FormalPara Key Summary Points

Why carry out this study?

 Surgeons, patients, and healthcare policymakers are overwhelmed by diverse strategies in cataract surgery. Previous studies have paid more attention to the effectiveness than the cost-effectiveness of presbyopia correction in cataract surgery.

 There is no indicator that can integrate distance, intermediate, and near (full-range) VA. Correlational research is lacking but urgent especially in low- and middle-income settings.

What was learned from the study?

 A novel indicator (objective spectacle independence rate) was proposed to summarize full-range VA as the effectiveness of presbyopia correction.

 We explored a method to rank seven common strategies of bilateral cataract surgery according to the cost-effectiveness of presbyopia correction by estimating ACERs and ICERs according to objective spectacle independence rate with data from a prospective single-blind two-center clinical trial in China.

Introduction

Cataract and presbyopia are the major cause of blindness and vision impairment in the world as well as China as a result of the aging population [1,2,3,4]. There were 94.0 million people in the world and 18.1 million people in China with a vision impairment or blindness due to cataract [2, 4]. The prevalence of presbyopia was 25% in the world and in China [5, 6]. About 90% of the global burden of presbyopia occurs in low- and middle-income settings including China, where presbyopia correction coverage rates are only 10% because of a lack of awareness and access to affordable interventions, and the costs due to uncorrected presbyopia both to the patient and to society are higher than those in high-income settings [5, 7,8,9]. Highly cost-effective interventions can offer enormous economic benefits to individuals and nations with relatively low costs. Correcting oncoming presbyopia simultaneously during cataract extraction and intraocular lens (IOL) implantation has been proven to be practical and economical [10].

There are various strategies for bilateral IOL implantation in clinical practice. The conventional strategy of bilateral monofocal IOL implantation targeting emmetropia presents lower subjective (self-reported) spectacle independence due to poor intermediate and near visual acuity (VA). Conversely, presbyopia-correcting strategies with higher subjective spectacle independence and better full-range (distance, intermediate, and near) VA include, but are not limited to, bilateral implantation of monofocal IOLs targeting monovision (emmetropia in one eye and myopia in the other eye), diffractive bifocal IOLs with the same or different near additional power (blended vision), refractive bifocal IOLs, trifocal IOLs, and extended depth of focus (EDOF) IOLs [11,12,13]. Facing diverse strategies, surgeons are expected to customize patient management with satisfactory effectiveness. How to measure and rank the effectiveness of presbyopia correction is a very controversial topic. There are multiple subjective factors disturbing the measurement of subjective spectacle independence rate at the same VA outcomes, and there is no uniform indicator to measure distance, intermediate, and near VA simultaneously. Therefore we defined a novel synthetic indicator to evaluate the effectiveness of presbyopia correction, called the objective spectacle independence rate, which means the proportion of individuals with good binocular full-range VA who might not need spectacles in daily tasks. The reason that we measured binocular VA rather than monocular VA was a consideration of the binocular visual re-establishment in bilateral surgery.

Previous studies pay more attention to the effectiveness rather than cost-effectiveness of presbyopia correction in various strategies of bilateral cataract surgery. Actually patients are not only responsive to the effectiveness but also sensitive to the cost. Presbyopia-correcting IOL (e.g., bifocal, trifocal, or EDOF IOL) is more expensive than monofocal IOL, which would increase cost to patients and to the healthcare insurance system. In high-income settings, a few studies indicate that bifocal IOL is more cost-effective than monofocal IOL in individuals desiring spectacle independence, but do not cover all strategies mentioned above [14,15,16,17]. Correlational research on the cost-effectiveness of presbyopia correction is lacking but urgent in low- and middle-income settings, such as China.

To provide references for surgeons customizing patient management and for healthcare policymakers allocating scarce resources, we conducted a cost-effectiveness analysis (CEA) according to objective spectacle independence rate, using data from a clinical trial covering seven strategies mentioned above, based on two centers located in Beijing city and Guangxi Zhuang Autonomous Region with the top and bottom three provincial GDP per capita in China from 2019 to 2021 respectively [18]. In the CEA, we estimated the average cost-effectiveness ratios (ACERs, defined as the ratio of the average costs per effectiveness) and incremental cost-effectiveness ratios (ICERs, defined as the ratio of the incremental costs to the incremental effectiveness) [19].

Ophthalmologists and policymakers could identify highly cost-effective presbyopia-correcting strategies in cataract surgery by this method in cost-effectiveness analysis with their own objective spectacle independence rate, cost, and wiliness-to-pay in different settings.

Methods

Clinical Trial Design

This CEA used data from a prospective single-blind nonrandomized controlled clinical trial based on two centers (center 1: Peking University Third Hospital located in North China; center 2: the People’s Hospital of Guangxi Zhuang Autonomous Region located in South China). The trial followed the tenets of the Declaration of Helsinki and was approved by the medical ethics committees in two centers and registered at clinicaltrials.gov (NCT04265846). All assessors responsible for data collection and the outcome measurements remained blind to groupings.

Participants

We enrolled participants between November 2019 and May 2021 in two centers. Each participant signed an informed consent form. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. The inclusion criteria were individuals who planned to undergo bilateral cataract surgery, aged between 55 and 75 years, axial length (AL) ranging from 22 to 26 mm, preoperative angle kappa distance less than 0.5 mm, and expected postoperative astigmatism no greater than 1.00 diopter (D) in any eye. The exclusion criteria were individuals with previous intraocular or corneal surgery, abnormal pupil or suspensory ligament of the lens, or any other significant ocular conditions in any eye.

Interventions and Groupings

All patients underwent bilateral phacoemulsification and IOL implantation by experienced surgeons (Dr. Qi in center 1, Dr. Zeng in center 2) and were divided into seven strategies depending on patients’ requirements and preferences: (1) monofocal strategy: bilateral monofocal IOLs [AcrySof IQ SN60WF (Alcon Laboratories, Inc., Fort Worth, TX, USA) or Rayner 920H (Rayner Intraocular Lenses Ltd., Hove, East Sussex, UK)] targeting emmetropia; (2) monovision strategy: monofocal IOLs [AcrySof IQ SN60WF or Rayner 920H] targeting emmetropia in the dominant eye and myopia of − 2.00 D in the nondominant eye; (3) diffractive bifocal strategy: bilateral diffractive bifocal IOLs [AcrySof IQ ReSTOR + 3.0 D SN6AD1 (Alcon Laboratories, Inc., Fort Worth, TX, USA)] targeting emmetropia; (4) blended strategy: blended implantation diffractive bifocal IOLs with near additional power of + 2.5 D [AcrySof IQ ReSTOR + 2.5 D SV25T0 (Alcon Laboratories, Inc., Fort Worth, TX, USA)] in the dominant eye and + 3.0 D [SN6AD1] in the nondominant eye all targeting emmetropia; (5) refractive bifocal strategy, bilateral refractive bifocal IOLs [SBL-3 (Lenstec. Inc., Christ Church, Barbados)] targeting emmetropia; (6) trifocal strategy: bilateral trifocal IOLs [AT LISA tri 839MP (Carl Zeiss Meditec AG)] targeting emmetropia; (7) micro-monovision EDOF strategy (hereafter “EDOF strategy”): bilateral EDOF IOLs [Tecnis Symfony ZXR00 (Johnson & Johnson Vision, Inc., USA)] targeting emmetropia in the dominant eye and myopia of − 0.50 D in the nondominant eye. The details of the design in the seven strategies are shown in Supplementary Table S1. We measured postoperative monocular refractive prediction error and recorded surgical complications.

Effectiveness Estimates

Effectiveness was estimated on the basis of the objective spectacle independence rate, which was defined as the proportion of individuals with binocular uncorrected distance VA (UDVA at 5 m), intermediate VA (UIVA at 80 cm or 60 cm), and near VA (UNVA at 40 cm) all no greater than 0.1 logMAR (logarithm of the minimum angle of resolution) at 3 months after the surgery on the second eye.

Cost Estimates

The total cost for each patient included the costs of IOLs and other costs. The costs of IOLs were available in the national procurement system (September 2021). Other costs were actual direct medical expenses before medical insurance reimbursement, including the costs of consultation and nursing care, examinations, medicines and surgery, covering the preoperative, intraoperative, and postoperative period in both inpatient and outpatient visits. All monetary values were collected in Chinese yuan (¥) and converted to US dollars ($) with an exchange rate of ¥1 = $0.156 (as of November 2021).

ACERs and ICERs Estimates

We estimated ACERs to rank the seven strategies intuitionally and ICERs to compare two strategies when necessary. ACER was calculated by the mean total cost per patient divided by effectiveness (objective spectacle independence rate) in each strategy respectively ($/1% rate). ICER was calculated by the incremental change in total cost per patient between two strategies divided by the incremental change in effectiveness (objective spectacle independence rate) between two strategies ($/1% incremental rate).

Sensitivity Analysis

We performed both one-way and multivariate probabilistic sensitivity analysis to test the robustness of cost-effectiveness comparisons. In the one-way sensitivity analysis, we took a variation of ± 20% at costs of IOLs, ± 50% at total costs, and ± 50% at effectiveness, respectively. In the multivariate sensitivity analysis, we plotted the incremental cost-effectiveness plane and cost-effectiveness acceptability curve by drawing 1000 iterative pairs using the bootstrap methods. Considering 1% spectacle independence rate resulted in a slight difference, we took the willingness-to-pay (WTP) threshold per 10% incremental objective spectacle independence rates (hereafter “WTP/10% incremental rates”) in the analysis. We set the WTP of very cost-effective and cost-effective thresholds in terms of one and three times the annual disposable income per capita in China in 2021 ($5480 [¥35,128]/10% incremental rates and $ 16,440 [¥105,384]/10% incremental rates, respectively) [20].

Sample Size Calculation

We used PASS 15.0 to perform sample-size calculation according to subjective spectacle independence rates in previous literature (8.2%, 55.0%, 76.5%, 87.5%, 88.0%, 88.0%, and 88.6% in the monofocal, monovision, diffractive bifocal, blended, refractive bifocal, trifocal, and micro-monovision EDOF strategies, respectively) [21,22,23,24,25,26]. For a = 0.05 and b = 0.9, the required sample size was 30 participants in each strategy (210 in total) by allowing a 30% dropout.

Statistical Analysis

We used STATA 13.1 to perform the statistical analysis. We conducted one-way analysis of variance (ANOVA) for comparisons across the seven strategies, performing the Wald test for group differences (P < 0.05). We used the log link function for binary variables and costs, assuming Poisson distribution and gamma distribution, respectively; and the identity link function for other continuous variables, assuming Gaussian distribution. Given the limited sample size, we adopted bootstrap methods with 500 replications (with a seed of 123,456) to estimate the standard errors and 95% confidence intervals (CIs).

Results

Clinical Trial Outcomes

We enrolled 210 participants totally and analyzed 194 participants (92.4%, 388 eyes) finally, with 16 participants withdrawn. The flow diagram of participant assignment is shown in Supplementary Fig.  S1. There were no significant differences in the baseline analysis of demographic statistics and preoperative ocular biometry among all strategies (P > 0.05) (Supplementary Table S2). There were no noteworthy surgical complications and no significant differences in the refractive prediction error among all strategies (P > 0.05) (Supplementary Table S3).

Effectiveness

The trifocal strategy showed the highest objective spectacle independence rate [93.1% (95% CI 77.2–99.2%)]. The refractive bifocal strategy yielded lower rates [75.0% (95% CI 55.1–89.3%)] but no significant difference compared with the trifocal strategy. These first two strategies were sequentially followed by the EDOF [67.9% (95% CI 47.6–84.1%)], blended [51.9% (95% CI 31.9–71.3%)], and diffractive bifocal strategy [44.4% (95% CI 25.5–64.7%)] but with no significant statistical power to justify the differences (P > 0.05). Notably, the monovision [14.3% (95% CI 1.4.0–32.7%)] and monofocal strategies [7.4% (95% CI 0.9–24.3%)] had the least favorable outcomes (Table 1).

Table 1 Effectiveness, total costs, average cost-effectiveness ratios, and one-way sensitivity analyses of the seven strategies
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Costs

The costs of IOLs sorted from low to high were the monofocal ($465.50), monovision ($465.50), diffractive bifocal ($1574.04), blended ($1574.04), refractive bifocal ($1923.79), EDOF ($3452.59), and trifocal ($7176.00) strategies. However other costs were similar across all strategies with no significant differences (P = 0.928). Consequently, the total costs per patient sorted from low to high were the monovision [$1955.34 (95% CI $1939.41–1971.27)], monofocal [$1959.61 (95% CI $1943.60–1975.62)], blended [$3064.58 (95% CI $3052.90–3076.25)], diffractive bifocal ($3069.04 [95% CI $3053.45–3084.62]), refractive bifocal [$3415.31 (95% CI $3392.36–3438.27)], EDOF [$4943.84 (95% CI $4929.05–4958.62)], and trifocal [$8659.69 (95% CI $8647.21–8672.17)] strategies. The details of the cost categories are presented in Table 2.

Table 2 Cost categories for bilateral cataract surgery in the seven strategies ($/patient)
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ACERs

The refractive bifocal strategy had the lowest ACER ($45.54/1% rate [95% CI 34.57–56.50)], followed by the blended [$59.10/1% rate (95% CI 31.72–86.48)], diffractive bifocal [$69.06/1% rate (95% CI 30.89–107.21)], EDOF [$72.85/1% rate (95% CI 52.02–93.70)], trifocal ($93.01/1% rate [95% CI 83.23–102.79]), monovision [$136.83/1% rate (95% CI − 55.40 to 329.14)], and monofocal [$264.45/1% rate (95% CI − 97.45 to 626.55)] strategies. The rank order of ACERs among all strategies was consistent with the main analysis in the one-way sensitivity analyses (Table 1).

ICERs

In the flow diagram of ICERs in pairwise comparisons (Fig. 1), firstly, the monovision strategy has better effectiveness but very similar cost compared to the monofocal strategy (the monovision strategy dominates the monofocal strategy); secondly, the blended strategy shows better effectiveness but very similar cost compared to the diffractive bifocal strategy (the blended strategy dominates the diffractive bifocal strategy); thirdly, the refractive bifocal strategy has better effectiveness but lower cost compared to the EDOF strategy (the refractive bifocal strategy dominates the EDOF strategy); fourthly, the trifocal strategy presents the best effectiveness but also the highest cost among all strategies; finally, the screened four strategies are arranged horizontally in order of total costs from low to high: the monovision strategy, blended strategy, refractive bifocal strategy, and trifocal strategy. The ICERs of the blended strategy compared with the monovision strategy, the refractive bifocal strategy compared with the blended strategy, and the trifocal strategy compared with the refractive bifocal strategy were $29.53, $15.15, and $289.74 per 1% incremental rate, respectively. According to the cost-effectiveness plane and the cost-effectiveness acceptability curves (Figs. 2 and 3), compared with the monovision strategy, the probabilities that the blended strategy is cost-effective and very cost-effective were 99.9% and 99.8%, respectively; compared with the blended strategy, the probabilities that the refractive bifocal strategy is cost-effective and very cost-effective were 96.7% and 96.3%, respectively; compared with the refractive bifocal strategy, the probabilities that the trifocal strategy is cost-effective and very cost-effective were 93.2% and 81.7%, respectively.

Fig. 1
figure 1

Flow diagram of ICERs in pairwise comparisons. The term “dominates” indicates the strategy is cost-effective with higher effectiveness at a lower cost compared with the other strategy. The cost-effective and very cost-effective thresholds were defined as $16,440/10% incremental rates and $5480/10% incremental rates, respectively. Abbreviations: “Rate” is the shortened form of objective spectacle independence rate; “E” is the shortened form of effectiveness (objective spectacle independence rates, %); “C” is the shortened form of total cost ($/patient); EDOF, extended depth of focus; ICER, incremental cost-effectiveness ratio; VS, versus; $, US dollar

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Fig. 2
figure 2

Cost-effectiveness plane. The scatter points represent the 1000 pairs of incremental cost (total cost) and incremental effectiveness (objective spectacle independence rate). The WTP lines representing the thresholds of cost-effective (WTP of $16,440/10% incremental rates) and very cost-effective (WTP of $5480/10% incremental rates). A The blended strategy compared with the monovision strategy. B The refractive bifocal strategy compared with the blended strategy. C The trifocal strategy compared with the refractive bifocal strategy. Abbreviations: “Rate” is the shortened form of objective spectacle independence rate; WTP, willingness-to-pay; $, US dollar

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Fig. 3
figure 3

Cost-effectiveness acceptability curves showing the probability (y-axis) that the strategy is cost-effective at different WTP thresholds per 10% incremental objective spectacle independence rates (x-axis). Abbreviations: WTP, willingness-to-pay; $, US dollar

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Discussion

Unlike some CEAs based on previously published data from different trials, we gathered data from a trial covering seven common strategies of bilateral cataract surgery in the real world to ensure the homogenization and reliability. We proposed a novel indicator named the objective spectacle independence rate which could summarize binocular full-range VA to evaluate the effectiveness and provide new insights into cost-effectiveness analysis on presbyopia correction in cataract surgery. The results implied that all presbyopia-correcting strategies achieved better effectiveness and higher cost-effectiveness than the monofocal strategy, the trifocal strategy had the best effectiveness, and the refractive bifocal strategy cost the least to achieve 1% objective spectacle independence rate. In addition, the acceptability curves of ICERs considering different WTP thresholds could provide references to assist surgeons in personalizing the IOL recommendation and healthcare policymakers in rationalizing limited resources.

In different studies, costs vary in regions and effectiveness varies in clinical outcomes, leading to a variation in CEA results. For instance, effectiveness was measured by quality-adjusted life years (QALYs) in Hu et al.’s study or by vision-related indicators in Lin and Yang’s study [14, 15]. In our study we evaluate effectiveness focused on full-range VA, which might attract the most attention from patients. In cataract surgery postoperative VA is not related to preoperative VA, and the factors affecting postoperative VA (preoperative ocular biometry and refractive prediction error) were consistent among all strategies. Therefore, the baseline for comparison of postoperative effectiveness was consistent. And we ignored the temporal discounting on the basis of the evidence of the long-term stability in postoperative VA [27].

Our study confirmed that in low- and middle-income settings the monofocal strategy was the least cost-effective of all with an inferior objective spectacle independence rate. The conclusion is consistent with the research in high-income settings [14, 15, 17, 28]. Although the monofocal strategy is the most commonly used in China owing to lowest cost, we call for an increase of presbyopia-correcting strategies in clinical practice and medical resource input.

The design of monovison aims to increase the binocular depth of focus with intentional anisometropia by sacrificing stereopsis [29, 30]. In this study, the monovison strategy was the cheapest but the least cost-effective presbyopia-correcting strategy. Nevertheless, Greenbaum believed that monovision design has a benefit advantage of 34% over multifocal IOLs (92% versus 80% subjective spectacle independence) [31]. Actually, objective spectacle independence of monovison strategy in our study was not as good as subjective spectacle independence in other studies.

Previous studies indicated that the blended implantation of two diffractive multifocal IOLs with different near additional power provides a broader range of binocular vision than the bilateral implantation of either one [23, 32]. Our study also demonstrated the objective spectacle independence rate in the blended strategy was slightly better than that in the diffractive bifocal strategy. Because the costs were similar in the two strategies, the blended strategy was more cost-effective than the diffractive bifocal strategy.

Previous studies reported that trifocal IOL achieves outstanding full-range VA outcomes [33, 34] and a rotationally asymmetric segmental refractive bifocal IOL provides a similar profile of defocus curve to that of trifocal IOLs [35]. Some experts believe that a neutral aberration profile of this IOL enables remnant corneal spherical aberration to somewhat increase the intermediate VA and focus depth [24]. We found that the trifocal strategy provided the best effectiveness but cost the most, and the refractive bifocal strategy was the most cost-effective strategy for achieving a satisfying effectiveness with relatively low costs according to ACERs.

In addition, micro-monovision implantation of EDOF IOLs may contribute an improved vision from far to near in comparison with bilateral implantation targeted emmetropia [11, 26, 36]. About objective spectacle independence, the EDOF strategy performed better than the diffractive bifocal and blended strategies, and slightly worse than the refractive bifocal strategy. However, the EDOF strategy was not as cost-effective compared with these three strategies owing to the relatively high costs of IOLs according to ACERs.

The WTP determines the threshold of cost-effectiveness. In the USA in 2008, the WTP was $1825 annually for spectacle independence in 80% of patients [17]. However, in China, no uniform threshold exists to measure whether a strategy is cost-effective for presbyopia correction. Therefore, we took the annual disposable income per capita in China as a reference to set the WTP thresholds. Actually everyone has their own WTP. The cost-effectiveness acceptability curve implies the probabilities that a strategy is cost-effective with different WTP thresholds. Patients, ophthalmologists, and policymakers could set their preferred WTP thresholds according to different requirements and measurement criteria.

In this study, cost of spectacles in the postoperation has not been counted. The primary reason is that the effectiveness refers to the objective spectacle independence rate and the total cost does not include the cost of spectacles in the ACERs and ICERs. Another reason is that the cost of spectacles is dramatically different for different individuals. Thus, the results presented in this study apply to the patients who want to spend less money to get a better chance of spectacle independence.

Limitations of this study should be mentioned. Firstly, the sample size was small, and the follow-up time was too short. Secondly, the nonrandomized trial owing to variation in the cost of IOLs resulted in a risk of selection bias. Thirdly, to achieve model simplification, we applied strict inclusion and exclusion criteria and did not consider some indirect costs, life expectancy, life quality years, or other clinical outcomes, which limits the generalizability of the findings. Large high-quality randomized controlled trials are needed to confirm the aforementioned findings. The findings of this study might only be appropriate for specific patients with cataracts who were candidates and could accept the shortcomings of presbyopia-correcting IOLs.

Conclusions

The objective spectacle independence rate could be used to summarize binocular full-range VA and evaluate the effectiveness of presbyopia correction. In different settings, cataract surgeons and healthcare policymakers could rank the cost-effectiveness of presbyopia correction among multiple strategies using ACERs and ICERs estimates with their diverse costs, objective spectacle independence rate, and WTP. We found that all presbyopia-correcting strategies can provide better effectiveness and higher cost-effectiveness than the monofocal strategy in China. For patients pursuing brilliant effectiveness regardless of the cost, the trifocal strategy may be the best choice. For patients requiring approximate effectiveness of the trifocal strategy with lower cost, more cost-effective strategies, e.g., the refractive bifocal, blended, or EDOF strategies, are reasonable choices, of which the refractive bifocal strategy is the most cost-effective option. For patients preferring the advantage of EDOF IOLs, the design of micro-monovision could avoid the disadvantage of poor near vision. For patients preferring diffractive bifocal IOLs, a blended design could enhance the cost-effectiveness. The monovision strategy is an alternative with the minimum cost for patients who cannot afford or are not eligible for presbyopia-correcting IOLs.