Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world, and given its chronic and progressive course altogether with the fact that AMD may require lifelong observation and therapy, it has become a major socioeconomic issue as the proportion of the aged population is increasing exponentially [
More recently it has been reported that, after extended follow-up periods, most patients exhibit persistent exudation of the choroidal neovascularization (CNV) with moderate vision loss with this PRN therapeutic approach [
A variety of publications of cohorts of patients with nv-AMD managed with a PRN strategy have been reported: a Swedish study showed an increase of 1 letter after 12 months, a Spanish showed an increase of 1.3 letters after 12 months, and a German study reported a stabilization of vision after 24 months [
This significant worsening of visual acuity after 12–24 months of follow-up may be related to a decrease in the number of follow-up visits and intravitreal drug injections when compared with the clinical trials. For instance, a Danish study with a mean number of injections of 8.7 in four years found a significant decrease in vision through that period [
Individualized treatment regimens impose a considerable burden for the patient, and good results might only be achieved if patients were able and willing to accept these monthly visits. However, the retinal physicians’ nonadherence to the nv-AMD treatment guidelines and the health systems organization may preclude an optimum treatment in some patients, making the translation of the clinical trial results to real life outcomes impossible. The decline in quality of life and increased need of daily living assistance after long follow-up of patients with nv-AMD substantiates the need for detecting deficiencies in real-life treatment in order to prevent vision loss and progression to blindness.
The purpose of this study was to perform a Delphi study with Spanish experts in nv-AMD treatment to identify major potential problems in its management and to propose actions that may improve the final outcomes of these patients.
A national survey was performed using a modified
In the present study a modified Delphi method was used, with the items to be surveyed previously selected by a general coordinator and discussed with an expert panel instead of provided by the participants.
Retinal experts were identified representing proportionally all the regions in Spain according to the following selection criteria: (1) Spanish Vitreoretinal Society (SERV) members; (2) active nv-AMD referral specialist; (3) involvement in postgraduate training.
As there is no formal consensus about the number of experts to be required for a Delphi study, a total of 100 retinal physicians were distributed according to the number of people aged over 50 years who live in the 52 Spanish provinces; sixteen leading SERV members (expert panel) identified these 100 experts based on the criteria afore mentioned.
The key issues about nv-AMD treatment to be surveyed were identified by the study coordinator (Alfredo García-Layana) and discussed with the expert panel based on the nv-AMD SERV guidelines [
An anonymized questionnaire was e-mailed to the 100 retinal physicians selected, including the guidelines to rate how often they performed several tasks or agree/disagree with different statements. They were requested to submit an email to the study coordinator with any relevant comment about the questionnaire and were encouraged to suggest new items that should be considered for further assessments. Each item was rated into a four-step scale provided with response anchors (1 = almost never; 2 = sometimes; 3 = frequently; 4 = almost always).
The ratings resulting from the first Delphi round were analyzed and the scores distribution was presented to the expert panel revised in a presentational meeting. All the submitted comments were addressed and ambiguous questions were reformulated. The questions remained unchanged but clarification was allowed. All new proposed elements were discussed and added next to the questions describing similar items, if they were considered relevant by the advisory panel. The study coordinator submitted the new survey to the entire participant pool that responded to the first round. Each one of the previous questions was provided with an anonymous summary of the expert’s opinion from the previous round. The study participants were encouraged to revise their earlier answers in light of the replies of other members of their panel. No elements were excluded between the first and second rounds.
The final content of the assessment instrument was based on the consensus achieved after the second Delphi round. Differences between the results of the survey and the recommendations of the nv-AMD SERV guidelines [
A predefined consensus level is an indicator good quality and best practice guidelines suggest that criteria for consensus should be defined in advance [
One hundred retina specialists were selected from a total of 537 SERV members. Eighty-seven completed the first Delphi round of answers, and 85 completed the second round. Sixty-nine of them (81%) had more than 10 years of experience treating vitreoretinal diseases. Forty-eight (56%) work both in National Health Service (NHS) and private facilities, 29 (35%) only in NHS, and 8 only in private facilities. Table
Final answers for the second Delphi round questionnaires.
Question | Almost never | Sometimes | Frequently | Almost always |
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Diagnosis and initial treatment | ||||
(1) Do you consider the metamorphopsia a red flag symptom? | 0% | 2% | 15% | 83% |
(2) Do you consider a strong decrease of VA a key symptom of alert? | 0% | 1% | 22% | 77% |
(3) Do you consider the appearance of a central scotoma a key symptom of alert? | 0% | 1% | 21% | 78% |
(4) Do you consider a macular hemorrhage in a patient with drusen a key symptom of alert? | 0% | 1% | 5% | 94% |
(5) Do you consider the macular edema in a patient with drusen a key symptom of alert? | 0% | 0% | 21% | 79% |
(6) Do you consider the corrected VA an essential initial test? | 0% | 1% | 8% | 91% |
(7) Do you consider the PPBMC an essential initial test? | 0% | 4% | 9% | 87% |
(8) Do you consider the macular OCT an essential initial test? | 0% | 0% | 6% | 94% |
(9) Do you consider the FA an essential initial test? | 0% | 18% | 42% | 40% |
(10) Do you consider the loading doses (3 intravitreal injections) the routine way to begin treatment in all cases? | 2% | 7% | 21% | 70% |
(11) Do you consider the initial loading dose feasible from a socio-sanitary point of view? | 5% | 15% | 46% | 34% |
(12) Do you consider the PRN regimen (1 intravitreal injection + PRN) the routine way to start treatment in all the cases? | 35% | 40% | 18% | 7% |
(13) Do you consider a complete series of diagnostic tests necessary during the loading phase? | 25% | 49% | 12% | 14% |
(14) Do you consider a limited amount of diagnostic testing necessary during the loading phase? | 7% | 39% | 20% | 34% |
(15) Do you consider monthly complete examinations in the PRN regimen feasible in NHS hospitals (Consider “complete examination” VA, OCT PPBMC)? | 35% | 48% | 15% | 2% |
(16) Do you consider monthly complete examinations in the PRN regimen feasible in private hospitals (Consider “complete examination” VA, OCT PPBMC)? | 8% | 27% | 45% | 20% |
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Individualized treatment therapy | ||||
(17) Do you have in consideration the balance of risk/profit in deciding which guidelines to follow? | 1% | 6% | 57% | 36% |
(18) Do you consider monthly treatment the most suitable regimen? | 16% | 21% | 40% | 23% |
(19) Do you consider monthly treatment feasible in NHS hospitals? | 73% | 22% | 3% | 2% |
(20) Do you consider monthly treatment feasible in public hospitals? | 30% | 37% | 28% | 5% |
(21) Do you consider the PRN regimen with monthly visits the most suitable practice? | 2% | 25% | 51% | 22% |
(22) Do you consider the PRN regimen with monthly visits feasible in NHS hospitals? | 32% | 36% | 30% | 2% |
(23) Do you consider the PRN regimen with monthly visits feasible in private hospitals? | 8% | 24% | 60% | 8% |
(24) Do you consider the T&E regimen the most suitable practice? | 3% | 53% | 38% | 6% |
(25) Do you consider the T&E regimen feasible in NHS hospitals? | 8% | 38% | 52% | 2% |
(26) Do you consider the T&E regimen feasible in private hospitals? | 5% | 25% | 58% | 12% |
(27) Do you consider the W&E regimen the most suitable practice? | 12% | 56% | 31% | 1% |
(28) Do you consider the W&E regimen feasible in NHS hospitals? | 2% | 26% | 67% | 5% |
(29) Do you consider the W&E regimen feasible in private hospitals? | 4% | 19% | 69% | 8% |
(30) Do you consider that, in general, most of the patients will be properly treated with seven injections during the first year of the treatment? | 0% | 10% | 80% | 10% |
(31) Do you consider that, in general, most of the patients will be properly treated with four injections during the second year of the treatment? | 1% | 27% | 52% | 5% |
(32) Do you consider it suitable to perform the intravitreal injection on the same day of the follow-up visit? | 3% | 23% | 22% | 52% |
(33) Do you consider it feasible to perform the intravitreal injection on the same day of the follow-up visit in NHS hospitals? | 29% | 43% | 14% | 14% |
(34) Do you consider it feasible to perform the intravitreal injection on the same day of the follow-up visit in private hospitals? | 5% | 24% | 42% | 29% |
(35) Aside from the logistical factors, if you have a clean room in the consulting area, would you consider it appropriate to perform an intravitreal injection there? | 38% | 19% | 19% | 24% |
(36) Do you consider performing the intravitreal injection in a clean room as safe as in the operating room? | 13% | 22% | 32% | 32% |
(37) Do you consider it necessary that the retinal specialist perform himself VA check? | 25% | 42% | 20% | 13% |
(38) Do you consider it necessary that the retinal specialist perform himself the OCT? | 15% | 32% | 27% | 26% |
(39) Do you consider it necessary that the retinal specialist perform himself the FA? | 12% | 20% | 27% | 41% |
(40) Do you consider it necessary that the retinal specialist perform by himself the PPBMC? | 2% | 16% | 24% | 58% |
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Nonresponders and referral to general ophthalmologist | ||||
(41) Do you consider an absolute nonresponder a patient with worsening VA and OCT macular thickness post-treatment? | 0% | 1% | 44% | 55% |
(42) In the case of a nonresponder, should the checkup interval be reduced to 15 days since the last injection in order to test for a response? | 18% | 48% | 19% | 15% |
(43) In the case of a nonresponder, should the AGF and ICG be repeated to rule out pathologies such as CP or RAP? | 0% | 13% | 28% | 59% |
(44) Do you consider visual acuity less than 20/400 a criteria to refer the patient to the GO? | 13% | 59% | 22% | 6% |
(45) Do you consider visual acuity less than 20/200 a criteria to refer the patient to the GO? | 42% | 49% | 6% | 3% |
(46) Do you consider a fibrosis over 50% of the lesion (disciform scar) criteria to refer the patient to the GO? | 7% | 48% | 38% | 7% |
(47) Do you consider the absence of retreatment criteria during the last 6 months a criterion to refer the patient to the GO? | 37% | 48% | 15% | 0% |
(48) Do you consider the absence of retreatment criteria during the last 9 months a criterion to refer the patient to the GO? | 25% | 34% | 35% | 6% |
(49) Do you consider the absence of retreatment criteria during the last 12 months a criterion to refer the patient to the GO? | 13% | 31% | 33% | 23% |
(50) How many monthly injections do you usually perform to treat the relapses? | At least, a fixed load phase until the criteria of re-treatment disappeared |
Only until the criteria of retreatment disappeared |
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(51) After how many injections do you define a nonresponder? | First injection |
After the loading phase |
After six months of treatment |
After first year of treatment |
(52) In the case of a nonresponder the second line treatment should be to | Interrupt the treatment with anti-VEGF |
Change the treatment with other anti-VEGF |
Use combined therapy |
Use the same treatment |
VA: best corrected visual acuity; OCT: optimal coherence tomography; PPBMC: posterior pole biomicroscopy; FA: fluorescein angiography; NHS: National Health System; PRN: pro re nata; T&E: treat and extend; W&E: wait and extend; ICG: indocyanine green angiography; CP: choroidal vascular polidopipathy; RAP: retinal angiomatous proliferation; GO: general ophthalmologist.
Final recommendations.
Item | Percentage of strongly agree | Percentage of agree | Percentage of neither agree nor disagree | Percentage of disagree | Percentage of strongly disagree |
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The results of antiangiogenic therapy could differ from the results of clinical trials because these protocols are frequently difficult to use in real clinical practice. | 62,5 | 37,5 | 0 | 0 | 0 |
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Ideally, a personalized retreatment that keeps in mind the risks and benefits and avoids the over- and undertreatment of the patient should be done. | 75 | 25 | 0 | 0 | 0 |
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Generally it is advisable to begin the treatment with a loading phase of three injections. | 87,5 | 12,5 | 0 | 0 | 0 |
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In order to reduce assistance burden, complementary examinations could be avoided during the loading phase or be reduced to a minimum exploring only VA and OCT. | 56,25 | 31,25 | 12,5 | 0 | 0 |
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In some monitoring visits in which the treatment has been previously decided, the examinations could be omitted. | 43,75 | 37,5 | 12,5 | 0 | 6,25 |
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It would be advisable that examinations such as VA and OCT would be performed by technical staff, while the ophthalmologist interprets the results and makes treatment decisions | 50 | 43,75 | 6,25 | 0 | 0 |
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In case of following the PRN regimen, reinjection is recommended in the case of evidence of disease activity in the OCT, new hemorrhage or vision loss due to the disease activity. | 62,5 | 37,5 | 0 | 0 | 0 |
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The T&E regimen could be a useful protocol to reduce the number of revisions and the burden of the disease. | 37,5 | 56,25 | 0 | 6,25 | 0 |
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In the presence of a relapse it is recommended to continue with the treatment until the retreatment criteria disappears. | 43,25 | 50 | 6,25 | 0 | 0 |
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When retreating due to a relapse, if it is not possible to follow established monitoring guidelines, a new loading phase may be considered without performing the associated examinations | 37,5 | 56,25 | 6,25 | 0 | 0 |
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Ideally, the relapses should be treated the same day they are diagnosed. | 62,25 | 25 | 12,5 | 0 | 0 |
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It is as adequate and safe to perform intravitreal injections in a clean room as in an operating room. | 56,25 | 31,25 | 12,5 | 0 | 0 |
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“Absolute” nonresponders are defined as those who after the three loading doses still have worsening VA and OCT | 68,75 | 31,25 | 0 | 0 | 0 |
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In nonresponders, the guidelines have to be decided after doing an ICG (to rule out diseases as CP or RAP) | 62,5 | 31,25 | 6,25 | 0 | 0 |
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It would be recommendable to refer patients to a general ophthalmologist who have not presented with retreatment criteria in the last 12 months or who have the disease in a disciform state. | 50 | 31,25 | 12,5 | 6,25 | 0 |
Although patients usually show a good adherence to individualized treatment strategies, the feasibility related to ophthalmologist and Healthcare resources, in addition to an increased number of patients with the need to be attended, carries a major clinical issue with the consequence of vision loss and suboptimal results compared to that achieved by the pivotal clinical trials [
The results of this analysis showed that there was a high degree of agreement about the signs and symptoms to refer a patient to a retina specialist (Table
Current Spanish and European guidelines recommend a PRN dosing strategy after the loading dose, where injections are administered when visual acuity loss and signs of lesion activity occur [
In order to lengthen the period between follow-up examinations, a protocol called
The majority of retina specialists surveyed considered that the best option is to perform intravitreal injections on the same day of follow-up visit. However, they also believe that to perform the injection on the same day represents a bigger burden due to flow-chart organization reasons (Table
The treatment may be done in a clean room just as safely as in an operating room as is recommended by the SERV guidelines for intravitreal injections [
Recently, the identification of “nonresponders” or “poor responders” is relevant as these might require more visits and injections. There is not any clear defined criterion to identify such cases. In this Delphi study, the participant agreed that an absolute bad responder is a patient losing vision with anatomical worsening after antiangiogenic therapy. In this case the most frequent protocol identified in the survey is to perform an indocyanine green angiography in order to identify as the presence of polypoidal choroidal vasculopathy or retinal angiomatous proliferation [
Another important gap is that once a patient has been treated and followed in a hospital, hospital ophthalmologists seldom refer this patient to the general ophthalmologist although they have reached a low level of vision, or a disciform scar have developed (Table
In summary, after the most important deficiencies were detected, an expert advisory panel used a new two-round Delphi method to describe some recommendations in order to reduce some of the problems detected.
Ideally, a personalized retreatment that keeps in mind the risks and benefits and avoid the over- and undertreatment of the patient should be done. Generally it is advisable to start the treatment with a loading phase of three injections. In order to reduce assistance burden, complementary examinations could be avoided during the loading phase or be reduced to a minimum, exploring only VA and OCT if the patient informs there is a problem. Moreover, in some monitoring visits, in which the treatment has been previously decided, the examinations could be omitted. It would be advisable that examinations such as VA and OCT would be performed by technical staff, while the ophthalmologist interprets the results and makes treatment decisions. When following the PRN protocol, reinjection is recommended in the case of evidence of disease activity in the OCT, new hemorrhage or vision loss due to the disease activity. The TER regimen could be a useful protocol to reduce the number of follow-up visits and the burden of the disease. In the presence of a relapse it is recommended to continue with the treatment until the retreatment criteria disappears. When retreating due to a relapse, if it is not possible to follow established monitoring guidelines, a new loading phase may be considered without performing the associated examinations. Ideally, the relapses should be treated the same day they are diagnosed. It is as adequate and safe to perform intravitreal injections in a clean room as in an operating room. Absolute nonresponders are defined as those who after the three loading doses still have worsening VA and OCT. In nonresponders, the treatment has to be decided after doing anindocyanine green angiography (to rule out diseases such as polypoidal choroidopathy or retina angiomatous proliferation). It would be recommendable to refer patients to a general ophthalmologist who have not presented with retreatment criteria in the last 12 months or who have the disease in a disciform state.
Although these are commonly occurring problems and some suggested solutions, the authors acknowledge that not all of these issues will apply to every clinic. Moreover, this Delphi study was done with Spanish retina specialists and the problems may not be the same in NHS from different countries. However, it is vital to detect the main bottlenecks in hospitals and clinical services to provide a fast and efficient service for patients with nv-AMD.
This work has been developed by members of the Spanish Vitreoretinal society (SERV), the RETICs: RD07-0062: “Age-Related Ocular Diseases, Quality of Life, and Vision”, and RETICS OFTARED (RD12/0034) “Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology” from the Instituto de Salud Carlos III from the Ministerio de Economía y Competitividad, Spain. This work has been partly funded by the PN I+D+i 2008–2011; thel ISCIII-Subdirección General de Redes y Centros de Investigación Cooperativa; and the European Program FEDER.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors want to acknowledge their cooperation to the members of the AMD Spanish Research Group: