Compliance with recommended dosing schedule allows for outcomes almost comparable to RCTs

Interim analysis of the real-world APOLLON study showed that aflibercept intravitreal injection treatment leads to significant visual and anatomic improvement in patients with diabetic macular edema (DME).  Real-world outcomes mirrored the results of randomized clinical trials (RCTs) with aflibercept, thanks to the overall good adherence to the recommended posology.

“If you replicate the treatment regimen of RCTs, you almost replicate the results of clinical trials, despite the fact that the population is less selected and more diverse. This is a very positive and important finding,” said Jean-François Korobelnik, MD, principal author of the study.

APOLLON was a prospective, observational cohort study that included a total of 402 patients receiving aflibercept intravitreal injections for DME in public hospitals and private clinics in France and followed up for 24 months between 2016 and 2019.  Both treatment-naïve patients and patients previously treated with other anti-VEGF agents were included.  Interim results at 12 months of 147 patients were published on January 2, while the overall results of the entire population at 2 years are expected to be disclosed later this year. 

Patients with both type 1 and type 2 diabetes were included.  Of the 147 patients followed for 12 months, 52.4% were treatment-naïve and 47.6% were previously treated with other anti-VEGF agents, laser or steroids.  

Study outcomes

An overall mean BCVA improvement of +6.5 letters was reported in the study population, with a greater improvement of +7.8 letters in the treatment-naïve cohort as compared with +5.0 letters in the previously treated cohort. 

“Treatment- naïve patients likely had DME for a shorter time and may be more receptive to VEGF inhibitors,” Korobelnik said.  “Patients with longer lasting disease typically have more severe, chronic changes in the retina, and the ability of the retina to recover is partly compromised.  We can say from experience that the lesser duration of DME, the better the VA results are.”

In both treatment cohorts, patients with the lower BCVA letter score at baseline obtained the highest BCVA changes. 

Another interesting observation was that patients receiving the full initial doses of 5 monthly injections prescribed for aflibercept in DME had a higher gain of +8.4 letters at 2 months.  A gain of 10 letters or more was achieved by more than half the patients who received the 5 initial doses and by 37.8% of patients who did not, despite an overall equivalent number of injections over 12 months which is 7,6. 

“The recommended protocol for DME is 5 monthly doses followed by visits and re-injection every 8 weeks the first year.  This treatment regimen has been shown to be the most beneficial,” Korobelnik said.

In the study, treatment-naïve patients were mostly treated according to this schedule, while the initial five doses were missed in several previously treated patients, based on the physician’s decision. 

Both patient cohorts had comparable improvements in anatomic outcomes and a decrease in subretinal and intraretinal fluid following aflibercept injection treatment. The incidence of adverse event, including cataract and recurrence of macular edema, were consistent with the safety profile of anti-VEGF agents. 

Treat according to the label

“Real-world studies are important, because they reflect the diverse population that we see in everyday clinical practice, and because they give us a more realistic picture of the outcomes of treatment when the follow up is not as strict as in randomized trials,” Korobelnik said. 

APOLLON, however showed that the treatment schedule of aflibercept injections was fairly consistent with the dosing schedule used in clinical trials.

“With aflibercept, physicians stick more to the label, probably because the label is “Q8” after the 5 monthly loading doses, one injection every 8 weeks, with visits every 8 weeks, rather than the 4 weeks of other anti-VEGF agents.  It is a more comfortable schedule that fits better into the daily life of patients.  Regular intervals that are not too close are probably the best way to ensure compliance,” Korobelnik said. 

In France, doctors receive a fee per-patient per-procedure, and this might be a further incentive to treat according to the label. 

“There are significant differences between countries.  In France we get reimbursement at each visit, and this encourages a regular and more frequent follow up, but it is very expensive. The same does not happen in the UK and Germany, and the results is a less regular and less close monitoring,” Korobelnik said.    “The money issue is very important for both physicians and patients, taking into account that money is not just the price of the drug, it is the cost of visits, of the procedure, of the OCT and other exams.”

Take-home messages of the APOLLON interim results are that treatment with aflibercept in real life leads to improved functional and anatomic outcomes. Also that outcomes are better when DME is treated in the early stages, and that the recommended protocol with the initial 5 monthly doses followed by re-injection every 8 weeks allows for best outcomes, quite comparable to those of RCTs.  

References:

Korobelnik JF, Daien V, Faure C, Tadayoni R, Giocanti-Auregan A, Dot C, Kodjikian L, Massin P.Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol. 2020 Jan 2. doi: 10.1007/s00417-019-04592-9

Contact information

Jean-François Korobelnik, MD, is Head of the Ophthalmology Department at the University Hospital of  Bordeaux, France.  Email: jean-francois.korobelnik@chu-bordeaux.fr