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Wet Age-Related Macular Degeneration: Presenting Options to Improve Adherence

  • Authors: Nancy M. Holekamp, MD
  • CME Released: 4/1/2022
  • Valid for credit through: 4/1/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for ophthalmologists, optometrists, and primary care providers.

The goal of this activity is that learners will be better able to present alternative forms of medication delivery to patients with age-related macular degeneration (AMD) in an effort to overcome adherence issues and improve quality of life.

Upon completion of this activity, participants will:

  • Have greater competence related to
    • Selection of newer delivery options for anti-vascular endothelial growth factor therapy when treating neovascular age-related macular degeneration (nAMD)
  • Demonstrate greater confidence in their ability to
    • Communicate therapy administration options to patients with nAMD


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  • Nancy M. Holekamp, MD

    Director, Retinal Services
    Pepose Vision Institute
    Chesterfield, Missouri


    Consultant or advisor for: Adverum; Allergan; Annexon; Apellis; Bayer; Cardinal; Clearside Biosciences; EyePoint Pharmaceuticals; Gemini; Genentech; Gyroscope; Katalyst Surgical; Nacuity; NGM; Notal Vision; Novartis; Ocuphire; Outlook Therapeutics; Regeneron; Thea Laboratories; Stealth Biosciences
    Speaker or member of speakers bureau for: Allergan; Genentech; Regeneron; Spark
    Research funding from: Genentech; Gemini; Gyroscope; Notal Vision
    Patent beneficiary of: Katalyst Surgical
    Stock options from: Gemini; Nacuity
    Owns stock (privately owned) in: Gemini
    Owns stock (publicly traded) in: Apellis


  • Pakinam Aboulsaoud, PharmD

    Medical Education Director, Medscape, LLC


    Disclosure: Pakinam Aboulsaoud, PharmD, has no relevant financial relationships.

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Developed through a partnership between Medscape and Post Graduate Institute for Medicine (PIM).


Interprofessional Continuing Education

In support of improving patient care, Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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  • Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    For Optometrists


    Interprofessional Continuing Education

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    Credit Statement: This course is COPE approved for 0.25 hours of CE credit. Activity #123398 and Course ID 76975-TD. Check with your local state licensing board to see if this counts toward your CE requirement for re-licensure. 

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Wet Age-Related Macular Degeneration: Presenting Options to Improve Adherence

Authors: Nancy M. Holekamp, MDFaculty and Disclosures

CME Released: 4/1/2022

Valid for credit through: 4/1/2023, 11:59 PM EST


Activity Transcript

Ophthalmologist: … As we discussed previously, Tom, you’ve definitely been responding to this treatment since we started it.

Patient: Yes, I can remember how distorted and blurry my vision was before.

Ophthalmologist: But I’m seeing a little more leakage of fluid into the eye than we would really want at this point.

Patient: Oh, really?

Ophthalmologist: I was supposed to see you a few weeks ago, wasn’t I?

Patient: Yes, I had to reschedule my appointment a couple of times.

Ophthalmologist: That probably explains the leakage that you’re having at the moment.

Patient: Oh, I didn’t realize a few weeks would make that much difference.

Ophthalmologist: Yes, for some people, delaying a few weeks can really have a noticeable effect.

Patient: I see.

Ophthalmologist: Have you been having difficulties with the injections?

Patient: I don't drive anymore, doctor. And I don't really have anyone to drive me. So, it's very hard to get here.

Ophthalmologist: I understand, Tom…

Nancy M. Holekamp, MD: Tom is like many patients who are receiving intravitreal anti-VEGF injections for AMD.

We know that these therapies are highly effective for preventing vision loss due to the macular neovascularization and fluid leakage that can occur as AMD progresses. And they have been shown to be safe for the majority of patients. For those reasons, they are now viewed as the standard of care for patients who have developed neovascular AMD.

In real-world patients like Tom, however, the results often fall short of those seen in the clinical trial setting. Anti-VEGF injections must be given on a regular, consistent schedule. Unfortunately,  frequent visits pose a significant burden on patients – and, in many cases, their family or other caregivers. Consequently, a significant proportion of patients initially show a good response to anti-VEGF injections, but then they don’t maintain the necessary frequency of visits. And their vision begins to decline again -- even though we have these great treatments. The AURA study tells us it's a global problem and that, at 2 years, some people’s vision ends up back where they started, or worse, because of undertreatment.

Several studies have explored the reasons why these injections pose such a burden. A survey of 253 patients receiving anti-VEGF injections found that in most cases, the barriers to adherence were numerous and multifactorial. The average number of barriers to treatment reported by patients in that survey was 3.1, with almost half of the patients reporting at least 3 different barriers. So, what are the things that we can do to motivate our patients to adhere to their prescribed treatment regimen? In my experience, it comes down to 3 factors: Number 1 is treatment effect. If we treat patients and they get better, then they’re motivated to come back. Number 2 is the patient-physician relationship. If it becomes a real therapeutic relationship, then patients have confidence in us, and they’re more likely to come back. And number 3 is patient education. If patients understand not only their disease, but the treatment for their disease and the consequences of not getting treated, then they want to come back.

So, of course, we aim to make sure that our patients are on the most effective therapy for them – which means a treatment regimen that they’re willing and able to stick to. And then beyond the treatment effect, we can all help to create a good, open, patient-physician relationship, and we can all help our patients to be adequately educated about their disease and its treatment.

Let’s return to our case, where Tom’s ophthalmologist is going to address the need for good adherence to anti-VEGF therapy…

Ophthalmologist: … The thing is, you’ve been responding well to the treatment – and you’ve noticed a real improvement in the sharpness of your vision.

Patient: Yes, that’s true.

Ophthalmologist: But these shots aren't magic – they're like most other medicines: they have to be dosed for your disease at regular intervals. In the majority of people, this particular medication is most effective for preventing worsening of macular degeneration when it’s administered every 6 to 8 weeks. And, unfortunately, if we don’t stick consistently to that schedule, new blood vessels will start to form again, and leak into the eye – which is what I’m seeing today.

Patient: But honestly, doctor, I just really dread the injections. I don't sleep at all the night before – it ruins my entire day. And then it takes me 2 or 3 days to recover.

Ophthalmologist: It sounds as though these injections are really quite a burden for you. And you’re not alone – I hear similar reactions from other patients. So, it would be best if we considered other options.

Patient: That would be great – I didn’t know there were any.

Ophthalmologist: Well, we could try something called photodynamic therapy. We’ve used it for many years, and it works in some patients. We would inject a medication into your arm. It travels to blood vessels in your eye, and then we activate it with a special laser. That causes the abnormal blood vessels to close, stopping the leakage.

Patient: Is it a 1-time injection, or will I still have to keep coming back?

Ophthalmologist: The treated blood vessels can reopen, so you may need the treatment repeated over time. The other option is a new implant, called a ‘port delivery system’. It gradually releases medication like the one you’re already getting in the injections.

Patient: An ‘implant’?

Dr Holekamp: The reality for patients like Tom is that there are not many good alternatives to anti-VEGF injections. Consequently, there has been an unmet need for effective wet AMD treatment options that sustain the clinical benefits of regular intravitreal anti-VEGF therapy, but without the burden of frequent treatment and monitoring. There has been significant progress in the development of sustained release technology that provides consistent medication over a prolonged period.

The first technology of this kind -- a ranibizumab port delivery system (or ‘PDS’) – was approved last year for the treatment of wet AMD in patients who have responded to at least 2 intravitreal injections of anti-VEGF therapy. It contains 100 mg/mL of ranibizumab -- 20 times the amount in the injectable solution. And this medication is continuously delivered directly into the vitreous cavity over a period of 24 weeks (or approximately 6 months). After 6 months, the implant is refilled in the office.

The effectiveness of the ranibizumab PDS was compared with intravitreal injections of ranibizumab in the Archway trial -- a phase 3 noninferiority and equivalence study involving 418 patients who had previously responded to anti-VEGF therapy. Patients were randomized to receive either the PDS, with refills every 24 weeks, or intravitreal injections every 4 weeks. The change in best-corrected visual acuity from baseline, averaged over weeks 36 and 40, was +0.2 letters in the PDS group and +0.5 letters in the group who received monthly injections. Those findings were within the predetermined noninferiority margin of minus 4.5 letters and the equivalence margin of plus-or-minus 4.5 letters.

Importantly, of the 248 patients who received the PDS implant and were assessed throughout the first 6 months, only 4 patients needed to be given any supplemental injections prior to the first refill exchange at 24 weeks. That is less than 2% of patients.

A bioresorbable hydrogel fiber implant is also in development. This implant is delivered via intravitreal injection and is designed to release medication over a period of around 6 months. It provides axitinib -- a different kind of drug that is not currently used for AMD. Axitinib is a tyrosine kinase inhibitor that acts directly on VEGF receptors. This implant is currently being evaluated in a clinical trial, and initial data have been encouraging.

We’ll look at the most important safety considerations relating to the ranibizumab PDS in a moment. But first, let’s return to the final part of our case, during which Tom’s ophthalmologist is going to describe the implant to him…

Ophthalmologist: …Yes, I’ve actually put the port delivery system into several patients now.

Patient: So. they have this implant instead of the injections.

Ophthalmologist: That’s right – and I’ve found that the majority of patients prefer the implant over the regular injections.

Patient: Really? How does it work then?

Ophthalmologist: Well, you had cataract surgery a little more than a year ago. We gave you a lens implant – it was placed in the operating room with you awake.

Patient: Yes, I remember that.

Ophthalmologist: The procedure took less than 45 minutes. And now you don’t even know it’s there.

Patient: Alright…

Ophthalmologist: The port delivery system is a drug delivery implant that's made out of a similar material to your lens implant. We insert it into your eye through a surgical procedure just like your cataract surgery. Then, it will stay in your eye permanently, and just like your lens implant, you won’t even know it's there.

Patient: I see…

Ophthalmologist: Once it’s in your eye, it will slowly release medication over the course of 6 months. Then, you’ll need to come back to the office just twice a year so that we can refill the implant with medication.  This refill procedure is similar to an injection, but the needle goes into the port of the implant and not your eye, so you don’t feel any pain.

Patient: So, then I won’t need the injections anymore?

Ophthalmologist: It’s unlikely. In most cases, my patients' vision remains stable after they have the implant. Very occasionally, somebody needs supplemental injections as well – but it’s less than 1 in 20 people.

Patient: That sounds great. And none of your patients have had any problems with it?

Ophthalmologist: It’s possible to have complications that would make us want to remove the implant. And it’s a surgical procedure, so very occasionally patients can have some bleeding into the eye after the surgery or an infection. But it’s uncommon.

Patient: OK, that’s good to know.

Ophthalmologist: There would be stitches on your eye and you’d have to use eye drops for 4 to 6 weeks. So, you’d need a bit of time to recover from the surgery – a normal healing process can take anywhere from 4 to 8 weeks. And there are a few other precautions that you’d have to take during that period. We can go over those with you when we put the implant in, if that’s the way you want to go.

Patient: It certainly sounds much better than coming in almost every 8 weeks for injections.

Ophthalmologist: Yes, as I said, almost all of my patients who have opted for the implant prefer it over the regular injections.

Patient: Alright, let’s give it a try then. When can you do it?

Ophthalmologist: I’ll ask the office staff to set that up for you. In the meantime, because you’re having some fluid leakage, you need an injection today.

Patient: Oh well, hopefully it’ll be the last one.

Dr. Holekamp: It is important, of course, that we explain to our patients, not only the advantages of sustained-release therapy, but also other important aspects of treatment that should be aware of. For example, we know that for most patients who have the ranibizumab PDS implant, the OCT retinal thickness is controlled, and the vision remains stable. In patients who are VEGF-responsive after injections, we now have data through 96 weeks.  Those data show that both vision and retinal thickness are controlled with the PDS and just a refill exchange procedure in the office every 6 months. However, patients should be aware that it’s normal to experience a transient decrease in vision for the first 4 to 8 weeks, until the eye heals from surgery. In the Archway study, this had generally resolved by the 12-week assessment. Because initial implantation of the ranibizumab PDS is a surgical procedure, the safety considerations are different from intravitreal injections. Prespecified ocular adverse events of special interest were reported in 19% of patients who received the implant, and in 6% of patients in the monthly injections group. The most significant of these events was endophthalmitis. Over time, this occurs in about 2% of patients with the implant.

It's important to treat endophthalmitis promptly, and all patients therefore need to be educated about the signs and symptoms of endophthalmitis, and instructed to immediately report anything that could be associated with these events. It’s also essential for ophthalmologists to routinely monitor the implant and the tissue overlying the implant flange for signs of conjunctival erosion or retraction, so that they can take action if necessary.

In my experience, once the pros and cons of the ranibizumab PDS have been explained to patients they jump at the opportunity to have the implant. And once they have it, they love it. More than 93% of the patients in the ARCHWAY study either strongly or very strongly preferred the implant over injections.

In summary then, most of us who administer intravitreal injections of anti-VEGF therapy to treat wet AMD have encountered patients like Tom who, for a variety of reasons, don’t adhere to the necessary treatment schedule – and subsequently are at risk for losing vision. Sustained delivery technology now allows us to overcome that problem for the majority of patients.

Thank you for watching this Medscape Clinic. Goodbye.

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