bevacizumab and laser would be even greater.  Will bevacizumab become a replacement for laser in treating CSME?  It’s too soon to say.  My hope is that the Sohelian et al will continue to follow these patients and report on results as they reach the 1 year and 2 year marks.

In clinical practice, this paper seems to support what many of us are currently doing:  using bevacizumab as first line treatment for diabetic macular edema to decrease the edema and improve the vision, and following it up with laser treatment for long term control.  I’d like to see a study that looks at this situation.  I use the sequential approach with greatest success in patients with massive or cystic macular edema.

Here is the abstract:

Ophthalmology. 2009 Jun;116(6):1142-50. Epub 2009 Apr 19.

Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema.

Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, Ahmadieh H, Dehghan MH, Azarmina M, Moradian S, Peyman GA.

Ophthalmology Department, Labbafinejad Medical Center, Shaheed Beheshti Medical University, Tehran, Iran. masoud_soheilian@yahoo.com

PURPOSE: To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME). DESIGN: Randomized 3-arm clinical trial. PARTICIPANTS: A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.

METHODS: The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated. MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (VA) at week 24.

RESULTS: VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.

CONCLUSIONS: Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.

Arch Ophthalmol. 2009 Sep;127(9):1115-28.
A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6.
Scott IU, Ip MS, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, Chan CK, Gonzalez VH, Singerman LJ, Tolentino M; SCORE Study Research Group.

OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: Multicenter, randomized clinical trial of 411 participants. Main Outcome Measure Gain in visual acuity letter score of 15 or more from baseline to month 12.

RESULTS: Twenty-nine percent, 26%, and 27% of participants achieved the primary outcome in the standard care, 1-mg, and 4-mg groups, respectively. None of the pairwise comparisons between the 3 groups was statistically significant at month 12. The rates of elevated intraocular pressure and cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group.

CONCLUSIONS: There was no difference identified in visual acuity at 12 months for the standard care group compared with the triamcinolone groups; however, rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group. Application to Clinical Practice Grid photocoagulation as applied in the SCORE Study remains the standard care for patients with vision loss associated with macular edema secondary to BRVO who have characteristics similar to participants in the SCORE-BRVO trial. Grid photocoagulation should remain the benchmark against which other treatments are compared in clinical trials for eyes with vision loss associated with macular edema secondary to BRVO.

Bottom line:  A single 1 mg dose of IVTA results in 26% of patients with CRVO and ME gaining 3 or more lines of vision, vs. 7% with observation.  The shortcoming of the data is that we only have 1 year results.  Time will tell whether the improvement will hold.

Here are links to the NIH/NEI press release, the article on Medscape.  The abstract is below.

http://www.nei.nih.gov/news/pressreleases/091409a.asp

http://www.medscape.com/viewarticle/709517

Arch Ophthalmol. 2009 Sep;127(9):1101-14.
A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.
Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, Singerman LJ, Tolentino M, Chan CK, Gonzalez VH; SCORE Study Research Group.
OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO).

METHODS: Multicenter, randomized, clinical trial of 271 participants. MAIN OUTCOME MEASURE: Gain in visual acuity letter score of 15 or more from baseline to month 12.

RESULTS: Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group.

CONCLUSIONS: Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial.

Ophthalmology. 2009 Jan;116(1):57-65.e5.
Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.
Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group.

Collaborators (87)
Vitreoretinal Consultants, Methodist Hospital, Houston, Texas 77030, USA. dmbmd@houstonretina.com
Comment in:

Ophthalmology. 2009 Aug;116(8):1593.
OBJECTIVE: The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. DESIGN: Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. PARTICIPANTS: Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs.

INTERVENTION: Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). MAIN OUTCOME MEASURES: The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored.

RESULTS: Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]).

CONCLUSIONS: In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The results showed that patients receiving bevacizumab cleared anywhere from 2-20 weeks (avg 12 weeks), whereas the patients who did not receive bevacizumab required 6-30 weeks (avg 18 weeks) to clear.  Only 10% of those receiving bevacizumab required PPV, whereas 40% of those who did not receive the drug required PPV.

So, clearly, intravitreal bevacizumab is helpful in the initial treatment of VH from proliferative diabetic retinopathy.  It improves the rate of resolution of VH, and decreases the need for surgery.  Two points were of interest to me.  Neither was specifically studied in the paper, but the authors raise the issues in their study design .  First, they remind us that bevacizumab can induce a fibrous response (“Avastin crunch”) and lead to tractional retinal detachments, and so they excluded patients whose ultrasounds showed the presence of tractional detachments or fibrous responses.  They repeated the B-scans as they followed the injected patients to watch for tractional detachments.  Second, they chose 4-6 weeks as the interval for re-injection of bevacizumab. They based this on two previous papers.  One by Jorge et al. which showed that peak regression of NV in diabetic retinopathy occured at 6 weeks, and that by 12 weeks, leakage had resumed; and the other by Arevalo et al. which showed that regression of NV could occur as quickly as 7-15 days after injection of bevacizumab.

Pearls to take away:  Inject bevacizumab for dense vitreous hemorrhages, get a baseline B-scan and follow the B-scans after injection for tractional detachments, and consider re-injections at 4-6 weeks.

Clinical trials are conducted in a series of steps, called phases – each phase is designed to answer a separate research question.

• Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
• Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
• Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
• Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.