This is the first study to evaluate the cost-effectiveness of an anti-VEGF agent for the treatment of patients with DME causing visual impairment. Our economic model, which was based on data from the RESTORE clinical trial, shows that ranibizumab monotherapy provides superior improvements in visual acuity and is cost-effective relative to the current standard of care, laser photocoagulation. Ranibizumab monotherapy was associated with an ICER of £24 028 per QALY gained relative to laser therapy alone, a value within the willingness-to-pay threshold of £30 000 per QALY gained that has generally been considered cost-effective in the UK. The results of our model may be applicable to a broad spectrum of patients with visual impairment due to DME, as the RESTORE trial showed consistent efficacy of ranibizumab therapy across patient subgroups based on a range of demographic and disease characteristics.
The cost-effectiveness of combined ranibizumab and laser therapy was less favourable than that of ranibizumab monotherapy (ICER £36 106 per QALY gained relative to laser therapy alone). While this in part reflects higher treatment costs, combination therapy also provided a lower predicted QALY gain than ranibizumab monotherapy (0.13 vs 0.17 QALY over the 15-year time horizon in the base case). A possible explanation for these results is the observation in RESTORE that combination therapy provided smaller improvements in BCVA in patients who had received prior laser therapy than those who had not (4.7 vs 6.9 letters gained, respectively).11
In RESTORE, the proportions of patients who received prior laser therapy were 52% (ranibizumab monotherapy), 47% (combination therapy) and 43% (laser therapy).
Sensitivity analyses showed that the model results were robust to reasonable alterations in inputs and assumptions; ICERs were particularly sensitive to changes in the number of ranibizumab injections and the time horizon of the model. The base case assumed an average of 10 ranibizumab injections over 2 years, based on data from the DRCR.net
protocol I study.1
Ranibizumab monotherapy remained cost-effective (ICER below £30 000 per QALY gained) up to a total of 13 injections. Increasing the number of injections beyond 13 resulted in an ICER outside the generally accepted threshold, emphasising that additional injections beyond 2 years of treatment will be an important cost driver. However, the current model is conservative in that it includes incremental costs for additional injections beyond year 2, but assumes no incremental benefit. The possible need for re-treatment beyond 2 years remains speculative; forthcoming data from the 2- and 3-year RESTORE follow-up and the DRCR.net
5-year data will improve our understanding of the likely duration of treatment. Longer time horizons would be expected to lead to improved cost-effectiveness of ranibizumab, because the benefits of improved vision accrue over time whereas treatment costs are incurred immediately once treatment is initiated.
We have identified only one previously reported cost-effectiveness study of interventions for DME. Sharma et al
modelled the cost-effectiveness of laser therapy alone for DME,27
comparing early and deferred laser treatment with no treatment based on 3-year outcomes from the Early Treatment Diabetic Retinopathy Study.28
The model included health states defined by BCVA and applied a 40-year time horizon based on a population with a mean age of 47 years. Over this time horizon, laser treatment was predicted to provide a gain of 0.236 QALY and was considered highly cost-effective for DME relative to no treatment. Our results cannot be compared directly with the Sharma et al27
study because RESTORE did not include a ‘no treatment’ arm; moreover, our model applied a 15-year time horizon from a baseline age of 63 years, consistent with RESTORE. However, if a baseline age of 47 years and time horizon of 40 years were applied to our model, as in the Sharma et al27
model, the RESTORE model would predict a 0.26 QALY gain and an ICER of £10 412 for ranibizumab monotherapy relative to laser therapy alone. This suggests that the cost-effectiveness of ranibizumab would be higher in patients with DME who were younger than the average in RESTORE (63 years) because of their longer life expectancy.
Several methodological considerations should be noted. While treatment effectiveness was based on 1-year data from RESTORE, we projected long-term changes in BCVA using the best available clinical evidence. For year 2, the DRCR.net
protocol I study supported the assumption that BCVA at 1 year was maintained on average to 2 years.1
BCVA changes in years 3–15 were based on reported progression in the WESDR study, which demonstrated a gradual decline in vision over time in DME. The rate of decline in BCVA was reduced by adjustment using data from both the Diabetes Control and Complications Trial and UK Prospective Diabetes Study to account for a less intensive systemic diabetes management regimen in the past relative to current practice.29–32
Sensitivity analysis showed that these assumptions had only a minor impact on the model results.
Utilities were estimated from the BCVA of treated eyes in RESTORE, irrespective of whether this was the better-seeing or worse-seeing eye. This approach links utility values directly to the eye receiving the intervention. The RESTORE study protocol required the worse-seeing eye to undergo intervention unless there was a medical contraindication; 32.8% of treated eyes were the better-seeing eye at baseline, and 37.3% were the better-seeing eye at 12 months. Using the better eye as reference is supported by quality of life studies in vision-related conditions, which have shown that the better eye is the major driver of overall quality of life and patient functioning.33
Indeed, patient-preference studies have shown that the utility gains associated with treating the worse-seeing eye are uncertain, even though good vision in two eyes confers better quality of life than good vision in only one eye.34
As expected, subdividing the elicited utilities in RESTORE by better-seeing or worse-seeing eye showed that patients being treated in the better-seeing eye reported lower utility at a given level of BCVA than those treated in the worse-seeing eye. Nevertheless, utility measured in patients treated in the worse-seeing eye demonstrated significant sensitivity to variation in the BCVA in the treated eye, comparable with that of patients treated in the better-seeing eye. Unfortunately, the small sample of RESTORE patients in each BCVA health state meant that the resulting utility functions were not sufficiently robust to allow separate cost-effectiveness analysis by better-seeing or worse-seeing eye. It should also be stated that the option of not treating visual impairment in a better-seeing eye is not an ethical stance.
We could not find published utility estimates from specific populations with DME. We performed sensitivity analysis using utilities reported in two studies based on populations with diabetic retinopathy (which includes a wider population than DME).12
Lloyd et al
reported utilities elicited by the general population, while Brown et al
reported utilities elicited by patients. This showed that applying the Lloyd et al12
utilities to the model greatly improved the cost-effectiveness of ranibizumab monotherapy, leading to a larger incremental gain of 0.22 QALY and a lower ICER of £19 238 per QALY gained relative to laser therapy alone. Applying the Brown et al13
utilities also increased the QALY gain with ranibizumab and led to an ICER of £21 953 per QALY gained for ranibizumab monotherapy versus laser therapy alone. The fact that the RESTORE utilities are less sensitive to BCVA decline may simply reflect the fact that a majority of the reference eyes in RESTORE were worse-seeing, while all reference eyes in the Lloyd et al12
and Brown et al13
studies were better-seeing.
Limitations of this analysis should be considered. First, we modelled treatment of unilateral DME based on RESTORE data, but did not estimate the cost-effectiveness of treating bilateral DME. While 82.8% of patients in RESTORE had signs of bilateral DME at baseline, the proportion of patients who would have become eligible for treatment because of vision impairment in their fellow eye was not known. Treatment of both eyes may be relevant in many patients with bilateral DME, but there is a lack of evidence for the additional utility benefit of treating the fellow eye. Uncertainty also exists regarding the cost consequences of treating both eyes, where total cost is not likely to double given the possibility of achieving economies of scale from shared categorical spending, such as administrative and monitoring costs. An additional limitation was that the model assumed the cost of blindness would be incurred in patients reaching health states with BCVA ≤35 letters (Snellen ≤6/60) in the treated eye.
There is also uncertainty inherent in working with published results of studies, as was necessary for incorporating the DRCR Network Protocol I results, as opposed to using patient-level data. While analysis using patient level data is clearly preferable, incorporation of findings from studies in addition to RESTORE, such as the highly comparable DRCR study, provide very useful data for answering critical questions relating to clinical practice in a broad spectrum of patients with DME. It should be noted, however, that some subgroups, such as patients with the poorest glycaemic control (high glycated haemoglobin), were excluded from these trials.
In conclusion, the results of our economic model show that ranibizumab monotherapy is cost-effective relative to laser therapy alone in the treatment of DME causing visual impairment, while combined ranibizumab and laser therapy may be cost-effective depending on patient characteristics. The cost-effectiveness of ranibizumab monotherapy or combination treatment is expected to be higher in younger patients who have a longer life expectancy. These findings have important practical implications, given the high socio-economic burden of DME and the need for new, cost-effective treatments that reduce long-term progression to blindness. Ongoing studies, such as the RESTORE extension, will provide additional clarification of current uncertainties such as the need for ranibizumab injections after 2 years and the likelihood of recurrent DME.