Trifocal versus extended depth of focus (EDOF) intraocular lenses for cataract extraction

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To compare visual outcomes after implantation of trifocal intraocular lenses (IOLs) to those of extended depth of focus (EDOF) IOLs.

To produce a brief economic commentary, summarising the relevant economic evaluations that compare trifocal IOLs to EDOF IOLs.

Background

Description of the condition

Cataract, defined as an opacity of the lens in one or both eyes, is the leading cause of blindness worldwide (Flaxman 2017). Global estimates report 52.6 million cases of moderate to severe visual impairment (visual acuity worse than 6/18 but better than or equal to 3/60 in the better eye), and 12.6 million cases of blindness (visual acuity of less than 3/60 in the better eye), as a result of cataract (Flaxman 2017). In 2010, cataract caused one‐third of blindness worldwide (10.8 million cases) (Khairallah 2015); the World Health Organization (WHO) estimates this number will increase to 40 million cases in 2025 (Pascolini 2012).

Cataract may present as one or more of the following: gradual loss of vision, change in refractive error, glare, and change in colour perception. Referral to an ophthalmic surgeon is often made via the general practitioner or optometrist.

Description of the intervention

In mild cases with minimal symptoms, the change in glasses prescription which occurs as a result of cataract development may be managed initially by conservative measures such as the provision of new glasses. In cases where the patient is symptomatic or where conservative measures are inadequate, the only available treatment option is surgery. Cataract surgery involves the extraction of the cataract and the implantation of an intraocular lens (IOL) to replace the focusing power of the crystalline lens.

With advancements in technology, cataract surgery has evolved over the years, from large‐incision manual extraction (in which a 10 mm incision is made) to small‐incision phacoemulsification (which uses a 2 mm to 4 mm incision). Cochrane Reviews comparing surgical approaches have previously been published (Ang 2012; de Silva 2014; Riaz 2013). Preoperative planning, through the use of specific formulae, allows the accurate prediction of postoperative refraction, with guidance on the IOL refractive power to implant at the time of cataract surgery.

Several IOL designs are currently available commercially. Standard monofocal IOLs are spherical IOLs that produce focus at a singular point, that is, they have a fixed refractive power with a fixed focal length. Both eyes are traditionally set for the same refractive target (typically distance vision), resulting in the need for spectacles for near work. Alternatively, some patients may prefer to be free of spectacles for near tasks and instead rely on corrective lenses for distant tasks. While the majority of people currently undergoing cataract surgery are happy to use reading glasses postoperatively, a sizeable portion prefer to be spectacle‐independent for all distances. One approach to achieving this through the use of monofocal IOLs is monovision, where one eye (typically the dominant eye) is set for distance and the other eye (typically the non‐dominant eye), is set for near vision. Limitations of this approach include reduced stereoacuity, aniseikonia, and subjective intolerance to monovision. More recent progression in IOL technology has led to the emergence of a diverse array of implantable lenses which aim to minimise spectacle dependence for all distances. In low‐income countries, the prevalence of cataract‐related blindness means that spectacle independence is a secondary concern for many patients.

How the intervention might work

One approach to the simultaneous correction of near and distance vision, is through the use of multifocal IOLs, in which both near and distance powers are present within the optical zone. This is achievable by utilising zones of differing refractive power (refractive multifocal IOLs) or through the use of diffractive optics (diffractive multifocal IOLs). Light rays are split to focus at two (bifocal) or more (multifocal) points, allowing simultaneous focusing over a range of distances.

A comparison of the use of multifocal IOLs to standard monofocal IOLs at the time of cataract surgery has been considered in a previous Cochrane Review (de Silva 2016). The salient finding was that those with a multifocal IOL had similar distance vision to those with a standard monofocal IOL. Near vision was better for those with a multifocal IOL and this group was more likely to be spectacle independent than those with a monofocal IOL. Conversely, the use of multifocal IOLs was more commonly associated with glare and haloes. Earlier generation multifocal lenses were bifocal in design, with two main foci corresponding to distance and near vision. However, with such bifocal lens designs, patients often experienced impaired intermediate vision (Alfonso 2010). This has led to the development of trifocal IOLs which, through the addition of a third focal point, allow improved intermediate vision (Carballo‐Alvarez 2015).

Extended depth of focus (EDOF) IOLs utilise a more novel approach to achieve spectacle independence. These IOLs have a longitudinally extended continuous focal point, in contrast to the biphasic or triphasic peaks of best acuity in bifocal or trifocal IOLs. EDOF IOLs achieve this continuum of foci effect through the use of multifocal/pinhole optical designs or through the implementation of spherical aberration and the presence of optically active transitional zones (Akella 2018). The elongated focal point of EDOF IOLs diminishes the overlap of far and near images and is hypothesised to reduce photic phenomena such as glare or haloes and provide better contrast sensitivity.

Several types of EDOF IOL are commercially available. Theoretical studies using interferometry suggest EDOF IOLs provide improved image quality at points between intermediate and near, compared to trifocal IOLs (Domínguez‐Vicent 2016). Results from non‐randomised studies also support this and suggest EDOF IOLs may provide improved vision at intermediate distances over multifocal IOLs (Savini 2018).

Given the plethora of available commercial IOLs with trifocal and EDOF designs, the key question is whether the different optical properties used in these designs lead to different visual acuity and quality at various focal points (near, intermediate and distance). Furthermore, the impact on visual quality, contrast sensitivity and visual aberrations (such as glares and haloes) must be compared.

Why it is important to do this review

There is an extensive body of published data describing largely successful outcomes for monofocal and multifocal IOLs, with more recent studies confirming similar trends for EDOF IOLs. To ascertain the relative merits of the most modern IOL designs, we will undertake a systematic review of the best quality data (from randomised controlled trials (RCTs)) to compare trifocal IOLs with EDOF IOLs.

In addition to understanding which IOL results in the optimum visual outcomes for patients, it is important to understand the resource implications that are associated with postoperative refractive error in cataract patients. Cuq 2008 estimated the per‐patient cost for spectacles post‐cataract surgery in four European countries. The mean costs were EUR 387.6 (standard deviation (SD) 248.5) in Germany; EUR 230.2 (SD 181.4) in Spain; EUR 578.9 (SD 241.1) in France; and EUR 310.5 (SD 190.9) in Italy (2006 values). Depending on the healthcare system or individual patient, this can be a significant cost. As such, understanding which IOL is the most efficient use of resources is very important.

Objectives

To compare visual outcomes after implantation of trifocal intraocular lenses (IOLs) to those of extended depth of focus (EDOF) IOLs.

To produce a brief economic commentary, summarising the relevant economic evaluations that compare trifocal IOLs to EDOF IOLs.

Methods

Criteria for considering studies for this review

Types of studies

We will include parallel‐group randomised controlled trials (RCTs) in this review. We will exclude within‐person studies.

Types of participants

We will include trials in which participants underwent cataract surgery and IOL implantation in one or both eyes. There will be no restrictions on race, gender or ocular comorbidity. We will include trials conducted in adults. Trials with paediatric participants (i.e. those in which cataract onset occurred prior to 16 years of age) will be excluded.

Types of interventions

We will include trials in which participants underwent cataract surgery and IOL implantation in one or both eyes. We will exclude RCTs including participants who underwent refractive lens exchange. If a study included both refractive lens exchange and cataract surgery, we will include the study if the results are reported separately for people undergoing cataract surgery.

Types of outcome measures

We will include studies that have measured one or more of the following outcomes. If, in our judgement, it is clear that a study is likely to have measured one or more of these outcomes, but has not reported any of them, we will include the study.

The primary time point will be 12 months postoperatively, which we will take to be the longest time postoperatively available in each study, after six months and up until 18 months. We will also collect longer follow‐up data if they are available.

Primary outcomes

• Near, intermediate and distance visual acuity (VA) (unaided and corrected). We will consider visual acuity data reported both as proportions and as means.

• • We shall use the cut‐point of worse than 6/6 for distance VA (20/20, logarithm of the Minimum Angle of Resolution (logMAR) score greater than 0.0), as 6/6 vision is usually considered normal VA. We shall use the cut‐point of worse than 0.2 (logMAR) or equivalent for near VA.

  • We will also consider VA as a continuous variable where it is reported in logMAR units.

Secondary outcomes

• Spectacle dependence, as reported by the participant and using any validated questionnaire.

• Mean quality of visual function, as measured by validated instruments (internal and total ocular aberrations)

• Participant‐reported outcomes, including:

• • quality of life or visual function, as measured by validated instruments;

  • informal (non‐validated) subjective assessment of visual function;

  • participant satisfaction;

  • glare (glare occurs when a light source other than the target image illuminates the retina, resulting in reduced contrast. Scatter of light from the glare source by the optics of an IOL may cause unequal glare between participants);

  • other optical aberrations, including haloes.

• Modulation transfer function (contrast sensitivity). (Contrast is the difference between the brightness of an image and its background, divided by the total brightness of the image plus background. Contrast sensitivity is the inverse of the target contrast threshold.)

We also plan to present any evidence regarding relevant economic evaluations, as a brief economic commentary.

Adverse effects

• Any other adverse effects or complications as reported in the trial reports, including:

  • posterior capsular opacification;

  • visual loss.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist will search the following electronic databases for RCTs and controlled clinical trials. There will be no restrictions to language or date of publication. In addition, searches will be carried out on MEDLINE and Embase using economic search filters to specifically identify economic studies, and for adverse effects information relevant to this review.

• Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (Appendix 1)

• MEDLINE Ovid (1946 to present) (Appendix 2)

• MEDLINE Ovid ‐ economic search (1946 to present) (Appendix 3)

• Embase Ovid (1980 to present) (Appendix 4)

• Embase Ovid ‐ economic search (1980 to present) (Appendix 5)

• International Standard Randomised Controlled Trial Number registry (www.isrctn.com/editAdvancedSearch) (Appendix 6)

• US National Institutes of Health Ongoing Trials Register ‐ ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 7)

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 8)

Searching other resources

We will search the reference lists of relevant articles. We will also contact investigators of included studies and the manufacturers of multifocal IOLs (Acute Care, Spectrum Ophthalmics, Storz Ophthalmics, Bausch + Lomb Surgical Limited, Alcon Laboratories Limited, Pharmacia & Upjohn, Rayner Intraocular Lenses Limited, Johnson & Johnson Vision, and PhysIOL) for details of additional published and unpublished trials.

Data collection and analysis

Selection of studies

Two review authors (ST/HZ) will screen independently the titles and abstracts resulting from the searches using internet‐based software (Covidence). We will resolve disagreements by discussion. In general, all citations considered irrelevant at this stage will not be documented in the review, other than to note their number in a flow chart. We will obtain full‐text copies of potentially relevant trials, which two review authors (ST/HZ) will independently assess for inclusion according to the Criteria for considering studies for this review. We will resolve disagreements by discussion. We will correspond with investigators to clarify study eligibility, as appropriate. We will not be masked to the names of the authors, institutions or journal publication when we do this.

We will list all excluded studies and provide a brief justification for their exclusion. In general, we would expect that all studies excluded after examination of the full text will be listed in the 'Characteristics of excluded studies' table.

For potentially eligible studies identified on trials registers, we will do the following.

• If the study has a completion date more than two years previously, we will look for publications of this trial and contact the investigators if necessary to obtain published or unpublished data from the trial. If eligible, the study will be included in the review irrespective of whether we can identify a publication.

• If the study has a completion date within two years, or in the future, we will document the study in the 'Ongoing studies' section.

Data extraction and management

For each included study, we will extract the information listed in Table 1, in order to populate the 'Characteristics of included studies' table. We will extract the data for all trials again using a piloted, customised data extraction template in the internet‐based review management software, Covidence. Two review authors will extract data independently (ST/HZ) and a third review author (AG) will adjudicate discrepancies as needed. We will import data directly from Covidence into Review Manager 5 (Review Manager), which will be checked by one review author (ST).

1. Data on study characteristics.

Mandatory items		Optional items
Methods
Study design	Parallel‐group RCT (i.e. people randomized to treatment)	Exclusions after randomization Losses to follow‐up Number randomized/analysed How were missing data handled (e.g. available case analysis, imputation methods)? Reported power calculation (Y/N) (if yes, sample size and power) Unusual study design/issues
Eyes or Unit of randomisation/ unit of analysis	One eye included in study (specify how eye selected) Two eyes included in study; both eyes received same treatment (briefly specify how analysed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) and specify if mixture one eye and two eye) Two eyes included in study; eyes received different treatments (specify if correct pair‐matched analysis done)
Participants
Country		Setting Ethnic group Equivalence of baseline characteristics (Y/N)
Total number of participants	(This information should be collected for total study population recruited into the study. If these data are only reported for the people who were followed up only, please indicate.)
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions
Intervention (n = ) Comparator (n = )	Number of people randomized to this group Intervention name Dose Frequency Route of administration
Outcomes
Primary and secondary outcomes (as defined in study reports )	List outcomes Adverse events reported (Y/N) Length of follow‐up and intervals at which outcomes assessed	Planned/actual length of follow‐up
Notes
Date conducted	Specify dates of recruitment of participants (month/year to month/year)	Full study name: (if applicable) Reported subgroup analyses (Y/N) Were trial investigators contacted?
Sources of funding
Declaration of interest
Included on trials registry	Y/N; include registration number if available

Data on outcomes

For dichotomous variables, we will collect the number of events and number of people followed up. For continuous variables, we will collect the mean, standard deviation and number of people followed up. If mean and standard deviation are not reported, we will attempt to calculate these from data in the report (for example, the standard error or confidence interval, or by using P values). We will use the Review Manager calculator to do this. We will check continuous data for skew using the methods outlined in Altman 1996.

If there are multiple study arms, we will take care to avoid “arbitrary omission of relevant groups and double‐counting of participants”. We will use guidance from Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions  (Higgins 2020a). We will either select the most relevant intervention, combine relevant intervention groups using the Review Manager calculator, or split the shared comparator group.

Assessment of risk of bias in included studies

Two review authors (ST/HZ) will independently assess risk of bias in Covidence, using the Cochrane 'Risk of bias' 1 (RoB 1) tool for RCTs, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017) and outlined in Table 2.

2. Risk of bias.

Domain	Low risk of bias	Unclear risk of bias	High risk of bias
Sequence generation	Computer‐generated list, random table, other method of generating random list	Not reported how list was generated Trial may be described as "randomized" but with no further details	Alternate allocation, date of birth, records (these RCTs were excluded)
Allocation concealment	Central centre (web/telephone access), sealed opaque envelopes	Not reported how allocation administered. Trial may be described as "randomized" but with no further details	Investigator involved in treatment allocation or treatment allocation clearly not masked
Masking of participants and personnel	Clearly stated that participants and personnel (apart from surgeon) not aware of which lens received	Described as "double blind" with no information on who was masked	No information on masking. As lenses were different, we will assume that in the absence of reporting on this participants and personnel were not masked
Masking of outcome assessment	Clearly stated the outcome assessment was masked	Described as "double blind" with no information on who was masked	No information on masking. As lenses were different, we will assume that in the absence of reporting on this participants and personnel were not masked
Incomplete outcome data	Missing data < 20% (i.e. > 80% follow‐up) and equal follow‐up in both groups and no obvious reason why loss to follow‐up should be related to outcome	Follow‐up not reported or missing data > 20% (i.e. follow‐up < 80%) but follow‐up equal in both groups	Follow‐up different in each group or related to outcome (or both)
Selective outcome reporting	All outcomes in protocol or trials registry entry (or both) are reported	No access to protocol or trials registry entry	Outcomes in protocol or trials registry entry (or both) selectively reported
Other sources of bias	No other source of bias	Trial stopped early due to poor recruitment Baseline imbalance but not clear that it is important	Trial stopped early because of outcome Important baseline imbalance that might have an effect on the results

Measures of treatment effect

Our measure of treatment effect will be the risk ratio (RR) for dichotomous outcomes such as glare/haloes and mean difference (MD) or standardised mean difference (SMD) for continuous outcomes such as distance/near visual acuity, with 95% confidence intervals (CI).

Unit of analysis issues

Trials may randomise one eye or both eyes to the intervention or comparator. If participants are randomly allocated to treatment but only one eye per person is included in the trial then there will not be a unit of analysis issue. In these cases, we will document how the eye was selected. If participants are randomly allocated to treatment but both eyes are included and reported, we will analyse as "clustered data", i.e. we will adjust for within‐person correlation. We may have to contact the trial investigators for further information to do this. We will exclude studies which have allocated different eyes to different treatments, as these studies will not be able to assess spectacle independence and quality of life.

Dealing with missing data

If possible, we will conduct an intention‐to‐treat (ITT) analysis. We will use imputed data if if they were computed by the trial investigators using an appropriate method, but will not impute missing data ourselves.

If ITT data are not available, we will conduct an available case analysis. This assumes that data are missing at random. We will assess whether this assumption is reasonable by collecting data from each included trial on the number of participants excluded or lost to follow‐up, and reasons for loss to follow‐up from the treatment group, if reported.

Assessment of heterogeneity

We will examine the overall characteristics of the studies, in particular the type of participants and types of interventions, to assess the extent to which the studies are similar enough to make pooling study results sensible. We will look at the forest plots of study results to see how consistent the results of the studies are, in particular looking at the size and direction of effects.

We will calculate I², which is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) (Higgins 2002). We will consider I² values over 50% to indicate substantial inconsistency. We will also consider the P value of Chi²; as this may have low power when there is a small number of studies, we will consider a P value of less than 0.1 to indicate statistical significance of the Chi² test.

Assessment of reporting biases

We will use the risk of selective outcome reporting bias assessment tool to look for selective or incomplete reporting (see Assessment of risk of bias in included studies). If there are 10 trials or more included in a meta‐analysis, we will construct funnel plots and consider tests for asymmetry for assessment of publication bias, according to Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Page 2020).

Data synthesis

We will pool data using a random‐effects model in Review Manager 5.4. If there are fewer than three trials in a comparison, or otherwise sparse data, we will use a fixed‐effect model as a random‐effects model may not be robust when data are sparse. If there is inconsistency between individual study results, such that a pooled result may not be a good summary of the individual trial results (for example, the effects are in different directions or the I² value if greater than 50% and the P value less than 0.1), we will not pool the data but will describe the pattern of the individual study results. If there is statistical heterogeneity but all the effect estimates are in the same direction, such that a pooled estimate would seem to provide a good summary of the individual trial results, we may pool the data.

If we are unable to perform a meta‐analysis of effect estimates, we will undertake a narrative synthesis following guidance in the Cochrane Handbook for Systematic Reviews of Interventions (McKenzie 2020). Specifically, we will display the effect estimates in structured tables and provide a descriptive summary of the range and distribution of the observed effects (median, interquartile range). We will note the direction of effect, in particular whether or not it is consistent in the individual studies, and note the results of any statistical tests reported.

Brief economic commentary

Following the search outlined in Search methods for identification of studies, we will develop a brief economic commentary to summarise the availability and principal findings of the full economic evaluations assessing interventions that compare trifocal IOLs with EDOF IOLs in those undergoing cataract surgery (Aluko  2020). This brief economic commentary will encompass full economic evaluations (i.e. cost‐effectiveness analyses, cost‐utility analyses, and cost‐benefit analyses) conducted as part of a single empirical study, such as a RCT, a model based on a single such study, or a model based on several such studies.

Subgroup analysis and investigation of heterogeneity

No subgroup analysis is planned.

Sensitivity analysis

For the primary outcomes, we will perform a sensitivity analysis excluding studies at high risk of bias in one or more domains.

Summary of findings and assessment of the certainty of the evidence

We will prepare a 'Summary of findings' table presenting absolute risks and RRs, with an assessment of the overall certainty of the evidence using the GRADE approach (GRADEpro GDT). Two review authors will make the GRADE assessment independently, with adjudication by a third author if necessary. We will consider study limitations, inconsistency of results, indirectness of evidence, imprecision and reporting bias (Guyatt 2008). We will include the following outcomes in the table, for the primary time point of 12 months postoperatively. 

• Unaided distance VA worse than 6/6

• Corrected distance VA worse than 6/6

• Unaided near VA worse than 0.2 logMAR

• Spectacle dependence

• Participant‐reported outcomes: quality of life or visual function

• Participant‐reported outcomes: optical aberrations (glare, haloes)

• Adverse effects (any time point)

For each outcome, we will assign one of the following GRADE Working Group grades of evidence.

• High quality: further research is very unlikely to change our confidence in the estimate of effect.

• Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

• Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

• Very low quality: we are very uncertain about the estimate.

History

Protocol first published: Issue 3, 2021

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Cataract] explode all trees
#2 MeSH descriptor: [Cataract Extraction] explode all trees
#3 MeSH descriptor: [Lenses, Intraocular] explode all trees
#4 MeSH descriptor: [Lens Implantation, Intraocular] this term only
#5 phacoemulsif* or phakoemulsif*
#6 phaco or phako
#7 capsulorhexis* or capsulotom*
#8 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*) near/3 cataract
#9 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*) near/3 lens
#10 #1 or # 2 or #3 or #4 or #5 or #6 or #7 or #8 or #9
#11 extend* near/2 depth near/3 focus
#12 extend* near/2 depth near/4 field*
#13 extend* near/2 range near/3 focus
#14 extend* near/2 range near/4 field*
#15 extend* near/2 DOF
#16 EDOF
#17 #11 or #12 or #13 or #14 or #15 or #16
#18 #10 and #17

Appendix 2. MEDLINE Ovid search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. (group or groups).ab,ti.
8. or/1‐7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp Cataract/
14. exp Cataract Extraction/
15. exp Lenses, Intraocular/
16. Lens Implantation, Intraocular/
17. pha?oemulsif$.tw.
18. (phaco or phako).tw.
19. (capsulor?hexis$ or capsulotom$).tw.
20. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
21. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
22. or/13‐21
23. (extend$ adj2 depth adj3 focus).tw.
24. (extend$ adj2 depth adj4 field$).tw.
25. (extend$ adj2 range adj3 focus).tw.
26. (extend$ adj2 range adj4 field$).tw.
27. (extend$ adj2 DOF).tw.
28. EDOF.tw.
29. or/23‐28
30. 22 and 29
31. 12 and 30

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.

Appendix 3. MEDLINE Ovid economics search strategy

1. Economics/
2. exp "costs and cost analysis"/
3. Economics, Dental/
4. exp economics, hospital/
5. Economics, Medical/
6. Economics, Nursing/
7. Economics, Pharmaceutical/
8. (economic$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab.
9. (expenditure$ not energy).ti,ab.
10. value for money.ti,ab.
11. budget$.ti,ab.
12. or/1‐11
13. ((energy or oxygen) adj cost).ti,ab.
14. (metabolic adj cost).ti,ab.
15. ((energy or oxygen) adj expenditure).ti,ab.
16. or/13‐15
17. 12 not 16
18. letter.pt.
19. editorial.pt.
20. historical article.pt.
21. or/18‐20
22. 17 not 21
23. exp animals/ not humans/
24. 22 not 23
25. bmj.jn.
26. "cochrane database of systematic reviews".jn.
27. health technology assessment winchester england.jn.
28. or/25‐27
29. 24 not 28
30. exp Cataract/
31. exp Cataract Extraction/
32. exp Lenses, Intraocular/
33. Lens Implantation, Intraocular/
34. pha?oemulsif$.tw.
35. (phaco or phako).tw.
36. (capsulor?hexis$ or capsulotom$).tw.
37. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
38. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
39. or/30‐38
40. (extend$ adj2 depth adj3 focus).tw.
41. (extend$ adj2 depth adj4 field$).tw.
42. (extend$ adj2 range adj3 focus).tw.
43. (extend$ adj2 range adj4 field$).tw.
44. (extend$ adj2 DOF).tw.
45. EDOF.tw.
46. or/40‐45
47. 39 and 46
48. 29 and 47

Appendix 4. Embase Ovid search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1‐5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12‐21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25‐28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp cataract/
34. exp cataract extraction/
35. lens implantation/
36. lens implant/
37. pseudophakia/
38. pha?oemulsif$.tw.
39. (phaco or phako).tw.
40. (capsulor?hexis$ or capsulotom$).tw.
41. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
42. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
43. or/33‐42
44. (extend$ adj2 depth adj3 focus).tw.
45. (extend$ adj2 depth adj4 field$).tw.
46. (extend$ adj2 range adj3 focus).tw.
47. (extend$ adj2 range adj4 field$).tw.
48. (extend$ adj2 DOF).tw.
49. EDOF.tw.
50. or/44‐49
51. 43 and 50
52. 32 and 51

Appendix 5. Embase Ovid economics search strategy

1. Health Economics/
2. exp Economic Evaluation/
3. exp Health Care Cost/
4. pharmacoeconomics/
5. or/1‐4
6. (econom$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab.
7. (expenditure$ not energy).ti,ab.
8. (value adj2 money).ti,ab.
9. budget$.ti,ab.
10. or/6‐9
11. 5 or 10
12. letter.pt.
13. editorial.pt.
14. note.pt.
15. or/12‐14
16. 11 not 15
17. (metabolic adj cost).ti,ab.
18. ((energy or oxygen) adj cost).ti,ab.
19. ((energy or oxygen) adj expenditure).ti,ab.
20. or/17‐19
21. 16 not 20
22. animal/
23. exp animal experiment/
24. nonhuman/
25. (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dog or dogs or cat or cats or bovine or sheep).ti,ab,sh.
26. or/22‐25
27. exp human/
28. human experiment/
29. or/27‐28
30. 26 not (26 and 29)
31. 21 not 30
32. 0959‐8146.is.
33. (1469‐493X or 1366‐5278).is.
34. 1756‐1833.en.
35. or/32‐34
36. 31 not 35
37. Conference abstract.pt.
38. 36 not 37
39. exp cataract/
40. exp cataract extraction/
41. lens implantation/
42. lens implant/
43. pseudophakia/
44. pha?oemulsif$.tw.
45. (phaco or phako).tw.
46. (capsulor?hexis$ or capsulotom$).tw.
47. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
48. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
49. or/39‐48
50. (extend$ adj2 depth adj3 focus).tw.
51. (extend$ adj2 depth adj4 field$).tw.
52. (extend$ adj2 range adj3 focus).tw.
53. (extend$ adj2 range adj4 field$).tw.
54. (extend$ adj2 DOF).tw.
55. EDOF.tw.
56. or/50‐55
57. 49 and 56
58. 38 and 57

Appendix 6. ISRCTN search strategy

EDOF OR "extended depth"

Appendix 7. ClinicalTrials.gov search strategy

(cataract OR lens OR IOL) AND ("extended depth of focus" OR EDOF)

Appendix 8. WHO ICTRP search strategy

extended depth of focus OR EDOF

Contributions of authors

JE, ST, HZ, MZ: developed the protocol, final approval of manuscript.
AG,  AK, MY: critical review of the clinical sections, final approval of manuscript.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research (NIHR), UK

  This protocol was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the CEV UK editorial base.

  The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Declarations of interest

ST: none known
HZ: none known
MY: none known
AG: none known
AK: none known
JE: none known
MZ: none known

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